Pain

Tender erythematous nodules or plaques on the extensor surfaces—usually on the legs and occasionally on the arms—are the hallmarks for erythema nodosum, which was diagnosed in this case. It typically occurs in young women, ages 15 to 30, and the nodules or plaques are often accompanied by prodromal fever and malaise. The lesions often are painful and tender to pressure or palpation; they are thought to be caused by a reaction to a stimulus, leading to inflammation of the septa in the subcutaneous fat. While the trigger is often unknown, in some cases, an underlying infection, particularly Streptococcus or tuberculosis (TB), is identified. Sarcoidosis, malignancy, or an increase in estrogen (exogenous or endogenous) also can provoke the disorder.

Due to the risk of underlying disease or triggers, it is prudent to perform radiography of the chest, as well as obtain a complete blood count, sedimentation rate or C reactive protein, and an antistreptolysin O titer when you suspect erythema nodosum. TB testing is also advised. Biopsy typically is not performed because the diagnosis usually is made clinically. If the diagnosis is in doubt, a biopsy can offer confirmation or lead to a different diagnosis such as vasculitis—especially if the lesions are eroded. Since erythema nodosum is an inflammation of the subcutaneous fat, it is important to sample skin lesions deeper than the usual punch biopsy; an incisional biopsy may be required to get an adequate sample.

Erythema nodosum typically resolves spontaneously over a period of weeks, even if there is underlying disease. Therefore, it may be possible to defer treatment if minimal symptoms are present. Otherwise, first-line treatment for the pain and malaise is a nonsteroidal anti-inflammatory drug (NSAID). Oral potassium iodide (360-900 mg/d) is considered second-line treatment and systemic corticosteroids are a third-line option.

For this patient, biopsy was deferred and diagnostic tests were all negative. She had notable pain and a history of good resolution of symptoms with prednisone (5 mg/d), so this drug was prescribed for a 7-day course. She was counseled to avoid taking the NSAIDs and prednisone together due to increased risk of gastritis and ulceration. Recurrent disease can be treated with dapsone (100 mg/d) or hydroxychloroquine (200 mg bid).

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

Tender erythematous nodules or plaques on the extensor surfaces—usually on the legs and occasionally on the arms—are the hallmarks for erythema nodosum, which was diagnosed in this case. It typically occurs in young women, ages 15 to 30, and the nodules or plaques are often accompanied by prodromal fever and malaise. The lesions often are painful and tender to pressure or palpation; they are thought to be caused by a reaction to a stimulus, leading to inflammation of the septa in the subcutaneous fat. While the trigger is often unknown, in some cases, an underlying infection, particularly Streptococcus or tuberculosis (TB), is identified. Sarcoidosis, malignancy, or an increase in estrogen (exogenous or endogenous) also can provoke the disorder.

Due to the risk of underlying disease or triggers, it is prudent to perform radiography of the chest, as well as obtain a complete blood count, sedimentation rate or C reactive protein, and an antistreptolysin O titer when you suspect erythema nodosum. TB testing is also advised. Biopsy typically is not performed because the diagnosis usually is made clinically. If the diagnosis is in doubt, a biopsy can offer confirmation or lead to a different diagnosis such as vasculitis—especially if the lesions are eroded. Since erythema nodosum is an inflammation of the subcutaneous fat, it is important to sample skin lesions deeper than the usual punch biopsy; an incisional biopsy may be required to get an adequate sample.

Erythema nodosum typically resolves spontaneously over a period of weeks, even if there is underlying disease. Therefore, it may be possible to defer treatment if minimal symptoms are present. Otherwise, first-line treatment for the pain and malaise is a nonsteroidal anti-inflammatory drug (NSAID). Oral potassium iodide (360-900 mg/d) is considered second-line treatment and systemic corticosteroids are a third-line option.

For this patient, biopsy was deferred and diagnostic tests were all negative. She had notable pain and a history of good resolution of symptoms with prednisone (5 mg/d), so this drug was prescribed for a 7-day course. She was counseled to avoid taking the NSAIDs and prednisone together due to increased risk of gastritis and ulceration. Recurrent disease can be treated with dapsone (100 mg/d) or hydroxychloroquine (200 mg bid).

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

Tender erythematous nodules or plaques on the extensor surfaces—usually on the legs and occasionally on the arms—are the hallmarks for erythema nodosum, which was diagnosed in this case. It typically occurs in young women, ages 15 to 30, and the nodules or plaques are often accompanied by prodromal fever and malaise. The lesions often are painful and tender to pressure or palpation; they are thought to be caused by a reaction to a stimulus, leading to inflammation of the septa in the subcutaneous fat. While the trigger is often unknown, in some cases, an underlying infection, particularly Streptococcus or tuberculosis (TB), is identified. Sarcoidosis, malignancy, or an increase in estrogen (exogenous or endogenous) also can provoke the disorder.

Due to the risk of underlying disease or triggers, it is prudent to perform radiography of the chest, as well as obtain a complete blood count, sedimentation rate or C reactive protein, and an antistreptolysin O titer when you suspect erythema nodosum. TB testing is also advised. Biopsy typically is not performed because the diagnosis usually is made clinically. If the diagnosis is in doubt, a biopsy can offer confirmation or lead to a different diagnosis such as vasculitis—especially if the lesions are eroded. Since erythema nodosum is an inflammation of the subcutaneous fat, it is important to sample skin lesions deeper than the usual punch biopsy; an incisional biopsy may be required to get an adequate sample.

Erythema nodosum typically resolves spontaneously over a period of weeks, even if there is underlying disease. Therefore, it may be possible to defer treatment if minimal symptoms are present. Otherwise, first-line treatment for the pain and malaise is a nonsteroidal anti-inflammatory drug (NSAID). Oral potassium iodide (360-900 mg/d) is considered second-line treatment and systemic corticosteroids are a third-line option.

For this patient, biopsy was deferred and diagnostic tests were all negative. She had notable pain and a history of good resolution of symptoms with prednisone (5 mg/d), so this drug was prescribed for a 7-day course. She was counseled to avoid taking the NSAIDs and prednisone together due to increased risk of gastritis and ulceration. Recurrent disease can be treated with dapsone (100 mg/d) or hydroxychloroquine (200 mg bid).

‌

Photo and text courtesy of Daniel Stulberg, MD, FAAFP, Department of Family and Community Medicine, University of New Mexico School of Medicine, Albuquerque.

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

A version of this article originally appeared on Medscape.com.

The Food and Drug Administration wants updated boxed warnings on benzodiazepines to reflect the “serious” risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions associated with these medications.

“The current prescribing information for benzodiazepines does not provide adequate warnings about these serious risks and harms associated with these medicines so they may be prescribed and used inappropriately,” the FDA said in a safety communication.

The FDA also wants revisions to the patient medication guides for benzodiazepines to help educate patients and caregivers about these risks.

“While benzodiazepines are important therapies for many Americans, they are also commonly abused and misused, often together with opioid pain relievers and other medicines, alcohol, and illicit drugs,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.

“We are taking measures and requiring new labeling information to help health care professionals and patients better understand that, while benzodiazepines have many treatment benefits, they also carry with them an increased risk of abuse, misuse, addiction, and dependence,” said Dr. Hahn.
 

Ninety-two million prescriptions in 2019

Benzodiazepines are widely used to treat anxiety, insomnia, seizures, and other conditions, often for extended periods of time.

According to the FDA, in 2019, an estimated 92 million benzodiazepine prescriptions were dispensed from U.S. outpatient pharmacies, most commonly alprazolam, clonazepam, and lorazepam.

Data from 2018 show that roughly 5.4 million people in the United States 12 years and older abused or misused benzodiazepines in the previous year.

Although the precise risk of benzodiazepine addiction remains unclear, population data “clearly indicate that both primary benzodiazepine use disorders and polysubstance addiction involving benzodiazepines do occur,” the FDA said.

Data from the National Survey on Drug Use and Health from 2015-2016 suggest that half million community-dwelling U.S. adults were estimated to have a benzodiazepine use disorder.
 

Jump in overdose deaths

Overdose deaths involving benzodiazepines jumped from 1,298 in 2010 to 11,537 in 2017 – an increase of more 780%. Most of these deaths involved benzodiazepines taken with prescription opioids.

Before prescribing a benzodiazepine and during treatment, a patient’s risk for abuse, misuse, and addiction should be assessed, the FDA said.

The agency urged particular caution when prescribing benzodiazepines with opioids and other central nervous system depressants, which has resulted in serious adverse events including severe respiratory depression and death.

The FDA also says patients and caregivers should be warned about the risks of abuse, misuse, addiction, dependence, and withdrawal with benzodiazepines and the associated signs and symptoms.

Physicians are encouraged to report adverse events involving benzodiazepines or other medicines to the FDA’s MedWatch program.
 

A version of this article originally appeared on Medscape.com.

From the University of California San Francisco (Dr. Treadwell, Dr. Hessler, Yumei Chen, Swapandeep Mushiana, Dr. Potter, and Dr. Vichinsky), the University of California Los Angeles (Dr. Jacob), and the University of California Berkeley (Alex Chen).

Abstract

• Objective: Adolescents and adults with sickle cell disease (SCD) face pervasive disparities in health resources and outcomes. We explored barriers to and facilitators of care to identify opportunities to support implementation of evidence-based interventions aimed at improving care quality for patients with SCD.
• Methods: We engaged a representative sample of adolescents and adults with SCD (n = 58), health care providers (n = 51), and community stakeholders (health care administrators and community-based organization leads (n = 5) in Northern California in a community-based needs assessment. We conducted group interviews separately with participant groups to obtain in-depth perspectives. Adolescents and adults with SCD completed validated measures of pain interference, quality of care, self-efficacy, and barriers to care. Providers and community stakeholders completed surveys about barriers to SCD care.
• Results: We triangulated qualitative and quantitative data and found that participants with SCD (mean age, 31 ± 8.6 years), providers, and community stakeholders emphasized the social and emotional burden of SCD as barriers. Concrete barriers agreed upon included insurance and lack of resources for addressing pain impact. Adolescents and adults with SCD identified provider issues (lack of knowledge, implicit bias), transportation, and limited social support as barriers. Negative encounters with the health care system contributed to 84% of adolescents and adults with SCD reporting they chose to manage severe pain at home. Providers focused on structural barriers: lack of access to care guidelines, comfort level with and knowledge of SCD management, and poor care coordination.
• Conclusion: Strategies for improving access to compassionate, evidence-based quality care, as well as strategies for minimizing the burden of having SCD, are warranted for this medically complex population.

Keywords: barriers to care; quality of care; care access; care coordination.

Sickle cell disease (SCD), an inherited chronic medical condition, affects about 100,000 individuals in the United States, a population that is predominantly African American.¹ These individuals experience multiple serious and life-threatening complications, most frequently recurrent vaso-occlusive pain episodes,² and they require interactions with multidisciplinary specialists from childhood. Because of advances in treatments, the majority are reaching adulthood; however, there is a dearth of adult health care providers with the training and expertise to manage their complex medical needs.³ Other concrete barriers to adequate SCD care include insurance and distance to comprehensive SCD centers.^4,5

Social, behavioral, and emotional factors may also contribute to challenges with SCD management. SCD may limit daily functional abilities and lead to diminished overall quality of life.^6,7 Some adolescents and adults may require high doses of opioids, which contributes to health care providers’ perceptions that there is a high prevalence of drug addiction in the population.^8,9 These providers express negative attitudes towards adults with SCD, and, consequently, delay medication administration when it is acutely needed and provide otherwise suboptimal treatment.^8,10,11 Adult care providers may also be uncomfortable with prescribing and managing disease-modifying therapies (blood transfusion, hydroxyurea) that have established efficacy.^12-17

As 1 of 8 programs funded by the National Heart, Lung, and Blood Institute’s (NHLBI) Sickle Cell Disease Implementation Consortium (SCDIC), we are using implementation science to reduce barriers to care and improve quality of care and health care outcomes in SCD.^18,19 Given that adolescents and adults with SCD experience high mortality, severe pain, and progressive decline in their ability to function day to day, and also face lack of access to knowledgeable, compassionate providers in primary and emergency settings, the SCDIC focuses on individuals aged 15 to 45 years.^6,8,9,11,12

Our regional SCDIC program, the Sickle Cell Care Coordination Initiative (SCCCI), brings together researchers, clinicians, adolescents, and adults with SCD and their families, dedicated community members, policy makers, and administrators to identify and address barriers to health care within 5 counties in Northern California. One of our first steps was to conduct a community-based needs assessment, designed to inform implementation of evidence-based interventions, accounting for unique contextual factors in our region.

Conceptual Framework for Improving Medical Practice

Our needs assessment is guided by Solberg’s Conceptual Framework for Improving Medical Practice (Figure 1).²⁰ Consistent with the overarching principles of the SCDIC, this conceptual framework focuses on the inadequate implementation of evidence-based guidelines, and on the need to first understand multifactorial facilitators and barriers to guideline implementation in order to effect change. The framework identifies 3 main elements that must be present to ensure improvements in quality-of-care processes and patient outcomes: priority, change process capability, and care process content. Priority refers to ample resource allocation for the specific change, as well as freedom from competing priorities for those implementing the change. Change process capability includes strong, effective leadership, adequate infrastructure for managing change (including resources and time), change management skills at all levels, and an established clinical information system. Care process content refers to context and systems-level changes, such as delivery system redesign as needed, support for self-management to lessen the impact of the disease, and decision support.^21-23

The purpose of our community-based needs assessment was to evaluate barriers to care and quality of care in SCD, within Solberg’s conceptual model for improving medical practice. The specific aims were to evaluate access and barriers to care (eg, lack of provider expertise and training, health care system barriers such as poor care coordination and provider communication); evaluate quality of care; and assess patient needs related to pain, pain interference, self-efficacy, and self-management for adolescents and adults with SCD. We gathered the perspectives of a representative community of adolescents and adults with SCD, their providers, and community stakeholders in order to examine barriers, quality of life and care, and patient experiences in our region.

Methods

Design

In this cross-sectional study, adolescents and adults with SCD, their providers, and community stakeholders participated in group or individual qualitative interviews and completed surveys between October 2017 and March 2018.

Setting and Sample

Recruitment flyers were posted on a regional SCD-focused website, and clinical providers or a study coordinator introduced information about the needs assessment to potential participants with SCD during clinic visits at the participating centers. Participants with SCD were eligible if they had any diagnosis of SCD, were aged 15 to 48 years, and received health services within 5 Northern California counties (Alameda, Contra Costa, Sacramento, San Francisco, and Solano). They were excluded if they did not have a SCD diagnosis or had not received health services within the catchment area. As the project proceeded, participants were asked to refer other adolescents and adults with SCD for the interviews and surveys (snowball sampling). Our goal was to recruit 50 adolescents and adults with SCD into the study, aiming for 10 representatives from each county.

Providers and community stakeholders were recruited via emails, letters and informational flyers. We engaged our partner, the Sickle Cell Data Collection Program,² to generate a list of providers and institutions that had seen patients with SCD in primary, emergency, or inpatient settings in the region. We contacted these institutions to describe the SCCCI and invite participation in the needs assessment. We also invited community-based organization leads and health care administrators who worked with SCD to participate. Providers accessed confidential surveys via a secure link on the study website or completed paper versions. Common data collected across providers included demographics and descriptions of practice settings.

Participants were eligible to be part of the study if they were health care providers (physicians and nurses) representing hematology, primary care, family medicine, internal medicine, or emergency medicine; ancillary staff (social work, psychology, child life); or leaders or administrators of clinical or sickle cell community-based organizations in Northern California (recruitment goal of n = 50). Providers were excluded if they practiced in specialties other than those noted or did not practice within the region.

Data Collection Procedures

After providing assent/consent, participating adolescents and adults with SCD took part in individual and group interviews and completed survey questionnaires. All procedures were conducted in a private space in the sickle cell center or community. Adolescents and adults with SCD completed the survey questionnaire on a tablet, with responses recorded directly in a REDCap (Research Electronic Data Capture) database,²⁴ or on a paper version. Interviews lasted 60 (individual) to 90 (group) minutes, while survey completion time was 20 to 25 minutes. Each participant received a gift card upon completion as an expression of appreciation. All procedures were approved by the institutional review boards of the participating health care facilities.

Group and Individual Interviews

Participants with SCD and providers were invited to participate in a semi-structured qualitative interview prior to being presented with the surveys. Adolescents and adults with SCD were interviewed about barriers to care, quality of care, and pain-related experiences. Providers were asked about barriers to care and treatments. Interview guides were modified for community-based organization leaders and health care administrators who did not provide clinical services. Interview guides can be found in the Appendix. Interviews were conducted by research coordinators trained in qualitative research methods by the first author (MT). As appropriate with semi-structured interviews, the interviewers could word questions spontaneously, change the order of questions for ease of flow of conversation, and inform simultaneous coding of interviews with new themes as those might arise, as long as they touched on all topics within the interview guide.²⁵ The interview guides were written, per qualitative research standards, based on the aims and purpose of the research,²⁶ and were informed by existing literature on access and barriers to care in SCD, quality of care, and the needs of individuals with SCD, including in relation to impact of the disease, self-efficacy, and self-management.

Interviewees participated in either individual or group interviews, but not both. The decision for which type of interview an individual participated in was based on 2 factors: if there were not comparable participants for group interviews (eg, health care administrator and community-based organization lead), these interviews were done individually; and given that we were drawing participants from a 5-county area in Northern California, scheduling was challenging for individuals with SCD with regard to aligning schedules and traveling to a central location where the group interviews were conducted. Provider group interviews were easier to arrange because we could schedule them at the same time as regularly scheduled meetings at the participants’ health care institutions.

Interview Data Gathering and Analysis

Digital recordings of the interviews were cleaned of any participant identifying data and sent for transcription to an outside service. Transcripts were reviewed for completeness and imported into NVivo (www.qsrinternational.com), a qualitative data management program.

A thematic content analysis and deductive and inductive approaches were used to analyze the verbatim transcripts generated from the interviews. The research team was trained in the use of NVivo software to facilitate the coding process. A deductive coding scheme was initially used based on existing concepts in the literature regarding challenges to optimal SCD care, with new codes added as the thematic content analyses progressed. The initial coding, pattern coding, and use of displays to examine the relationships between different categories were conducted simultaneously.^27,28 Using the constant comparative method, new concepts from participants with SCD and providers could be incorporated into subsequent interviews with other participants. For this study, the only additional concepts added were in relation to participant recruitment and retention in the SCDIC Registry. Research team members coded transcripts separately and came together weekly, constantly comparing codes and developing the consensus coding scheme. Where differences between coders existed, code meanings were discussed and clarified until consensus was reached.²⁹

Quantitative data were analyzed using SPSS (v. 25, Chicago, IL). Descriptive statistics (means, standard deviations, frequencies, percentages) were used to summarize demographics (eg, age, gender, and race), economic status, and type of SCD. No systematic differences were detected from cases with missing values. Scale reliabilities (ie, Cronbach α) were evaluated for self-report measures.

Measurement

Adolescents and adults with SCD completed items from the PhenX Toolkit (consensus measures for Phenotypes and eXposures), assessing sociodemographics (age, sex, race, ethnicity, educational attainment, occupation, marital status, annual income, insurance), and clinical characteristics (sickle cell diagnosis and emergency department [ED] and hospital utilization for pain).³⁰

Pain Interference Short Form (Patient-Reported Outcomes Measurement Information System [PROMIS]). The Pain Interference Form consists of 8 items that assess the degree to which pain interfered with day-to-day activities in the previous 7 days at home, including impacts on social, cognitive, emotional, and physical functioning; household chores and recreational activities; sleep; and enjoyment in life. Reliability and validity of the PROMIS Pain Interference Scale has been demonstrated, with strong negative correlations with Physical Function Scales (r = 0.717, P < 0.01), indicating that higher scores are associated with lower function (β = 0.707, P < 0.001).³¹ The Cronbach α estimate for the other items on the pain interference scale was 0.99. Validity analysis indicated strong correlations with pain-related domains: BPI Interference Subscale (rho = 0.90), SF-36 Bodily Pain Subscale (rho = –0.84), and 0–10 Numerical Rating of Pain Intensity (rho = 0.48).³²

Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Quality of Care (QOC). ASCQ-Me QOC consists of 27 items that measure the quality of care that adults with SCD have received from health care providers.³³ There are 3 composites: provider communication (quality of patient and provider communication), ED care (quality of care in the ED), and access (to routine and emergency care). Internal consistency reliability for all 3 composites is greater than 0.70. Strong correlations of the provider communication composite with overall ratings of routine care (r = 0.65) and overall provider ratings (r = 0.83) provided evidence of construct validity. Similarly, the ED care composite was strongly correlated with overall ratings of QOC in the ED, and the access composite was highly correlated with overall evaluations of ED care (r = 0.70). Access, provider interaction, and ED care composites were reliable (Cronbach α, 0.70–0.83) and correlated with ratings of global care (r = 0.32–0.83), further indicating construct validity.³³

Sickle Cell Self-Efficacy Scale (SCSES). The SCSES is a 9-item, self-administered questionnaire measuring perceptions of the ability to manage day-to-day issues resulting from SCD. SCSES items are scored on a 5-point scale ranging from Not sure at all (1) to Very sure (5). Individual item responses are summed to give an overall score, with higher scores indicating greater self-efficacy. The SCSES has acceptable reliability (r = 0.45, P < 0.001) and validity (α = 0.89).^34,35

Sickle Cell Disease Barriers Checklist. This checklist consists of 53 items organized into 8 categories: insurance, transportation, accommodations and accessibility, provider knowledge and attitudes, social support, individual barriers such as forgetting or difficulties understanding instructions, emotional barriers (fear, anger), and disease-related barriers. Participants check applicable barriers, with a total score range of 0 to 53 and higher scores indicating more barriers to care. The SCD Barriers Checklist has demonstrated face validity and test-retest reliability (Pearson r = 0.74, P < 0.05).⁵

ED Provider Checklist. The ED provider survey is a checklist of 14 statements pertaining to issues regarding patient care, with which the provider rates level of agreement. Items representing the attitudes and beliefs of providers towards patients with SCD are rated on a Likert-type scale, with level of agreement indicated as 1 (strongly disagree) to 6 (strongly agree). The positive attitudes subscale consists of 4 items (Cronbach α= 0.85), and the negative attitudes subscale consists of 6 items (Cronbach α = 0.89). The Red-Flag Behaviors subscale includes 4 items that indicate behavior concerns about drug-seeking, such as requesting specific narcotics and changing behavior when the provider walks in.^8,36,37

Sickle cell and primary care providers also completed a survey consisting of sets of items compiled from existing provider surveys; this survey consisted of a list of 16 barriers to using opioids, which the providers rated on a 5-point Likert-type scale (1, not a barrier; 5, complete barrier).^13,16,38 Providers indicated their level of experience with caring for patients with SCD; care provided, such as routine health screenings; and comfort level with providing preventive care, managing comorbidities, and managing acute and chronic pain. Providers were asked what potential facilitators might improve care for patients with SCD, including higher reimbursement, case management services, access to pain management specialists, and access to clinical decision-support tools. Providers responded to specific questions about management with hydroxyurea (eg, criteria for, barriers to, and comfort level with prescribing).³⁹ The surveys are included in the Appendix.

Triangulation

Data from the interviews and surveys were triangulated to enhance understanding of results generated from the different data sources.⁴⁰ Convergence of findings, different facets of the same phenomenon, or new perspectives were examined.

Qualitative Data

Adolescents and adults with SCD (n = 55) and health care providers and community stakeholders (n = 56) participated in group or individual interviews to help us gain an in-depth understanding of the needs and barriers related to SCD care in our 5-county region. Participants with SCD described their experiences, which included stigma, racism, labeling, and, consequently, stress. They also identified barriers such as lack of transportation, challenges with insurance, and lack of access to providers who were competent with pain management. They reported that having SCD in a health care system that was unable to meet their needs was burdensome.

Barriers to Care and Treatments. Adolescents and adults indicated that SCD and its sequelae posed significant barriers to health care. Feelings of tiredness and pain make it more difficult for them to seek care. The emotional burden of SCD (fear and anger) was a frequently cited barrier, which was fueled by previous negative encounters with the health care system. All adolescents and adults with SCD reported that they knew of stigma in relation to seeking pain management that was pervasive and long-standing, and the majority reported they had directly experienced stigma. They reported that being labeled as “drug-seekers” was typical when in the ED for pain management. Participants articulated unconscious bias or overt racism among providers: “people with sickle cell are Black ... and Black pain is never as valuable as White pain” (25-year-old male). Respondents with SCD described challenges to the credibility of their pain reports in the ED. They reported that ED providers expressed doubts regarding the existence and/or severity of their pain, consequently creating a feeling of disrespect for patients seeking pain relief. The issue of stigma was mentioned by only 2 of 56 providers during their interviews.

Lack of Access to Knowledgeable, Compassionate Providers. Lack of access to knowledgeable care providers was another prevalent theme expressed by adolescents and adults with SCD. Frustration occurred when providers did not have knowledge of SCD and its management, particularly pain assessment. Adolescents and adults with SCD noted the lack of compassion among providers: “I’ve been kicked out of the hospital because they felt like okay, well we gave you enough medication, you should be all right” (29-year-old female). Providers specifically mentioned lack of compassion and knowledge as barriers to SCD care much less often during their interviews compared with the adolescents and adults with SCD.

Health Care System Barriers. Patient participants often expressed concerns about concrete and structural aspects of care. Getting to their appointments was a challenge for half of the interviewees, as they either did not have access to a vehicle or could not afford to travel the needed distance to obtain quality care. Even when hospitals were accessible by public transportation, those with excruciating pain understandably preferred a more comfortable and private way to travel: “I would like to change that, something that will be much easier, convenient for sickle cell patients that do suffer with pain, that they don’t have to travel always to see the doctor” (30-year-old male).

Insurance and other financial barriers also played an important role in influencing decisions to seek health care services. Medical expenses were not covered, or co-pays were too high. The Medicaid managed care system could prevent access to knowledgeable providers who were not within network. Such a lack of access discouraged some adolescents and adults with SCD from seeking acute and preventive care.

Transition From Pediatric to Adult Care. Interviewees with SCD expressed distress about the gap between pediatric and adult care. They described how they had a long-standing relationship with their medical providers, who were familiar with their medical background and history from childhood. Adolescent interviewees reported an understanding of their own pain management as well as adherence to and satisfaction with their individualized pain plans. However, adults noted that satisfaction plummeted with increasing age due to the limited number of experienced adult SCD providers, which was compounded by negative experiences (stigma, racism, drug-seeking label).

One interviewee emphasized the difficulty of finding knowledgeable providers after transition: “When you’re a pediatric sickle cell [patient], you have the doctors there every step of the way, but not with adult sickle cell… I know when I first transitioned I never felt more alone in my life… you look at that ER doctor kind of with the same mindset as you would your hematologist who just hand walked you through everything. And adult care providers were a lot more blunt and cold and they’re like… ‘I don’t know; I’m not really educated in sickle cell.’” A sickle cell provider shared his insight about the problem of transitioning: “I think it’s particularly challenging because we, as a community, don’t really set them up for success. It’s different from other chronic conditions [in that] it’s much harder to find an adult sickle cell provider. There’s not a lot of adult hematologists that will take care of our adult patients, and so I know statistically, there’s like a drop-down in the overall outcomes of our kids after they age out of our pediatric program.”

Self-Management, Supporting Hydroxyurea Use. Interview participants with SCD reported using a variety of methods to manage pain at home and chose to go to the ED only when the pain became intolerable. Patients and providers expressed awareness of different resources for managing pain at home, yet they also indicated that these resources have not been consolidated in an accessible way for patients and families. Some resources cited included heat therapy, acupuncture, meditation, medical marijuana, virtual reality devices, and pain medications other than opioids.

Patients and providers expressed the need for increasing awareness and education about hydroxyurea. Many interview participants with SCD were concerned about side effects, multiple visits with a provider during dose titration, and ongoing laboratory monitoring. They also expressed difficulties with scheduling multiple appointments, depending on access to transportation and limited provider clinic hours. They were aware of strategies for improving adherence with hydroxyurea, including setting phone alarms, educating family members about hydroxyurea, and eliciting family support, but expressed needing help to consistently implement these strategies.

Safe Opioid Prescribing. Adult care providers expressed concerns about safe opioid prescribing for patients with SCD. They were reluctant to prescribe opioid doses needed to adequately control SCD pain. Providers expressed uncertainty and fear or concern about medical/legal liability or about their judgment about what’s safe and not safe for patients with chronic use/very high doses of opioids. “I know we’re in like this opiate epidemic here in this country but I feel like these patients don’t really fit under that umbrella that the problem is coming from so [I am] just trying to learn more about how to take care of them.”

Care Coordination and Provider Communication. Adolescents and adults with SCD reported having positive experiences—good communication, established trust, and compassionate care—with their usual providers. However, they perceived that ED physicians and nurses did not really care about them. Both interviewees with SCD and providers recognized the importance of good communication in all settings as the key to overcoming barriers to receiving quality care. All agreed on the importance of using individual pain plans so that all providers, especially ED providers, can be more at ease with treating adolescents and adults with SCD.

Quantitative Data: Adolescents and Adults With SCD

Fifty-eight adolescents and adults with SCD (aged 15 to 48 years) completed the survey. Three additional individuals who did not complete the interview completed the survey. Reasons for not completing the interview included scheduling challenges (n = 2) or a sickle cell pain episode (n = 1). The average age of participants was 31 years ± 8.6, more than half (57%) were female, and the majority (93%) were African American (Table 1). Most (71%) had never been married. Half (50%) had some college or an associate degree, and 40% were employed and reported an annual household income of less than $30,000. Insurance coverage was predominantly Medi-Cal (Medicaid, 69%). The majority of participants resided in Alameda (34.5%) or Contra Costa (21%) counties. The majority of sickle cell care was received in Alameda County, whether outpatient (52%), inpatient (40%), or ED care (41%). The majority (71%) had a diagnosis of SCD hemoglobin SS.

Pain. More than one-third of individuals with SCD reported 1 or 2 ED visits for pain in the previous 6 months (34%), and more than 3 hospitalizations (36%) related to pain in the previous year (Table 2). The majority (85%) reported having severe pain at home in the previous 6 months that they did not seek health care for, consistent with their reports in the qualitative interviews. More than half (59%) reported 4 or more of these severe pain episodes that led to inability to perform daily activities for 1 week or more. While pain interference on the PROMIS Pain Interference Short Form on average (T-score, 59.6 ± 8.6) was similar to that of the general population (T-score, 50 ± 10), a higher proportion of patients with SCD reported pain interference compared with the general population. The mean self-efficacy (confidence in ability to manage complications of SCD) score on the SCSES of 30.0 ± 7.3 (range, 9–45) was similar to that of other adults with SCD (mean, 32.2 ± 7.0). Twenty-five percent of the present sample had a low self-efficacy score (< 25).

Barriers to Care and Treatments. Consistent with the qualitative data, SCD-related symptoms such as tiredness (64%) and pain (62%) were reported most often as barriers to care (Table 3). Emotions (> 25%) such as worry/fear, frustration/anger, and lack of confidence were other important barriers to care. Provider knowledge and attitudes were cited next most often, with 38% of the sample indicating “Providers accuse me of drug-seeking” and “It is hard for me to find a provider who has enough experiences with or knowledge about SCD.” Participants expressed that they were not believed when in pain and “I am treated differently from other patients.” Almost half of respondents cited “I am not seen quickly enough when I am in pain” as a barrier to their care.

Consistent with the qualitative data, transportation barriers (not having a vehicle, costs of transportation, public transit not easy to get to) were cited by 55% of participants. About half of participants reported that insurance was an important barrier, with high co-pays and medications and other services not covered. In addition, gathering approvals was a long and fragmented process, particularly for consultations among providers (hematology, primary care provider, pain specialist). Furthermore, insurance provided limited choices about location for services.

Participants reported social support system burnout (22%), help needed with daily activities (21%), and social isolation or generally not having enough support (33%) as ongoing barriers. Difficulties were encountered with self-management (eg, taking medications on time or making follow-up appointments, 19%), with 22% of participants finding the health care system confusing or hard to understand. Thirty percent reported “Places for me to go to learn how to stay well are not close by or easy to get to.” ”Worry about side effects” (33%) was a common barrier to hydroxyurea use. Participants described “forgetting to take the medicine,” “tried before but it did not work,” “heard scary things” about hydroxyurea, and “not interested in taking another medicine” as barriers.

Quality of Care. More than half (51%) of the 53 participants who had accessed health care in the previous year rated their overall health care as poor on the ASCQ-Me QOC measure. This was significantly higher compared to the reports from more than 47,000 adults with Medicaid in 2017 (16%),⁴¹ and to the 2008-2009 report from 556 adults with SCD from across the United States (37%, Figure 2).³³ The major contributor to these poor ratings for participants in our sample was low satisfaction with ED care.

Sixty percent of the 42 participants who had accessed ED care in the past year indicated “never” or “sometimes” to the question “When you went to the ED for care, how often did you get it as soon as you wanted?” compared with only 16% of the 2017 adult Medicaid population responding (n = 25,789) (Figure 3). Forty-seven percent of those with an ED visit indicated that, in the previous 12 months, they had been made to wait “more than 2 hours before receiving treatment for acute pain in the ED.” However, in the previous 12 months, 39% reported that their wait time in the ED had been only “between five minutes and one hour.”

On the ASCQ-Me QOC Access to Care composite measure, 33% of 42 participants responding reported they were seen at a routine appointment as soon as they would have liked. This is significantly lower compared to 56% of the adult Medicaid population responding to the same question. Reports of provider communication (Provider Communication composite) for adolescents and adults with SCD were comparable to reports of adults with SCD from the ASCQ-Me field test,³³ but adults with Medicaid reported higher ratings of quality communication behaviors (Figure 4).^33,41 Nearly 60% of both groups with SCD reported that providers “always” performed quality communication behaviors—listened carefully, spent enough time, treated them with respect, and explained things well—compared with more than 70% of adults with Medicaid.

Participants from all counties reported the same number of barriers to care on average (3.3 ± 2.1). Adolescents and adults who reported more barriers to care also reported lower satisfaction with care (r = –0.47, P < 0.01) and less confidence in their ability to manage their SCD (self-efficacy, r = – 0.36, P < 0.05). Female participants reported more barriers to care on average compared with male participants (2.6 ± 2.4 vs 1.4 ± 2.0, P = 0.05). Participants with higher self-efficacy reported lower pain ratings (r = –0.47, P < 0.001).

Quantitative Data: Health Care Providers

Providers (n = 56) and community stakeholders (2 leaders of community-based organizations and 3 health care administrators) were interviewed, with 29 also completing the survey. The reason for not completing (n = 22) was not having the time once the interview was complete. A link to the survey was sent to any provider not completing at the time of the interview, with 2 follow-up reminders. The majority of providers were between the ages of 31 and 50 years (46.4%), female (71.4%), and white (66.1%) (Table 4). None were of Hispanic, Latinx, or Spanish origin. Thirty-six were physicians (64.3%), and 16 were allied health professionals (28.6%). Of the 56 providers, 32 indicated they had expertise caring for patients with SCD (57.1%), 14 were ED providers (25%), and 5 were primary care providers. Most of the providers practiced in an urban setting (91.1%).

Barriers to Care: ED Provider Perspectives. Nine of 14 ED providers interviewed completed the survey on their perspectives regarding barriers to care in the ED, difficulty with follow-ups, ED training resources, and pain control for patients with SCD. ED providers (n = 8) indicated that “provider attitudes” were a barrier to care delivery in the ED for patients with SCD. Some providers (n = 7) indicated that “implicit bias,” “opioid epidemic,” “concern about addiction,” and “patient behavior” were barriers. Respondents indicated that “overcrowding” (n = 6) and “lack of care pathway/protocol” (n = 5) were barriers. When asked to express their level of agreement with statements about SCD care in the ED, respondents disagreed/strongly disagreed (n = 5) that they were “able to make a follow-up appointment” with a sickle cell specialist or primary care provider upon discharge from the ED, and others disagreed/strongly disagreed (n = 4) that they were able to make a “referral to a case management program.”

ED training and resources. Providers agreed/strongly agreed (n = 8) that they had the knowledge and training to care for patients with SCD, that they had access to needed medications, and that they had access to knowledgeable nursing staff with expertise in SCD care. All 9 ED providers indicated that they had sufficient physician/provider staffing to provide good pain management to persons with SCD in the ED.

Pain control in the ED. Seven ED providers indicated that their ED used individualized dosing protocols to treat sickle cell pain, and 5 respondents indicated their ED had a protocol for treating sickle cell pain. Surprisingly, only 3 indicated that they were aware of the NHLBI recommendations for the treatment of vaso-occlusive pain.

Barriers to Care: Primary Care Provider Perspectives. Twenty providers completed the SCD provider section of the survey, including 17 multidisciplinary SCD providers from 4 sickle cell special care centers and 3 community primary care providers. Of the 20, 12 were primary care providers for patients with SCD (Table 4).

Patient needs. Six primary care providers indicated that the medical needs of patients with SCD were being met, but none indicated that the behavioral health or mental health needs were being met.

Managing SCD comorbidities. Five primary care providers indicated they were very comfortable providing preventive ambulatory care to patients with SCD. Six indicated they were very comfortable managing acute pain episodes, but none were very comfortable managing comorbidities such as pulmonary hypertension, diabetes, or chronic pain.

Barriers to opioid use. Only 3 of 12 providers reviewing a list of 15 potential barriers to the use of opioids for SCD pain management indicated a perceived lack of efficacy of opioids, development of tolerance and dependence, and concerns about community perceptions as barriers. Two providers selected potential for diversion as a moderate barrier to opioid use.

Barriers to hydroxyurea use. Eight of 12 providers indicated that the common reasons that patients/families refuse hydroxyurea were “worry about side effects”; 7 chose “don’t want to take another medicine,” and 6 chose “worry about carcinogenic potential.” Others (n = 10) indicated that “patient/family adherence with hydroxyurea” and “patient/family adherence with required blood tests” were important barriers to hydroxyurea use. Eight of the 12 providers indicated that they were comfortable with managing hydroxyurea in patients with SCD.

Care redesign. Twenty SCD and primary care providers completed the Care Redesign section of the survey. Respondents (n = 11) indicated that they would see more patients with SCD if they had accessible case management services available without charge or if patient access to transportation to clinic was also available. Ten indicated that they would see more patients with SCD if they had an accessible community health worker (who understands patient’s/family’s social situation) and access to a pain management specialist on call to answer questions and who would manage chronic pain. All (n = 20) were willing to see more patients with SCD in their practices. Most reported that a clinical decision-support tool for SCD treatment (n = 13) and avoidance of complications (n = 12) would be useful.

Discussion

We evaluated access and barriers to care, quality of care, care coordination, and provider communication from the perspectives of adolescents and adults with SCD, their care providers, and community stakeholders, within the Solberg conceptual model for quality improvement. We found that barriers within the care process content domain (context and systems) were most salient for this population of adolescents and adults with SCD, with lack of provider knowledge and poor attitudes toward adolescents and adults with SCD, particularly in the ED, cited consistently by participant groups. Stigmatization and lack of provider compassion that affected the quality of care were particularly problematic. These findings are consistent with previous reports.^42,43 Adult health care (particularly ED) provider biases and negative attitudes have been recognized as major barriers to optimal pain management in SCD.^8,11,44,45 Interestingly, ED providers in our needs assessment indicated that they felt they had the training and resources to manage patients with SCD. However, only a few actually reported knowing about the NHLBI recommendations for the treatment of vaso-occlusive pain.

Within the care process content domain, we also found that SCD-related complications and associated emotions (fear, worry, anxiety), compounded by lack of access to knowledgeable and compassionate providers, pose a significant burden. Negative encounters with the health care system contributed to a striking 84% of patient participants choosing to manage severe pain at home, with pain seriously interfering with their ability to function on a daily basis. ED providers agreed that provider attitudes and implicit bias pose important barriers to care for adolescents and adults with SCD. Adolescents and adults with SCD wanted, and understood the need, to enhance self-management skills. Both they and their providers agreed that barriers to hydroxyurea uptake included worries about potential side effects, challenges with adherence to repeated laboratory testing, and support with remembering to take the medicine. However, providers uniformly expressed that access to behavioral and mental health services were, if not nonexistent, impossible to access.

Participants with SCD and their providers reported infrastructural challenges (change process capability), as manifested in limitations with accessing acute and preventive care due to transportation- and insurance- related issues. There were health system barriers that were particularly encountered during the transition from pediatric to adult care. These findings are consistent with previous reports that have found fewer interdisciplinary services available in the adult care settings compared with pediatrics.^46,47 Furthermore, adult care providers were less willing to accept adults with SCD because of the complexity of their management, for which the providers did not have the necessary expertise.^3,48-50 In addition, both adolescents and adults with SCD and primary care providers highlighted the inadequacies of the current system in addressing the chronic pain needs of this population. Linking back to the Solberg conceptual framework, our needs assessment results confirm the important role of establishing SCD care as a priority within a health care system—this requires leadership and vision. The vision and priorities must be implemented by effective health care teams. Multilevel approaches or interventions, when implemented, will lead to the desired outcomes.

Findings from our needs assessment within our 5-county region mirror needs assessment results from the broader consortium.⁵¹ The SCDIC has prioritized developing an intervention that addresses the challenges identified within the care process domain by directly enhancing provider access to patient individualized care plans in the electronic health record in the ED. Importantly, ED providers will be asked to view a short video that directly challenges bias and stigma in the ED. Previous studies have indeed found that attitudes can be improved by providers viewing short video segments of adults with SCD discussing their experiences.^36,52 This ED protocol will be one of the interventions that we will roll out in Northern California, given the significance of negative ED encounters reported by needs assessment participants. An additional feature of the intervention is a script for adults with SCD that guides them through introducing their individualized pain plan to their ED providers, thereby enhancing their self-efficacy in a situation that has been so overwhelmingly challenging.

We will implement a second SCDIC intervention that utilizes a mobile app to support self-management on the part of the patient, by supporting motivation and adherence with hydroxyurea.⁵³ A companion app supports hydroxyurea guideline adherence on the part of the provider, in keeping with one of our findings that providers are in need of decision-support tools. Elements of the intervention also align with our findings related to the importance of a support system in managing SCD, in that participants will identify a supportive partner who will play a specific role in supporting their adherence with hydroxyurea.

On our local level, we have, by necessity, partnered with leaders and community stakeholders throughout the region to ensure that these interventions to improve SCD care are prioritized. Grant funds provide initial resources for the SCDIC interventions, but our partnering health care administrators and medical directors must ensure that participating ED and hematology providers are free from competing priorities in order to implement the changes. We have partnered with a SCD community-based organization that is designing additional educational presentations for local emergency medicine providers, with the goal to bring to life very personal stories of bias and stigma within the EDs that directly contribute to decisions to avoid ED care despite severe symptoms.

Although we attempted to obtain samples of adolescents and adults with SCD and their providers that were representative across the 5-county region, the larger proportion of respondents were from 1 county. We did not assess concerns of age- and race-matched adults in our catchment area, so we cannot definitively say that our findings are unique to SCD. However, our results are consistent with findings from the national sample of adults with SCD who participated in the ASCQ-Me field test, and with results from the SCDIC needs assessment.^33,51 Interviews and surveys are subject to self-report bias and, therefore, may or may not reflect the actual behaviors or thoughts of participants. Confidence is increased in our results given the triangulation of expressed concerns across participant groups and across data collection strategies. The majority of adolescents and adults with SCD (95%) completed both the interview and survey, while 64% of ED providers interviewed completed the survey, compared with 54% of SCD specialists and primary care providers. These response rates are more than acceptable within the realm of survey response rates.^54,55

Although we encourage examining issues with care delivery within the conceptual framework for quality improvement presented, we recognize that grant funding allowed us to conduct an in-depth needs assessment that might not be feasible in other settings. Still, we would like readers to understand the importance of gathering data for improvement in a systematic manner across a range of participant groups, to ultimately inform the development of interventions and provide for evaluation of outcomes as a result of the interventions. This is particularly important for a disease, such as SCD, that is both medically and sociopolitically complex.

Conclusion

Our needs assessment brought into focus the multiple factors contributing to the disparities in health care experienced by adolescents and adults with SCD on our local level, and within the context of inequities in health resources and outcomes on the national level. We propose solutions that include specific interventions developed by a consortium of SCD and implementation science experts. We utilize a quality improvement framework to ensure that the elements of the interventions also address the barriers identified by our local providers and patients that are unique to our community. The pervasive challenges in SCD care, coupled with its medical complexities, may seem insurmountable, but our survey and qualitative results provide us with a road map for the way forward.

Acknowledgments: The authors thank the adolescents and adults with sickle cell disease, the providers, and the community stakeholders who completed the interviews and surveys. The authors also acknowledge the SCCCI co-investigators for their contributions to this project, including Michael Bell, MD, Ward Hagar, MD, Christine Hoehner, FNP, Kimberly Major, MSW, Anne Marsh, MD, Lynne Neumayr, MD, and Ted Wun, MD. We also thank Kamilah Bailey, Jameelah Hodge, Jennifer Kim, Michael Rowland, Adria Stauber, Amber Fearon, and Shanda Robertson, and the Sickle Cell Data Collection Program for their contributions.

Corresponding author: Marsha J. Treadwell, PhD, University of California San Francisco Benioff Children’s Hospital Oakland, 747 52nd St., Oakland, CA 94609; [email protected].

Financial disclosures: None.

Funding/support: This work was supported by grant # 1U01HL134007 from the National Heart, Lung, and Blood Institute to the University of California San Francisco Benioff Children’s Hospital Oakland.

From the University of California San Francisco (Dr. Treadwell, Dr. Hessler, Yumei Chen, Swapandeep Mushiana, Dr. Potter, and Dr. Vichinsky), the University of California Los Angeles (Dr. Jacob), and the University of California Berkeley (Alex Chen).

Abstract

• Objective: Adolescents and adults with sickle cell disease (SCD) face pervasive disparities in health resources and outcomes. We explored barriers to and facilitators of care to identify opportunities to support implementation of evidence-based interventions aimed at improving care quality for patients with SCD.
• Methods: We engaged a representative sample of adolescents and adults with SCD (n = 58), health care providers (n = 51), and community stakeholders (health care administrators and community-based organization leads (n = 5) in Northern California in a community-based needs assessment. We conducted group interviews separately with participant groups to obtain in-depth perspectives. Adolescents and adults with SCD completed validated measures of pain interference, quality of care, self-efficacy, and barriers to care. Providers and community stakeholders completed surveys about barriers to SCD care.
• Results: We triangulated qualitative and quantitative data and found that participants with SCD (mean age, 31 ± 8.6 years), providers, and community stakeholders emphasized the social and emotional burden of SCD as barriers. Concrete barriers agreed upon included insurance and lack of resources for addressing pain impact. Adolescents and adults with SCD identified provider issues (lack of knowledge, implicit bias), transportation, and limited social support as barriers. Negative encounters with the health care system contributed to 84% of adolescents and adults with SCD reporting they chose to manage severe pain at home. Providers focused on structural barriers: lack of access to care guidelines, comfort level with and knowledge of SCD management, and poor care coordination.
• Conclusion: Strategies for improving access to compassionate, evidence-based quality care, as well as strategies for minimizing the burden of having SCD, are warranted for this medically complex population.

Keywords: barriers to care; quality of care; care access; care coordination.

Sickle cell disease (SCD), an inherited chronic medical condition, affects about 100,000 individuals in the United States, a population that is predominantly African American.¹ These individuals experience multiple serious and life-threatening complications, most frequently recurrent vaso-occlusive pain episodes,² and they require interactions with multidisciplinary specialists from childhood. Because of advances in treatments, the majority are reaching adulthood; however, there is a dearth of adult health care providers with the training and expertise to manage their complex medical needs.³ Other concrete barriers to adequate SCD care include insurance and distance to comprehensive SCD centers.^4,5

Social, behavioral, and emotional factors may also contribute to challenges with SCD management. SCD may limit daily functional abilities and lead to diminished overall quality of life.^6,7 Some adolescents and adults may require high doses of opioids, which contributes to health care providers’ perceptions that there is a high prevalence of drug addiction in the population.^8,9 These providers express negative attitudes towards adults with SCD, and, consequently, delay medication administration when it is acutely needed and provide otherwise suboptimal treatment.^8,10,11 Adult care providers may also be uncomfortable with prescribing and managing disease-modifying therapies (blood transfusion, hydroxyurea) that have established efficacy.^12-17

As 1 of 8 programs funded by the National Heart, Lung, and Blood Institute’s (NHLBI) Sickle Cell Disease Implementation Consortium (SCDIC), we are using implementation science to reduce barriers to care and improve quality of care and health care outcomes in SCD.^18,19 Given that adolescents and adults with SCD experience high mortality, severe pain, and progressive decline in their ability to function day to day, and also face lack of access to knowledgeable, compassionate providers in primary and emergency settings, the SCDIC focuses on individuals aged 15 to 45 years.^6,8,9,11,12

Our regional SCDIC program, the Sickle Cell Care Coordination Initiative (SCCCI), brings together researchers, clinicians, adolescents, and adults with SCD and their families, dedicated community members, policy makers, and administrators to identify and address barriers to health care within 5 counties in Northern California. One of our first steps was to conduct a community-based needs assessment, designed to inform implementation of evidence-based interventions, accounting for unique contextual factors in our region.

Conceptual Framework for Improving Medical Practice

Our needs assessment is guided by Solberg’s Conceptual Framework for Improving Medical Practice (Figure 1).²⁰ Consistent with the overarching principles of the SCDIC, this conceptual framework focuses on the inadequate implementation of evidence-based guidelines, and on the need to first understand multifactorial facilitators and barriers to guideline implementation in order to effect change. The framework identifies 3 main elements that must be present to ensure improvements in quality-of-care processes and patient outcomes: priority, change process capability, and care process content. Priority refers to ample resource allocation for the specific change, as well as freedom from competing priorities for those implementing the change. Change process capability includes strong, effective leadership, adequate infrastructure for managing change (including resources and time), change management skills at all levels, and an established clinical information system. Care process content refers to context and systems-level changes, such as delivery system redesign as needed, support for self-management to lessen the impact of the disease, and decision support.^21-23

The purpose of our community-based needs assessment was to evaluate barriers to care and quality of care in SCD, within Solberg’s conceptual model for improving medical practice. The specific aims were to evaluate access and barriers to care (eg, lack of provider expertise and training, health care system barriers such as poor care coordination and provider communication); evaluate quality of care; and assess patient needs related to pain, pain interference, self-efficacy, and self-management for adolescents and adults with SCD. We gathered the perspectives of a representative community of adolescents and adults with SCD, their providers, and community stakeholders in order to examine barriers, quality of life and care, and patient experiences in our region.

Methods

Design

In this cross-sectional study, adolescents and adults with SCD, their providers, and community stakeholders participated in group or individual qualitative interviews and completed surveys between October 2017 and March 2018.

Setting and Sample

Recruitment flyers were posted on a regional SCD-focused website, and clinical providers or a study coordinator introduced information about the needs assessment to potential participants with SCD during clinic visits at the participating centers. Participants with SCD were eligible if they had any diagnosis of SCD, were aged 15 to 48 years, and received health services within 5 Northern California counties (Alameda, Contra Costa, Sacramento, San Francisco, and Solano). They were excluded if they did not have a SCD diagnosis or had not received health services within the catchment area. As the project proceeded, participants were asked to refer other adolescents and adults with SCD for the interviews and surveys (snowball sampling). Our goal was to recruit 50 adolescents and adults with SCD into the study, aiming for 10 representatives from each county.

Providers and community stakeholders were recruited via emails, letters and informational flyers. We engaged our partner, the Sickle Cell Data Collection Program,² to generate a list of providers and institutions that had seen patients with SCD in primary, emergency, or inpatient settings in the region. We contacted these institutions to describe the SCCCI and invite participation in the needs assessment. We also invited community-based organization leads and health care administrators who worked with SCD to participate. Providers accessed confidential surveys via a secure link on the study website or completed paper versions. Common data collected across providers included demographics and descriptions of practice settings.

Participants were eligible to be part of the study if they were health care providers (physicians and nurses) representing hematology, primary care, family medicine, internal medicine, or emergency medicine; ancillary staff (social work, psychology, child life); or leaders or administrators of clinical or sickle cell community-based organizations in Northern California (recruitment goal of n = 50). Providers were excluded if they practiced in specialties other than those noted or did not practice within the region.

Data Collection Procedures

After providing assent/consent, participating adolescents and adults with SCD took part in individual and group interviews and completed survey questionnaires. All procedures were conducted in a private space in the sickle cell center or community. Adolescents and adults with SCD completed the survey questionnaire on a tablet, with responses recorded directly in a REDCap (Research Electronic Data Capture) database,²⁴ or on a paper version. Interviews lasted 60 (individual) to 90 (group) minutes, while survey completion time was 20 to 25 minutes. Each participant received a gift card upon completion as an expression of appreciation. All procedures were approved by the institutional review boards of the participating health care facilities.

Group and Individual Interviews

Participants with SCD and providers were invited to participate in a semi-structured qualitative interview prior to being presented with the surveys. Adolescents and adults with SCD were interviewed about barriers to care, quality of care, and pain-related experiences. Providers were asked about barriers to care and treatments. Interview guides were modified for community-based organization leaders and health care administrators who did not provide clinical services. Interview guides can be found in the Appendix. Interviews were conducted by research coordinators trained in qualitative research methods by the first author (MT). As appropriate with semi-structured interviews, the interviewers could word questions spontaneously, change the order of questions for ease of flow of conversation, and inform simultaneous coding of interviews with new themes as those might arise, as long as they touched on all topics within the interview guide.²⁵ The interview guides were written, per qualitative research standards, based on the aims and purpose of the research,²⁶ and were informed by existing literature on access and barriers to care in SCD, quality of care, and the needs of individuals with SCD, including in relation to impact of the disease, self-efficacy, and self-management.

Interviewees participated in either individual or group interviews, but not both. The decision for which type of interview an individual participated in was based on 2 factors: if there were not comparable participants for group interviews (eg, health care administrator and community-based organization lead), these interviews were done individually; and given that we were drawing participants from a 5-county area in Northern California, scheduling was challenging for individuals with SCD with regard to aligning schedules and traveling to a central location where the group interviews were conducted. Provider group interviews were easier to arrange because we could schedule them at the same time as regularly scheduled meetings at the participants’ health care institutions.

Interview Data Gathering and Analysis

Digital recordings of the interviews were cleaned of any participant identifying data and sent for transcription to an outside service. Transcripts were reviewed for completeness and imported into NVivo (www.qsrinternational.com), a qualitative data management program.

A thematic content analysis and deductive and inductive approaches were used to analyze the verbatim transcripts generated from the interviews. The research team was trained in the use of NVivo software to facilitate the coding process. A deductive coding scheme was initially used based on existing concepts in the literature regarding challenges to optimal SCD care, with new codes added as the thematic content analyses progressed. The initial coding, pattern coding, and use of displays to examine the relationships between different categories were conducted simultaneously.^27,28 Using the constant comparative method, new concepts from participants with SCD and providers could be incorporated into subsequent interviews with other participants. For this study, the only additional concepts added were in relation to participant recruitment and retention in the SCDIC Registry. Research team members coded transcripts separately and came together weekly, constantly comparing codes and developing the consensus coding scheme. Where differences between coders existed, code meanings were discussed and clarified until consensus was reached.²⁹

Quantitative data were analyzed using SPSS (v. 25, Chicago, IL). Descriptive statistics (means, standard deviations, frequencies, percentages) were used to summarize demographics (eg, age, gender, and race), economic status, and type of SCD. No systematic differences were detected from cases with missing values. Scale reliabilities (ie, Cronbach α) were evaluated for self-report measures.

Measurement

Adolescents and adults with SCD completed items from the PhenX Toolkit (consensus measures for Phenotypes and eXposures), assessing sociodemographics (age, sex, race, ethnicity, educational attainment, occupation, marital status, annual income, insurance), and clinical characteristics (sickle cell diagnosis and emergency department [ED] and hospital utilization for pain).³⁰

Pain Interference Short Form (Patient-Reported Outcomes Measurement Information System [PROMIS]). The Pain Interference Form consists of 8 items that assess the degree to which pain interfered with day-to-day activities in the previous 7 days at home, including impacts on social, cognitive, emotional, and physical functioning; household chores and recreational activities; sleep; and enjoyment in life. Reliability and validity of the PROMIS Pain Interference Scale has been demonstrated, with strong negative correlations with Physical Function Scales (r = 0.717, P < 0.01), indicating that higher scores are associated with lower function (β = 0.707, P < 0.001).³¹ The Cronbach α estimate for the other items on the pain interference scale was 0.99. Validity analysis indicated strong correlations with pain-related domains: BPI Interference Subscale (rho = 0.90), SF-36 Bodily Pain Subscale (rho = –0.84), and 0–10 Numerical Rating of Pain Intensity (rho = 0.48).³²

Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Quality of Care (QOC). ASCQ-Me QOC consists of 27 items that measure the quality of care that adults with SCD have received from health care providers.³³ There are 3 composites: provider communication (quality of patient and provider communication), ED care (quality of care in the ED), and access (to routine and emergency care). Internal consistency reliability for all 3 composites is greater than 0.70. Strong correlations of the provider communication composite with overall ratings of routine care (r = 0.65) and overall provider ratings (r = 0.83) provided evidence of construct validity. Similarly, the ED care composite was strongly correlated with overall ratings of QOC in the ED, and the access composite was highly correlated with overall evaluations of ED care (r = 0.70). Access, provider interaction, and ED care composites were reliable (Cronbach α, 0.70–0.83) and correlated with ratings of global care (r = 0.32–0.83), further indicating construct validity.³³

Sickle Cell Self-Efficacy Scale (SCSES). The SCSES is a 9-item, self-administered questionnaire measuring perceptions of the ability to manage day-to-day issues resulting from SCD. SCSES items are scored on a 5-point scale ranging from Not sure at all (1) to Very sure (5). Individual item responses are summed to give an overall score, with higher scores indicating greater self-efficacy. The SCSES has acceptable reliability (r = 0.45, P < 0.001) and validity (α = 0.89).^34,35

Sickle Cell Disease Barriers Checklist. This checklist consists of 53 items organized into 8 categories: insurance, transportation, accommodations and accessibility, provider knowledge and attitudes, social support, individual barriers such as forgetting or difficulties understanding instructions, emotional barriers (fear, anger), and disease-related barriers. Participants check applicable barriers, with a total score range of 0 to 53 and higher scores indicating more barriers to care. The SCD Barriers Checklist has demonstrated face validity and test-retest reliability (Pearson r = 0.74, P < 0.05).⁵

ED Provider Checklist. The ED provider survey is a checklist of 14 statements pertaining to issues regarding patient care, with which the provider rates level of agreement. Items representing the attitudes and beliefs of providers towards patients with SCD are rated on a Likert-type scale, with level of agreement indicated as 1 (strongly disagree) to 6 (strongly agree). The positive attitudes subscale consists of 4 items (Cronbach α= 0.85), and the negative attitudes subscale consists of 6 items (Cronbach α = 0.89). The Red-Flag Behaviors subscale includes 4 items that indicate behavior concerns about drug-seeking, such as requesting specific narcotics and changing behavior when the provider walks in.^8,36,37

Sickle cell and primary care providers also completed a survey consisting of sets of items compiled from existing provider surveys; this survey consisted of a list of 16 barriers to using opioids, which the providers rated on a 5-point Likert-type scale (1, not a barrier; 5, complete barrier).^13,16,38 Providers indicated their level of experience with caring for patients with SCD; care provided, such as routine health screenings; and comfort level with providing preventive care, managing comorbidities, and managing acute and chronic pain. Providers were asked what potential facilitators might improve care for patients with SCD, including higher reimbursement, case management services, access to pain management specialists, and access to clinical decision-support tools. Providers responded to specific questions about management with hydroxyurea (eg, criteria for, barriers to, and comfort level with prescribing).³⁹ The surveys are included in the Appendix.

Triangulation

Data from the interviews and surveys were triangulated to enhance understanding of results generated from the different data sources.⁴⁰ Convergence of findings, different facets of the same phenomenon, or new perspectives were examined.

Qualitative Data

Adolescents and adults with SCD (n = 55) and health care providers and community stakeholders (n = 56) participated in group or individual interviews to help us gain an in-depth understanding of the needs and barriers related to SCD care in our 5-county region. Participants with SCD described their experiences, which included stigma, racism, labeling, and, consequently, stress. They also identified barriers such as lack of transportation, challenges with insurance, and lack of access to providers who were competent with pain management. They reported that having SCD in a health care system that was unable to meet their needs was burdensome.

Barriers to Care and Treatments. Adolescents and adults indicated that SCD and its sequelae posed significant barriers to health care. Feelings of tiredness and pain make it more difficult for them to seek care. The emotional burden of SCD (fear and anger) was a frequently cited barrier, which was fueled by previous negative encounters with the health care system. All adolescents and adults with SCD reported that they knew of stigma in relation to seeking pain management that was pervasive and long-standing, and the majority reported they had directly experienced stigma. They reported that being labeled as “drug-seekers” was typical when in the ED for pain management. Participants articulated unconscious bias or overt racism among providers: “people with sickle cell are Black ... and Black pain is never as valuable as White pain” (25-year-old male). Respondents with SCD described challenges to the credibility of their pain reports in the ED. They reported that ED providers expressed doubts regarding the existence and/or severity of their pain, consequently creating a feeling of disrespect for patients seeking pain relief. The issue of stigma was mentioned by only 2 of 56 providers during their interviews.

Lack of Access to Knowledgeable, Compassionate Providers. Lack of access to knowledgeable care providers was another prevalent theme expressed by adolescents and adults with SCD. Frustration occurred when providers did not have knowledge of SCD and its management, particularly pain assessment. Adolescents and adults with SCD noted the lack of compassion among providers: “I’ve been kicked out of the hospital because they felt like okay, well we gave you enough medication, you should be all right” (29-year-old female). Providers specifically mentioned lack of compassion and knowledge as barriers to SCD care much less often during their interviews compared with the adolescents and adults with SCD.

Health Care System Barriers. Patient participants often expressed concerns about concrete and structural aspects of care. Getting to their appointments was a challenge for half of the interviewees, as they either did not have access to a vehicle or could not afford to travel the needed distance to obtain quality care. Even when hospitals were accessible by public transportation, those with excruciating pain understandably preferred a more comfortable and private way to travel: “I would like to change that, something that will be much easier, convenient for sickle cell patients that do suffer with pain, that they don’t have to travel always to see the doctor” (30-year-old male).

Insurance and other financial barriers also played an important role in influencing decisions to seek health care services. Medical expenses were not covered, or co-pays were too high. The Medicaid managed care system could prevent access to knowledgeable providers who were not within network. Such a lack of access discouraged some adolescents and adults with SCD from seeking acute and preventive care.

Transition From Pediatric to Adult Care. Interviewees with SCD expressed distress about the gap between pediatric and adult care. They described how they had a long-standing relationship with their medical providers, who were familiar with their medical background and history from childhood. Adolescent interviewees reported an understanding of their own pain management as well as adherence to and satisfaction with their individualized pain plans. However, adults noted that satisfaction plummeted with increasing age due to the limited number of experienced adult SCD providers, which was compounded by negative experiences (stigma, racism, drug-seeking label).

One interviewee emphasized the difficulty of finding knowledgeable providers after transition: “When you’re a pediatric sickle cell [patient], you have the doctors there every step of the way, but not with adult sickle cell… I know when I first transitioned I never felt more alone in my life… you look at that ER doctor kind of with the same mindset as you would your hematologist who just hand walked you through everything. And adult care providers were a lot more blunt and cold and they’re like… ‘I don’t know; I’m not really educated in sickle cell.’” A sickle cell provider shared his insight about the problem of transitioning: “I think it’s particularly challenging because we, as a community, don’t really set them up for success. It’s different from other chronic conditions [in that] it’s much harder to find an adult sickle cell provider. There’s not a lot of adult hematologists that will take care of our adult patients, and so I know statistically, there’s like a drop-down in the overall outcomes of our kids after they age out of our pediatric program.”

Self-Management, Supporting Hydroxyurea Use. Interview participants with SCD reported using a variety of methods to manage pain at home and chose to go to the ED only when the pain became intolerable. Patients and providers expressed awareness of different resources for managing pain at home, yet they also indicated that these resources have not been consolidated in an accessible way for patients and families. Some resources cited included heat therapy, acupuncture, meditation, medical marijuana, virtual reality devices, and pain medications other than opioids.

Patients and providers expressed the need for increasing awareness and education about hydroxyurea. Many interview participants with SCD were concerned about side effects, multiple visits with a provider during dose titration, and ongoing laboratory monitoring. They also expressed difficulties with scheduling multiple appointments, depending on access to transportation and limited provider clinic hours. They were aware of strategies for improving adherence with hydroxyurea, including setting phone alarms, educating family members about hydroxyurea, and eliciting family support, but expressed needing help to consistently implement these strategies.

Safe Opioid Prescribing. Adult care providers expressed concerns about safe opioid prescribing for patients with SCD. They were reluctant to prescribe opioid doses needed to adequately control SCD pain. Providers expressed uncertainty and fear or concern about medical/legal liability or about their judgment about what’s safe and not safe for patients with chronic use/very high doses of opioids. “I know we’re in like this opiate epidemic here in this country but I feel like these patients don’t really fit under that umbrella that the problem is coming from so [I am] just trying to learn more about how to take care of them.”

Care Coordination and Provider Communication. Adolescents and adults with SCD reported having positive experiences—good communication, established trust, and compassionate care—with their usual providers. However, they perceived that ED physicians and nurses did not really care about them. Both interviewees with SCD and providers recognized the importance of good communication in all settings as the key to overcoming barriers to receiving quality care. All agreed on the importance of using individual pain plans so that all providers, especially ED providers, can be more at ease with treating adolescents and adults with SCD.

Quantitative Data: Adolescents and Adults With SCD

Fifty-eight adolescents and adults with SCD (aged 15 to 48 years) completed the survey. Three additional individuals who did not complete the interview completed the survey. Reasons for not completing the interview included scheduling challenges (n = 2) or a sickle cell pain episode (n = 1). The average age of participants was 31 years ± 8.6, more than half (57%) were female, and the majority (93%) were African American (Table 1). Most (71%) had never been married. Half (50%) had some college or an associate degree, and 40% were employed and reported an annual household income of less than $30,000. Insurance coverage was predominantly Medi-Cal (Medicaid, 69%). The majority of participants resided in Alameda (34.5%) or Contra Costa (21%) counties. The majority of sickle cell care was received in Alameda County, whether outpatient (52%), inpatient (40%), or ED care (41%). The majority (71%) had a diagnosis of SCD hemoglobin SS.

Pain. More than one-third of individuals with SCD reported 1 or 2 ED visits for pain in the previous 6 months (34%), and more than 3 hospitalizations (36%) related to pain in the previous year (Table 2). The majority (85%) reported having severe pain at home in the previous 6 months that they did not seek health care for, consistent with their reports in the qualitative interviews. More than half (59%) reported 4 or more of these severe pain episodes that led to inability to perform daily activities for 1 week or more. While pain interference on the PROMIS Pain Interference Short Form on average (T-score, 59.6 ± 8.6) was similar to that of the general population (T-score, 50 ± 10), a higher proportion of patients with SCD reported pain interference compared with the general population. The mean self-efficacy (confidence in ability to manage complications of SCD) score on the SCSES of 30.0 ± 7.3 (range, 9–45) was similar to that of other adults with SCD (mean, 32.2 ± 7.0). Twenty-five percent of the present sample had a low self-efficacy score (< 25).

Barriers to Care and Treatments. Consistent with the qualitative data, SCD-related symptoms such as tiredness (64%) and pain (62%) were reported most often as barriers to care (Table 3). Emotions (> 25%) such as worry/fear, frustration/anger, and lack of confidence were other important barriers to care. Provider knowledge and attitudes were cited next most often, with 38% of the sample indicating “Providers accuse me of drug-seeking” and “It is hard for me to find a provider who has enough experiences with or knowledge about SCD.” Participants expressed that they were not believed when in pain and “I am treated differently from other patients.” Almost half of respondents cited “I am not seen quickly enough when I am in pain” as a barrier to their care.

Consistent with the qualitative data, transportation barriers (not having a vehicle, costs of transportation, public transit not easy to get to) were cited by 55% of participants. About half of participants reported that insurance was an important barrier, with high co-pays and medications and other services not covered. In addition, gathering approvals was a long and fragmented process, particularly for consultations among providers (hematology, primary care provider, pain specialist). Furthermore, insurance provided limited choices about location for services.

Participants reported social support system burnout (22%), help needed with daily activities (21%), and social isolation or generally not having enough support (33%) as ongoing barriers. Difficulties were encountered with self-management (eg, taking medications on time or making follow-up appointments, 19%), with 22% of participants finding the health care system confusing or hard to understand. Thirty percent reported “Places for me to go to learn how to stay well are not close by or easy to get to.” ”Worry about side effects” (33%) was a common barrier to hydroxyurea use. Participants described “forgetting to take the medicine,” “tried before but it did not work,” “heard scary things” about hydroxyurea, and “not interested in taking another medicine” as barriers.

Quality of Care. More than half (51%) of the 53 participants who had accessed health care in the previous year rated their overall health care as poor on the ASCQ-Me QOC measure. This was significantly higher compared to the reports from more than 47,000 adults with Medicaid in 2017 (16%),⁴¹ and to the 2008-2009 report from 556 adults with SCD from across the United States (37%, Figure 2).³³ The major contributor to these poor ratings for participants in our sample was low satisfaction with ED care.

Sixty percent of the 42 participants who had accessed ED care in the past year indicated “never” or “sometimes” to the question “When you went to the ED for care, how often did you get it as soon as you wanted?” compared with only 16% of the 2017 adult Medicaid population responding (n = 25,789) (Figure 3). Forty-seven percent of those with an ED visit indicated that, in the previous 12 months, they had been made to wait “more than 2 hours before receiving treatment for acute pain in the ED.” However, in the previous 12 months, 39% reported that their wait time in the ED had been only “between five minutes and one hour.”

On the ASCQ-Me QOC Access to Care composite measure, 33% of 42 participants responding reported they were seen at a routine appointment as soon as they would have liked. This is significantly lower compared to 56% of the adult Medicaid population responding to the same question. Reports of provider communication (Provider Communication composite) for adolescents and adults with SCD were comparable to reports of adults with SCD from the ASCQ-Me field test,³³ but adults with Medicaid reported higher ratings of quality communication behaviors (Figure 4).^33,41 Nearly 60% of both groups with SCD reported that providers “always” performed quality communication behaviors—listened carefully, spent enough time, treated them with respect, and explained things well—compared with more than 70% of adults with Medicaid.

Participants from all counties reported the same number of barriers to care on average (3.3 ± 2.1). Adolescents and adults who reported more barriers to care also reported lower satisfaction with care (r = –0.47, P < 0.01) and less confidence in their ability to manage their SCD (self-efficacy, r = – 0.36, P < 0.05). Female participants reported more barriers to care on average compared with male participants (2.6 ± 2.4 vs 1.4 ± 2.0, P = 0.05). Participants with higher self-efficacy reported lower pain ratings (r = –0.47, P < 0.001).

Quantitative Data: Health Care Providers

Providers (n = 56) and community stakeholders (2 leaders of community-based organizations and 3 health care administrators) were interviewed, with 29 also completing the survey. The reason for not completing (n = 22) was not having the time once the interview was complete. A link to the survey was sent to any provider not completing at the time of the interview, with 2 follow-up reminders. The majority of providers were between the ages of 31 and 50 years (46.4%), female (71.4%), and white (66.1%) (Table 4). None were of Hispanic, Latinx, or Spanish origin. Thirty-six were physicians (64.3%), and 16 were allied health professionals (28.6%). Of the 56 providers, 32 indicated they had expertise caring for patients with SCD (57.1%), 14 were ED providers (25%), and 5 were primary care providers. Most of the providers practiced in an urban setting (91.1%).

Barriers to Care: ED Provider Perspectives. Nine of 14 ED providers interviewed completed the survey on their perspectives regarding barriers to care in the ED, difficulty with follow-ups, ED training resources, and pain control for patients with SCD. ED providers (n = 8) indicated that “provider attitudes” were a barrier to care delivery in the ED for patients with SCD. Some providers (n = 7) indicated that “implicit bias,” “opioid epidemic,” “concern about addiction,” and “patient behavior” were barriers. Respondents indicated that “overcrowding” (n = 6) and “lack of care pathway/protocol” (n = 5) were barriers. When asked to express their level of agreement with statements about SCD care in the ED, respondents disagreed/strongly disagreed (n = 5) that they were “able to make a follow-up appointment” with a sickle cell specialist or primary care provider upon discharge from the ED, and others disagreed/strongly disagreed (n = 4) that they were able to make a “referral to a case management program.”

ED training and resources. Providers agreed/strongly agreed (n = 8) that they had the knowledge and training to care for patients with SCD, that they had access to needed medications, and that they had access to knowledgeable nursing staff with expertise in SCD care. All 9 ED providers indicated that they had sufficient physician/provider staffing to provide good pain management to persons with SCD in the ED.

Pain control in the ED. Seven ED providers indicated that their ED used individualized dosing protocols to treat sickle cell pain, and 5 respondents indicated their ED had a protocol for treating sickle cell pain. Surprisingly, only 3 indicated that they were aware of the NHLBI recommendations for the treatment of vaso-occlusive pain.

Barriers to Care: Primary Care Provider Perspectives. Twenty providers completed the SCD provider section of the survey, including 17 multidisciplinary SCD providers from 4 sickle cell special care centers and 3 community primary care providers. Of the 20, 12 were primary care providers for patients with SCD (Table 4).

Patient needs. Six primary care providers indicated that the medical needs of patients with SCD were being met, but none indicated that the behavioral health or mental health needs were being met.

Managing SCD comorbidities. Five primary care providers indicated they were very comfortable providing preventive ambulatory care to patients with SCD. Six indicated they were very comfortable managing acute pain episodes, but none were very comfortable managing comorbidities such as pulmonary hypertension, diabetes, or chronic pain.

Barriers to opioid use. Only 3 of 12 providers reviewing a list of 15 potential barriers to the use of opioids for SCD pain management indicated a perceived lack of efficacy of opioids, development of tolerance and dependence, and concerns about community perceptions as barriers. Two providers selected potential for diversion as a moderate barrier to opioid use.

Barriers to hydroxyurea use. Eight of 12 providers indicated that the common reasons that patients/families refuse hydroxyurea were “worry about side effects”; 7 chose “don’t want to take another medicine,” and 6 chose “worry about carcinogenic potential.” Others (n = 10) indicated that “patient/family adherence with hydroxyurea” and “patient/family adherence with required blood tests” were important barriers to hydroxyurea use. Eight of the 12 providers indicated that they were comfortable with managing hydroxyurea in patients with SCD.

Care redesign. Twenty SCD and primary care providers completed the Care Redesign section of the survey. Respondents (n = 11) indicated that they would see more patients with SCD if they had accessible case management services available without charge or if patient access to transportation to clinic was also available. Ten indicated that they would see more patients with SCD if they had an accessible community health worker (who understands patient’s/family’s social situation) and access to a pain management specialist on call to answer questions and who would manage chronic pain. All (n = 20) were willing to see more patients with SCD in their practices. Most reported that a clinical decision-support tool for SCD treatment (n = 13) and avoidance of complications (n = 12) would be useful.

Discussion

We evaluated access and barriers to care, quality of care, care coordination, and provider communication from the perspectives of adolescents and adults with SCD, their care providers, and community stakeholders, within the Solberg conceptual model for quality improvement. We found that barriers within the care process content domain (context and systems) were most salient for this population of adolescents and adults with SCD, with lack of provider knowledge and poor attitudes toward adolescents and adults with SCD, particularly in the ED, cited consistently by participant groups. Stigmatization and lack of provider compassion that affected the quality of care were particularly problematic. These findings are consistent with previous reports.^42,43 Adult health care (particularly ED) provider biases and negative attitudes have been recognized as major barriers to optimal pain management in SCD.^8,11,44,45 Interestingly, ED providers in our needs assessment indicated that they felt they had the training and resources to manage patients with SCD. However, only a few actually reported knowing about the NHLBI recommendations for the treatment of vaso-occlusive pain.

Within the care process content domain, we also found that SCD-related complications and associated emotions (fear, worry, anxiety), compounded by lack of access to knowledgeable and compassionate providers, pose a significant burden. Negative encounters with the health care system contributed to a striking 84% of patient participants choosing to manage severe pain at home, with pain seriously interfering with their ability to function on a daily basis. ED providers agreed that provider attitudes and implicit bias pose important barriers to care for adolescents and adults with SCD. Adolescents and adults with SCD wanted, and understood the need, to enhance self-management skills. Both they and their providers agreed that barriers to hydroxyurea uptake included worries about potential side effects, challenges with adherence to repeated laboratory testing, and support with remembering to take the medicine. However, providers uniformly expressed that access to behavioral and mental health services were, if not nonexistent, impossible to access.

Participants with SCD and their providers reported infrastructural challenges (change process capability), as manifested in limitations with accessing acute and preventive care due to transportation- and insurance- related issues. There were health system barriers that were particularly encountered during the transition from pediatric to adult care. These findings are consistent with previous reports that have found fewer interdisciplinary services available in the adult care settings compared with pediatrics.^46,47 Furthermore, adult care providers were less willing to accept adults with SCD because of the complexity of their management, for which the providers did not have the necessary expertise.^3,48-50 In addition, both adolescents and adults with SCD and primary care providers highlighted the inadequacies of the current system in addressing the chronic pain needs of this population. Linking back to the Solberg conceptual framework, our needs assessment results confirm the important role of establishing SCD care as a priority within a health care system—this requires leadership and vision. The vision and priorities must be implemented by effective health care teams. Multilevel approaches or interventions, when implemented, will lead to the desired outcomes.

Findings from our needs assessment within our 5-county region mirror needs assessment results from the broader consortium.⁵¹ The SCDIC has prioritized developing an intervention that addresses the challenges identified within the care process domain by directly enhancing provider access to patient individualized care plans in the electronic health record in the ED. Importantly, ED providers will be asked to view a short video that directly challenges bias and stigma in the ED. Previous studies have indeed found that attitudes can be improved by providers viewing short video segments of adults with SCD discussing their experiences.^36,52 This ED protocol will be one of the interventions that we will roll out in Northern California, given the significance of negative ED encounters reported by needs assessment participants. An additional feature of the intervention is a script for adults with SCD that guides them through introducing their individualized pain plan to their ED providers, thereby enhancing their self-efficacy in a situation that has been so overwhelmingly challenging.

We will implement a second SCDIC intervention that utilizes a mobile app to support self-management on the part of the patient, by supporting motivation and adherence with hydroxyurea.⁵³ A companion app supports hydroxyurea guideline adherence on the part of the provider, in keeping with one of our findings that providers are in need of decision-support tools. Elements of the intervention also align with our findings related to the importance of a support system in managing SCD, in that participants will identify a supportive partner who will play a specific role in supporting their adherence with hydroxyurea.

On our local level, we have, by necessity, partnered with leaders and community stakeholders throughout the region to ensure that these interventions to improve SCD care are prioritized. Grant funds provide initial resources for the SCDIC interventions, but our partnering health care administrators and medical directors must ensure that participating ED and hematology providers are free from competing priorities in order to implement the changes. We have partnered with a SCD community-based organization that is designing additional educational presentations for local emergency medicine providers, with the goal to bring to life very personal stories of bias and stigma within the EDs that directly contribute to decisions to avoid ED care despite severe symptoms.

Although we attempted to obtain samples of adolescents and adults with SCD and their providers that were representative across the 5-county region, the larger proportion of respondents were from 1 county. We did not assess concerns of age- and race-matched adults in our catchment area, so we cannot definitively say that our findings are unique to SCD. However, our results are consistent with findings from the national sample of adults with SCD who participated in the ASCQ-Me field test, and with results from the SCDIC needs assessment.^33,51 Interviews and surveys are subject to self-report bias and, therefore, may or may not reflect the actual behaviors or thoughts of participants. Confidence is increased in our results given the triangulation of expressed concerns across participant groups and across data collection strategies. The majority of adolescents and adults with SCD (95%) completed both the interview and survey, while 64% of ED providers interviewed completed the survey, compared with 54% of SCD specialists and primary care providers. These response rates are more than acceptable within the realm of survey response rates.^54,55

Although we encourage examining issues with care delivery within the conceptual framework for quality improvement presented, we recognize that grant funding allowed us to conduct an in-depth needs assessment that might not be feasible in other settings. Still, we would like readers to understand the importance of gathering data for improvement in a systematic manner across a range of participant groups, to ultimately inform the development of interventions and provide for evaluation of outcomes as a result of the interventions. This is particularly important for a disease, such as SCD, that is both medically and sociopolitically complex.

Conclusion

Our needs assessment brought into focus the multiple factors contributing to the disparities in health care experienced by adolescents and adults with SCD on our local level, and within the context of inequities in health resources and outcomes on the national level. We propose solutions that include specific interventions developed by a consortium of SCD and implementation science experts. We utilize a quality improvement framework to ensure that the elements of the interventions also address the barriers identified by our local providers and patients that are unique to our community. The pervasive challenges in SCD care, coupled with its medical complexities, may seem insurmountable, but our survey and qualitative results provide us with a road map for the way forward.

Acknowledgments: The authors thank the adolescents and adults with sickle cell disease, the providers, and the community stakeholders who completed the interviews and surveys. The authors also acknowledge the SCCCI co-investigators for their contributions to this project, including Michael Bell, MD, Ward Hagar, MD, Christine Hoehner, FNP, Kimberly Major, MSW, Anne Marsh, MD, Lynne Neumayr, MD, and Ted Wun, MD. We also thank Kamilah Bailey, Jameelah Hodge, Jennifer Kim, Michael Rowland, Adria Stauber, Amber Fearon, and Shanda Robertson, and the Sickle Cell Data Collection Program for their contributions.

Corresponding author: Marsha J. Treadwell, PhD, University of California San Francisco Benioff Children’s Hospital Oakland, 747 52nd St., Oakland, CA 94609; [email protected].

Financial disclosures: None.

Funding/support: This work was supported by grant # 1U01HL134007 from the National Heart, Lung, and Blood Institute to the University of California San Francisco Benioff Children’s Hospital Oakland.

From the University of California San Francisco (Dr. Treadwell, Dr. Hessler, Yumei Chen, Swapandeep Mushiana, Dr. Potter, and Dr. Vichinsky), the University of California Los Angeles (Dr. Jacob), and the University of California Berkeley (Alex Chen).

Abstract

• Objective: Adolescents and adults with sickle cell disease (SCD) face pervasive disparities in health resources and outcomes. We explored barriers to and facilitators of care to identify opportunities to support implementation of evidence-based interventions aimed at improving care quality for patients with SCD.
• Methods: We engaged a representative sample of adolescents and adults with SCD (n = 58), health care providers (n = 51), and community stakeholders (health care administrators and community-based organization leads (n = 5) in Northern California in a community-based needs assessment. We conducted group interviews separately with participant groups to obtain in-depth perspectives. Adolescents and adults with SCD completed validated measures of pain interference, quality of care, self-efficacy, and barriers to care. Providers and community stakeholders completed surveys about barriers to SCD care.
• Results: We triangulated qualitative and quantitative data and found that participants with SCD (mean age, 31 ± 8.6 years), providers, and community stakeholders emphasized the social and emotional burden of SCD as barriers. Concrete barriers agreed upon included insurance and lack of resources for addressing pain impact. Adolescents and adults with SCD identified provider issues (lack of knowledge, implicit bias), transportation, and limited social support as barriers. Negative encounters with the health care system contributed to 84% of adolescents and adults with SCD reporting they chose to manage severe pain at home. Providers focused on structural barriers: lack of access to care guidelines, comfort level with and knowledge of SCD management, and poor care coordination.
• Conclusion: Strategies for improving access to compassionate, evidence-based quality care, as well as strategies for minimizing the burden of having SCD, are warranted for this medically complex population.

Keywords: barriers to care; quality of care; care access; care coordination.

Sickle cell disease (SCD), an inherited chronic medical condition, affects about 100,000 individuals in the United States, a population that is predominantly African American.¹ These individuals experience multiple serious and life-threatening complications, most frequently recurrent vaso-occlusive pain episodes,² and they require interactions with multidisciplinary specialists from childhood. Because of advances in treatments, the majority are reaching adulthood; however, there is a dearth of adult health care providers with the training and expertise to manage their complex medical needs.³ Other concrete barriers to adequate SCD care include insurance and distance to comprehensive SCD centers.^4,5

Social, behavioral, and emotional factors may also contribute to challenges with SCD management. SCD may limit daily functional abilities and lead to diminished overall quality of life.^6,7 Some adolescents and adults may require high doses of opioids, which contributes to health care providers’ perceptions that there is a high prevalence of drug addiction in the population.^8,9 These providers express negative attitudes towards adults with SCD, and, consequently, delay medication administration when it is acutely needed and provide otherwise suboptimal treatment.^8,10,11 Adult care providers may also be uncomfortable with prescribing and managing disease-modifying therapies (blood transfusion, hydroxyurea) that have established efficacy.^12-17

As 1 of 8 programs funded by the National Heart, Lung, and Blood Institute’s (NHLBI) Sickle Cell Disease Implementation Consortium (SCDIC), we are using implementation science to reduce barriers to care and improve quality of care and health care outcomes in SCD.^18,19 Given that adolescents and adults with SCD experience high mortality, severe pain, and progressive decline in their ability to function day to day, and also face lack of access to knowledgeable, compassionate providers in primary and emergency settings, the SCDIC focuses on individuals aged 15 to 45 years.^6,8,9,11,12

Our regional SCDIC program, the Sickle Cell Care Coordination Initiative (SCCCI), brings together researchers, clinicians, adolescents, and adults with SCD and their families, dedicated community members, policy makers, and administrators to identify and address barriers to health care within 5 counties in Northern California. One of our first steps was to conduct a community-based needs assessment, designed to inform implementation of evidence-based interventions, accounting for unique contextual factors in our region.

Conceptual Framework for Improving Medical Practice

Our needs assessment is guided by Solberg’s Conceptual Framework for Improving Medical Practice (Figure 1).²⁰ Consistent with the overarching principles of the SCDIC, this conceptual framework focuses on the inadequate implementation of evidence-based guidelines, and on the need to first understand multifactorial facilitators and barriers to guideline implementation in order to effect change. The framework identifies 3 main elements that must be present to ensure improvements in quality-of-care processes and patient outcomes: priority, change process capability, and care process content. Priority refers to ample resource allocation for the specific change, as well as freedom from competing priorities for those implementing the change. Change process capability includes strong, effective leadership, adequate infrastructure for managing change (including resources and time), change management skills at all levels, and an established clinical information system. Care process content refers to context and systems-level changes, such as delivery system redesign as needed, support for self-management to lessen the impact of the disease, and decision support.^21-23

The purpose of our community-based needs assessment was to evaluate barriers to care and quality of care in SCD, within Solberg’s conceptual model for improving medical practice. The specific aims were to evaluate access and barriers to care (eg, lack of provider expertise and training, health care system barriers such as poor care coordination and provider communication); evaluate quality of care; and assess patient needs related to pain, pain interference, self-efficacy, and self-management for adolescents and adults with SCD. We gathered the perspectives of a representative community of adolescents and adults with SCD, their providers, and community stakeholders in order to examine barriers, quality of life and care, and patient experiences in our region.

Methods

Design

In this cross-sectional study, adolescents and adults with SCD, their providers, and community stakeholders participated in group or individual qualitative interviews and completed surveys between October 2017 and March 2018.

Setting and Sample

Recruitment flyers were posted on a regional SCD-focused website, and clinical providers or a study coordinator introduced information about the needs assessment to potential participants with SCD during clinic visits at the participating centers. Participants with SCD were eligible if they had any diagnosis of SCD, were aged 15 to 48 years, and received health services within 5 Northern California counties (Alameda, Contra Costa, Sacramento, San Francisco, and Solano). They were excluded if they did not have a SCD diagnosis or had not received health services within the catchment area. As the project proceeded, participants were asked to refer other adolescents and adults with SCD for the interviews and surveys (snowball sampling). Our goal was to recruit 50 adolescents and adults with SCD into the study, aiming for 10 representatives from each county.

Providers and community stakeholders were recruited via emails, letters and informational flyers. We engaged our partner, the Sickle Cell Data Collection Program,² to generate a list of providers and institutions that had seen patients with SCD in primary, emergency, or inpatient settings in the region. We contacted these institutions to describe the SCCCI and invite participation in the needs assessment. We also invited community-based organization leads and health care administrators who worked with SCD to participate. Providers accessed confidential surveys via a secure link on the study website or completed paper versions. Common data collected across providers included demographics and descriptions of practice settings.

Participants were eligible to be part of the study if they were health care providers (physicians and nurses) representing hematology, primary care, family medicine, internal medicine, or emergency medicine; ancillary staff (social work, psychology, child life); or leaders or administrators of clinical or sickle cell community-based organizations in Northern California (recruitment goal of n = 50). Providers were excluded if they practiced in specialties other than those noted or did not practice within the region.

Data Collection Procedures

After providing assent/consent, participating adolescents and adults with SCD took part in individual and group interviews and completed survey questionnaires. All procedures were conducted in a private space in the sickle cell center or community. Adolescents and adults with SCD completed the survey questionnaire on a tablet, with responses recorded directly in a REDCap (Research Electronic Data Capture) database,²⁴ or on a paper version. Interviews lasted 60 (individual) to 90 (group) minutes, while survey completion time was 20 to 25 minutes. Each participant received a gift card upon completion as an expression of appreciation. All procedures were approved by the institutional review boards of the participating health care facilities.

Group and Individual Interviews

Participants with SCD and providers were invited to participate in a semi-structured qualitative interview prior to being presented with the surveys. Adolescents and adults with SCD were interviewed about barriers to care, quality of care, and pain-related experiences. Providers were asked about barriers to care and treatments. Interview guides were modified for community-based organization leaders and health care administrators who did not provide clinical services. Interview guides can be found in the Appendix. Interviews were conducted by research coordinators trained in qualitative research methods by the first author (MT). As appropriate with semi-structured interviews, the interviewers could word questions spontaneously, change the order of questions for ease of flow of conversation, and inform simultaneous coding of interviews with new themes as those might arise, as long as they touched on all topics within the interview guide.²⁵ The interview guides were written, per qualitative research standards, based on the aims and purpose of the research,²⁶ and were informed by existing literature on access and barriers to care in SCD, quality of care, and the needs of individuals with SCD, including in relation to impact of the disease, self-efficacy, and self-management.

Interviewees participated in either individual or group interviews, but not both. The decision for which type of interview an individual participated in was based on 2 factors: if there were not comparable participants for group interviews (eg, health care administrator and community-based organization lead), these interviews were done individually; and given that we were drawing participants from a 5-county area in Northern California, scheduling was challenging for individuals with SCD with regard to aligning schedules and traveling to a central location where the group interviews were conducted. Provider group interviews were easier to arrange because we could schedule them at the same time as regularly scheduled meetings at the participants’ health care institutions.

Interview Data Gathering and Analysis

Digital recordings of the interviews were cleaned of any participant identifying data and sent for transcription to an outside service. Transcripts were reviewed for completeness and imported into NVivo (www.qsrinternational.com), a qualitative data management program.

A thematic content analysis and deductive and inductive approaches were used to analyze the verbatim transcripts generated from the interviews. The research team was trained in the use of NVivo software to facilitate the coding process. A deductive coding scheme was initially used based on existing concepts in the literature regarding challenges to optimal SCD care, with new codes added as the thematic content analyses progressed. The initial coding, pattern coding, and use of displays to examine the relationships between different categories were conducted simultaneously.^27,28 Using the constant comparative method, new concepts from participants with SCD and providers could be incorporated into subsequent interviews with other participants. For this study, the only additional concepts added were in relation to participant recruitment and retention in the SCDIC Registry. Research team members coded transcripts separately and came together weekly, constantly comparing codes and developing the consensus coding scheme. Where differences between coders existed, code meanings were discussed and clarified until consensus was reached.²⁹

Quantitative data were analyzed using SPSS (v. 25, Chicago, IL). Descriptive statistics (means, standard deviations, frequencies, percentages) were used to summarize demographics (eg, age, gender, and race), economic status, and type of SCD. No systematic differences were detected from cases with missing values. Scale reliabilities (ie, Cronbach α) were evaluated for self-report measures.

Measurement

Adolescents and adults with SCD completed items from the PhenX Toolkit (consensus measures for Phenotypes and eXposures), assessing sociodemographics (age, sex, race, ethnicity, educational attainment, occupation, marital status, annual income, insurance), and clinical characteristics (sickle cell diagnosis and emergency department [ED] and hospital utilization for pain).³⁰

Pain Interference Short Form (Patient-Reported Outcomes Measurement Information System [PROMIS]). The Pain Interference Form consists of 8 items that assess the degree to which pain interfered with day-to-day activities in the previous 7 days at home, including impacts on social, cognitive, emotional, and physical functioning; household chores and recreational activities; sleep; and enjoyment in life. Reliability and validity of the PROMIS Pain Interference Scale has been demonstrated, with strong negative correlations with Physical Function Scales (r = 0.717, P < 0.01), indicating that higher scores are associated with lower function (β = 0.707, P < 0.001).³¹ The Cronbach α estimate for the other items on the pain interference scale was 0.99. Validity analysis indicated strong correlations with pain-related domains: BPI Interference Subscale (rho = 0.90), SF-36 Bodily Pain Subscale (rho = –0.84), and 0–10 Numerical Rating of Pain Intensity (rho = 0.48).³²

Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Quality of Care (QOC). ASCQ-Me QOC consists of 27 items that measure the quality of care that adults with SCD have received from health care providers.³³ There are 3 composites: provider communication (quality of patient and provider communication), ED care (quality of care in the ED), and access (to routine and emergency care). Internal consistency reliability for all 3 composites is greater than 0.70. Strong correlations of the provider communication composite with overall ratings of routine care (r = 0.65) and overall provider ratings (r = 0.83) provided evidence of construct validity. Similarly, the ED care composite was strongly correlated with overall ratings of QOC in the ED, and the access composite was highly correlated with overall evaluations of ED care (r = 0.70). Access, provider interaction, and ED care composites were reliable (Cronbach α, 0.70–0.83) and correlated with ratings of global care (r = 0.32–0.83), further indicating construct validity.³³

Sickle Cell Self-Efficacy Scale (SCSES). The SCSES is a 9-item, self-administered questionnaire measuring perceptions of the ability to manage day-to-day issues resulting from SCD. SCSES items are scored on a 5-point scale ranging from Not sure at all (1) to Very sure (5). Individual item responses are summed to give an overall score, with higher scores indicating greater self-efficacy. The SCSES has acceptable reliability (r = 0.45, P < 0.001) and validity (α = 0.89).^34,35

Sickle Cell Disease Barriers Checklist. This checklist consists of 53 items organized into 8 categories: insurance, transportation, accommodations and accessibility, provider knowledge and attitudes, social support, individual barriers such as forgetting or difficulties understanding instructions, emotional barriers (fear, anger), and disease-related barriers. Participants check applicable barriers, with a total score range of 0 to 53 and higher scores indicating more barriers to care. The SCD Barriers Checklist has demonstrated face validity and test-retest reliability (Pearson r = 0.74, P < 0.05).⁵

ED Provider Checklist. The ED provider survey is a checklist of 14 statements pertaining to issues regarding patient care, with which the provider rates level of agreement. Items representing the attitudes and beliefs of providers towards patients with SCD are rated on a Likert-type scale, with level of agreement indicated as 1 (strongly disagree) to 6 (strongly agree). The positive attitudes subscale consists of 4 items (Cronbach α= 0.85), and the negative attitudes subscale consists of 6 items (Cronbach α = 0.89). The Red-Flag Behaviors subscale includes 4 items that indicate behavior concerns about drug-seeking, such as requesting specific narcotics and changing behavior when the provider walks in.^8,36,37

Sickle cell and primary care providers also completed a survey consisting of sets of items compiled from existing provider surveys; this survey consisted of a list of 16 barriers to using opioids, which the providers rated on a 5-point Likert-type scale (1, not a barrier; 5, complete barrier).^13,16,38 Providers indicated their level of experience with caring for patients with SCD; care provided, such as routine health screenings; and comfort level with providing preventive care, managing comorbidities, and managing acute and chronic pain. Providers were asked what potential facilitators might improve care for patients with SCD, including higher reimbursement, case management services, access to pain management specialists, and access to clinical decision-support tools. Providers responded to specific questions about management with hydroxyurea (eg, criteria for, barriers to, and comfort level with prescribing).³⁹ The surveys are included in the Appendix.

Triangulation

Data from the interviews and surveys were triangulated to enhance understanding of results generated from the different data sources.⁴⁰ Convergence of findings, different facets of the same phenomenon, or new perspectives were examined.

Qualitative Data

Adolescents and adults with SCD (n = 55) and health care providers and community stakeholders (n = 56) participated in group or individual interviews to help us gain an in-depth understanding of the needs and barriers related to SCD care in our 5-county region. Participants with SCD described their experiences, which included stigma, racism, labeling, and, consequently, stress. They also identified barriers such as lack of transportation, challenges with insurance, and lack of access to providers who were competent with pain management. They reported that having SCD in a health care system that was unable to meet their needs was burdensome.

Barriers to Care and Treatments. Adolescents and adults indicated that SCD and its sequelae posed significant barriers to health care. Feelings of tiredness and pain make it more difficult for them to seek care. The emotional burden of SCD (fear and anger) was a frequently cited barrier, which was fueled by previous negative encounters with the health care system. All adolescents and adults with SCD reported that they knew of stigma in relation to seeking pain management that was pervasive and long-standing, and the majority reported they had directly experienced stigma. They reported that being labeled as “drug-seekers” was typical when in the ED for pain management. Participants articulated unconscious bias or overt racism among providers: “people with sickle cell are Black ... and Black pain is never as valuable as White pain” (25-year-old male). Respondents with SCD described challenges to the credibility of their pain reports in the ED. They reported that ED providers expressed doubts regarding the existence and/or severity of their pain, consequently creating a feeling of disrespect for patients seeking pain relief. The issue of stigma was mentioned by only 2 of 56 providers during their interviews.

Lack of Access to Knowledgeable, Compassionate Providers. Lack of access to knowledgeable care providers was another prevalent theme expressed by adolescents and adults with SCD. Frustration occurred when providers did not have knowledge of SCD and its management, particularly pain assessment. Adolescents and adults with SCD noted the lack of compassion among providers: “I’ve been kicked out of the hospital because they felt like okay, well we gave you enough medication, you should be all right” (29-year-old female). Providers specifically mentioned lack of compassion and knowledge as barriers to SCD care much less often during their interviews compared with the adolescents and adults with SCD.

Health Care System Barriers. Patient participants often expressed concerns about concrete and structural aspects of care. Getting to their appointments was a challenge for half of the interviewees, as they either did not have access to a vehicle or could not afford to travel the needed distance to obtain quality care. Even when hospitals were accessible by public transportation, those with excruciating pain understandably preferred a more comfortable and private way to travel: “I would like to change that, something that will be much easier, convenient for sickle cell patients that do suffer with pain, that they don’t have to travel always to see the doctor” (30-year-old male).

Insurance and other financial barriers also played an important role in influencing decisions to seek health care services. Medical expenses were not covered, or co-pays were too high. The Medicaid managed care system could prevent access to knowledgeable providers who were not within network. Such a lack of access discouraged some adolescents and adults with SCD from seeking acute and preventive care.

Transition From Pediatric to Adult Care. Interviewees with SCD expressed distress about the gap between pediatric and adult care. They described how they had a long-standing relationship with their medical providers, who were familiar with their medical background and history from childhood. Adolescent interviewees reported an understanding of their own pain management as well as adherence to and satisfaction with their individualized pain plans. However, adults noted that satisfaction plummeted with increasing age due to the limited number of experienced adult SCD providers, which was compounded by negative experiences (stigma, racism, drug-seeking label).

One interviewee emphasized the difficulty of finding knowledgeable providers after transition: “When you’re a pediatric sickle cell [patient], you have the doctors there every step of the way, but not with adult sickle cell… I know when I first transitioned I never felt more alone in my life… you look at that ER doctor kind of with the same mindset as you would your hematologist who just hand walked you through everything. And adult care providers were a lot more blunt and cold and they’re like… ‘I don’t know; I’m not really educated in sickle cell.’” A sickle cell provider shared his insight about the problem of transitioning: “I think it’s particularly challenging because we, as a community, don’t really set them up for success. It’s different from other chronic conditions [in that] it’s much harder to find an adult sickle cell provider. There’s not a lot of adult hematologists that will take care of our adult patients, and so I know statistically, there’s like a drop-down in the overall outcomes of our kids after they age out of our pediatric program.”

Self-Management, Supporting Hydroxyurea Use. Interview participants with SCD reported using a variety of methods to manage pain at home and chose to go to the ED only when the pain became intolerable. Patients and providers expressed awareness of different resources for managing pain at home, yet they also indicated that these resources have not been consolidated in an accessible way for patients and families. Some resources cited included heat therapy, acupuncture, meditation, medical marijuana, virtual reality devices, and pain medications other than opioids.

Patients and providers expressed the need for increasing awareness and education about hydroxyurea. Many interview participants with SCD were concerned about side effects, multiple visits with a provider during dose titration, and ongoing laboratory monitoring. They also expressed difficulties with scheduling multiple appointments, depending on access to transportation and limited provider clinic hours. They were aware of strategies for improving adherence with hydroxyurea, including setting phone alarms, educating family members about hydroxyurea, and eliciting family support, but expressed needing help to consistently implement these strategies.

Safe Opioid Prescribing. Adult care providers expressed concerns about safe opioid prescribing for patients with SCD. They were reluctant to prescribe opioid doses needed to adequately control SCD pain. Providers expressed uncertainty and fear or concern about medical/legal liability or about their judgment about what’s safe and not safe for patients with chronic use/very high doses of opioids. “I know we’re in like this opiate epidemic here in this country but I feel like these patients don’t really fit under that umbrella that the problem is coming from so [I am] just trying to learn more about how to take care of them.”

Care Coordination and Provider Communication. Adolescents and adults with SCD reported having positive experiences—good communication, established trust, and compassionate care—with their usual providers. However, they perceived that ED physicians and nurses did not really care about them. Both interviewees with SCD and providers recognized the importance of good communication in all settings as the key to overcoming barriers to receiving quality care. All agreed on the importance of using individual pain plans so that all providers, especially ED providers, can be more at ease with treating adolescents and adults with SCD.

Quantitative Data: Adolescents and Adults With SCD

Fifty-eight adolescents and adults with SCD (aged 15 to 48 years) completed the survey. Three additional individuals who did not complete the interview completed the survey. Reasons for not completing the interview included scheduling challenges (n = 2) or a sickle cell pain episode (n = 1). The average age of participants was 31 years ± 8.6, more than half (57%) were female, and the majority (93%) were African American (Table 1). Most (71%) had never been married. Half (50%) had some college or an associate degree, and 40% were employed and reported an annual household income of less than $30,000. Insurance coverage was predominantly Medi-Cal (Medicaid, 69%). The majority of participants resided in Alameda (34.5%) or Contra Costa (21%) counties. The majority of sickle cell care was received in Alameda County, whether outpatient (52%), inpatient (40%), or ED care (41%). The majority (71%) had a diagnosis of SCD hemoglobin SS.

Pain. More than one-third of individuals with SCD reported 1 or 2 ED visits for pain in the previous 6 months (34%), and more than 3 hospitalizations (36%) related to pain in the previous year (Table 2). The majority (85%) reported having severe pain at home in the previous 6 months that they did not seek health care for, consistent with their reports in the qualitative interviews. More than half (59%) reported 4 or more of these severe pain episodes that led to inability to perform daily activities for 1 week or more. While pain interference on the PROMIS Pain Interference Short Form on average (T-score, 59.6 ± 8.6) was similar to that of the general population (T-score, 50 ± 10), a higher proportion of patients with SCD reported pain interference compared with the general population. The mean self-efficacy (confidence in ability to manage complications of SCD) score on the SCSES of 30.0 ± 7.3 (range, 9–45) was similar to that of other adults with SCD (mean, 32.2 ± 7.0). Twenty-five percent of the present sample had a low self-efficacy score (< 25).

Barriers to Care and Treatments. Consistent with the qualitative data, SCD-related symptoms such as tiredness (64%) and pain (62%) were reported most often as barriers to care (Table 3). Emotions (> 25%) such as worry/fear, frustration/anger, and lack of confidence were other important barriers to care. Provider knowledge and attitudes were cited next most often, with 38% of the sample indicating “Providers accuse me of drug-seeking” and “It is hard for me to find a provider who has enough experiences with or knowledge about SCD.” Participants expressed that they were not believed when in pain and “I am treated differently from other patients.” Almost half of respondents cited “I am not seen quickly enough when I am in pain” as a barrier to their care.

Consistent with the qualitative data, transportation barriers (not having a vehicle, costs of transportation, public transit not easy to get to) were cited by 55% of participants. About half of participants reported that insurance was an important barrier, with high co-pays and medications and other services not covered. In addition, gathering approvals was a long and fragmented process, particularly for consultations among providers (hematology, primary care provider, pain specialist). Furthermore, insurance provided limited choices about location for services.

Participants reported social support system burnout (22%), help needed with daily activities (21%), and social isolation or generally not having enough support (33%) as ongoing barriers. Difficulties were encountered with self-management (eg, taking medications on time or making follow-up appointments, 19%), with 22% of participants finding the health care system confusing or hard to understand. Thirty percent reported “Places for me to go to learn how to stay well are not close by or easy to get to.” ”Worry about side effects” (33%) was a common barrier to hydroxyurea use. Participants described “forgetting to take the medicine,” “tried before but it did not work,” “heard scary things” about hydroxyurea, and “not interested in taking another medicine” as barriers.

Quality of Care. More than half (51%) of the 53 participants who had accessed health care in the previous year rated their overall health care as poor on the ASCQ-Me QOC measure. This was significantly higher compared to the reports from more than 47,000 adults with Medicaid in 2017 (16%),⁴¹ and to the 2008-2009 report from 556 adults with SCD from across the United States (37%, Figure 2).³³ The major contributor to these poor ratings for participants in our sample was low satisfaction with ED care.

Sixty percent of the 42 participants who had accessed ED care in the past year indicated “never” or “sometimes” to the question “When you went to the ED for care, how often did you get it as soon as you wanted?” compared with only 16% of the 2017 adult Medicaid population responding (n = 25,789) (Figure 3). Forty-seven percent of those with an ED visit indicated that, in the previous 12 months, they had been made to wait “more than 2 hours before receiving treatment for acute pain in the ED.” However, in the previous 12 months, 39% reported that their wait time in the ED had been only “between five minutes and one hour.”

On the ASCQ-Me QOC Access to Care composite measure, 33% of 42 participants responding reported they were seen at a routine appointment as soon as they would have liked. This is significantly lower compared to 56% of the adult Medicaid population responding to the same question. Reports of provider communication (Provider Communication composite) for adolescents and adults with SCD were comparable to reports of adults with SCD from the ASCQ-Me field test,³³ but adults with Medicaid reported higher ratings of quality communication behaviors (Figure 4).^33,41 Nearly 60% of both groups with SCD reported that providers “always” performed quality communication behaviors—listened carefully, spent enough time, treated them with respect, and explained things well—compared with more than 70% of adults with Medicaid.

Participants from all counties reported the same number of barriers to care on average (3.3 ± 2.1). Adolescents and adults who reported more barriers to care also reported lower satisfaction with care (r = –0.47, P < 0.01) and less confidence in their ability to manage their SCD (self-efficacy, r = – 0.36, P < 0.05). Female participants reported more barriers to care on average compared with male participants (2.6 ± 2.4 vs 1.4 ± 2.0, P = 0.05). Participants with higher self-efficacy reported lower pain ratings (r = –0.47, P < 0.001).

Quantitative Data: Health Care Providers

Providers (n = 56) and community stakeholders (2 leaders of community-based organizations and 3 health care administrators) were interviewed, with 29 also completing the survey. The reason for not completing (n = 22) was not having the time once the interview was complete. A link to the survey was sent to any provider not completing at the time of the interview, with 2 follow-up reminders. The majority of providers were between the ages of 31 and 50 years (46.4%), female (71.4%), and white (66.1%) (Table 4). None were of Hispanic, Latinx, or Spanish origin. Thirty-six were physicians (64.3%), and 16 were allied health professionals (28.6%). Of the 56 providers, 32 indicated they had expertise caring for patients with SCD (57.1%), 14 were ED providers (25%), and 5 were primary care providers. Most of the providers practiced in an urban setting (91.1%).

Barriers to Care: ED Provider Perspectives. Nine of 14 ED providers interviewed completed the survey on their perspectives regarding barriers to care in the ED, difficulty with follow-ups, ED training resources, and pain control for patients with SCD. ED providers (n = 8) indicated that “provider attitudes” were a barrier to care delivery in the ED for patients with SCD. Some providers (n = 7) indicated that “implicit bias,” “opioid epidemic,” “concern about addiction,” and “patient behavior” were barriers. Respondents indicated that “overcrowding” (n = 6) and “lack of care pathway/protocol” (n = 5) were barriers. When asked to express their level of agreement with statements about SCD care in the ED, respondents disagreed/strongly disagreed (n = 5) that they were “able to make a follow-up appointment” with a sickle cell specialist or primary care provider upon discharge from the ED, and others disagreed/strongly disagreed (n = 4) that they were able to make a “referral to a case management program.”

ED training and resources. Providers agreed/strongly agreed (n = 8) that they had the knowledge and training to care for patients with SCD, that they had access to needed medications, and that they had access to knowledgeable nursing staff with expertise in SCD care. All 9 ED providers indicated that they had sufficient physician/provider staffing to provide good pain management to persons with SCD in the ED.

Pain control in the ED. Seven ED providers indicated that their ED used individualized dosing protocols to treat sickle cell pain, and 5 respondents indicated their ED had a protocol for treating sickle cell pain. Surprisingly, only 3 indicated that they were aware of the NHLBI recommendations for the treatment of vaso-occlusive pain.

Barriers to Care: Primary Care Provider Perspectives. Twenty providers completed the SCD provider section of the survey, including 17 multidisciplinary SCD providers from 4 sickle cell special care centers and 3 community primary care providers. Of the 20, 12 were primary care providers for patients with SCD (Table 4).

Patient needs. Six primary care providers indicated that the medical needs of patients with SCD were being met, but none indicated that the behavioral health or mental health needs were being met.

Managing SCD comorbidities. Five primary care providers indicated they were very comfortable providing preventive ambulatory care to patients with SCD. Six indicated they were very comfortable managing acute pain episodes, but none were very comfortable managing comorbidities such as pulmonary hypertension, diabetes, or chronic pain.

Barriers to opioid use. Only 3 of 12 providers reviewing a list of 15 potential barriers to the use of opioids for SCD pain management indicated a perceived lack of efficacy of opioids, development of tolerance and dependence, and concerns about community perceptions as barriers. Two providers selected potential for diversion as a moderate barrier to opioid use.

Barriers to hydroxyurea use. Eight of 12 providers indicated that the common reasons that patients/families refuse hydroxyurea were “worry about side effects”; 7 chose “don’t want to take another medicine,” and 6 chose “worry about carcinogenic potential.” Others (n = 10) indicated that “patient/family adherence with hydroxyurea” and “patient/family adherence with required blood tests” were important barriers to hydroxyurea use. Eight of the 12 providers indicated that they were comfortable with managing hydroxyurea in patients with SCD.

Care redesign. Twenty SCD and primary care providers completed the Care Redesign section of the survey. Respondents (n = 11) indicated that they would see more patients with SCD if they had accessible case management services available without charge or if patient access to transportation to clinic was also available. Ten indicated that they would see more patients with SCD if they had an accessible community health worker (who understands patient’s/family’s social situation) and access to a pain management specialist on call to answer questions and who would manage chronic pain. All (n = 20) were willing to see more patients with SCD in their practices. Most reported that a clinical decision-support tool for SCD treatment (n = 13) and avoidance of complications (n = 12) would be useful.

Discussion

We evaluated access and barriers to care, quality of care, care coordination, and provider communication from the perspectives of adolescents and adults with SCD, their care providers, and community stakeholders, within the Solberg conceptual model for quality improvement. We found that barriers within the care process content domain (context and systems) were most salient for this population of adolescents and adults with SCD, with lack of provider knowledge and poor attitudes toward adolescents and adults with SCD, particularly in the ED, cited consistently by participant groups. Stigmatization and lack of provider compassion that affected the quality of care were particularly problematic. These findings are consistent with previous reports.^42,43 Adult health care (particularly ED) provider biases and negative attitudes have been recognized as major barriers to optimal pain management in SCD.^8,11,44,45 Interestingly, ED providers in our needs assessment indicated that they felt they had the training and resources to manage patients with SCD. However, only a few actually reported knowing about the NHLBI recommendations for the treatment of vaso-occlusive pain.

Within the care process content domain, we also found that SCD-related complications and associated emotions (fear, worry, anxiety), compounded by lack of access to knowledgeable and compassionate providers, pose a significant burden. Negative encounters with the health care system contributed to a striking 84% of patient participants choosing to manage severe pain at home, with pain seriously interfering with their ability to function on a daily basis. ED providers agreed that provider attitudes and implicit bias pose important barriers to care for adolescents and adults with SCD. Adolescents and adults with SCD wanted, and understood the need, to enhance self-management skills. Both they and their providers agreed that barriers to hydroxyurea uptake included worries about potential side effects, challenges with adherence to repeated laboratory testing, and support with remembering to take the medicine. However, providers uniformly expressed that access to behavioral and mental health services were, if not nonexistent, impossible to access.

Participants with SCD and their providers reported infrastructural challenges (change process capability), as manifested in limitations with accessing acute and preventive care due to transportation- and insurance- related issues. There were health system barriers that were particularly encountered during the transition from pediatric to adult care. These findings are consistent with previous reports that have found fewer interdisciplinary services available in the adult care settings compared with pediatrics.^46,47 Furthermore, adult care providers were less willing to accept adults with SCD because of the complexity of their management, for which the providers did not have the necessary expertise.^3,48-50 In addition, both adolescents and adults with SCD and primary care providers highlighted the inadequacies of the current system in addressing the chronic pain needs of this population. Linking back to the Solberg conceptual framework, our needs assessment results confirm the important role of establishing SCD care as a priority within a health care system—this requires leadership and vision. The vision and priorities must be implemented by effective health care teams. Multilevel approaches or interventions, when implemented, will lead to the desired outcomes.

Findings from our needs assessment within our 5-county region mirror needs assessment results from the broader consortium.⁵¹ The SCDIC has prioritized developing an intervention that addresses the challenges identified within the care process domain by directly enhancing provider access to patient individualized care plans in the electronic health record in the ED. Importantly, ED providers will be asked to view a short video that directly challenges bias and stigma in the ED. Previous studies have indeed found that attitudes can be improved by providers viewing short video segments of adults with SCD discussing their experiences.^36,52 This ED protocol will be one of the interventions that we will roll out in Northern California, given the significance of negative ED encounters reported by needs assessment participants. An additional feature of the intervention is a script for adults with SCD that guides them through introducing their individualized pain plan to their ED providers, thereby enhancing their self-efficacy in a situation that has been so overwhelmingly challenging.

We will implement a second SCDIC intervention that utilizes a mobile app to support self-management on the part of the patient, by supporting motivation and adherence with hydroxyurea.⁵³ A companion app supports hydroxyurea guideline adherence on the part of the provider, in keeping with one of our findings that providers are in need of decision-support tools. Elements of the intervention also align with our findings related to the importance of a support system in managing SCD, in that participants will identify a supportive partner who will play a specific role in supporting their adherence with hydroxyurea.

On our local level, we have, by necessity, partnered with leaders and community stakeholders throughout the region to ensure that these interventions to improve SCD care are prioritized. Grant funds provide initial resources for the SCDIC interventions, but our partnering health care administrators and medical directors must ensure that participating ED and hematology providers are free from competing priorities in order to implement the changes. We have partnered with a SCD community-based organization that is designing additional educational presentations for local emergency medicine providers, with the goal to bring to life very personal stories of bias and stigma within the EDs that directly contribute to decisions to avoid ED care despite severe symptoms.

Although we attempted to obtain samples of adolescents and adults with SCD and their providers that were representative across the 5-county region, the larger proportion of respondents were from 1 county. We did not assess concerns of age- and race-matched adults in our catchment area, so we cannot definitively say that our findings are unique to SCD. However, our results are consistent with findings from the national sample of adults with SCD who participated in the ASCQ-Me field test, and with results from the SCDIC needs assessment.^33,51 Interviews and surveys are subject to self-report bias and, therefore, may or may not reflect the actual behaviors or thoughts of participants. Confidence is increased in our results given the triangulation of expressed concerns across participant groups and across data collection strategies. The majority of adolescents and adults with SCD (95%) completed both the interview and survey, while 64% of ED providers interviewed completed the survey, compared with 54% of SCD specialists and primary care providers. These response rates are more than acceptable within the realm of survey response rates.^54,55

Although we encourage examining issues with care delivery within the conceptual framework for quality improvement presented, we recognize that grant funding allowed us to conduct an in-depth needs assessment that might not be feasible in other settings. Still, we would like readers to understand the importance of gathering data for improvement in a systematic manner across a range of participant groups, to ultimately inform the development of interventions and provide for evaluation of outcomes as a result of the interventions. This is particularly important for a disease, such as SCD, that is both medically and sociopolitically complex.

Conclusion

Our needs assessment brought into focus the multiple factors contributing to the disparities in health care experienced by adolescents and adults with SCD on our local level, and within the context of inequities in health resources and outcomes on the national level. We propose solutions that include specific interventions developed by a consortium of SCD and implementation science experts. We utilize a quality improvement framework to ensure that the elements of the interventions also address the barriers identified by our local providers and patients that are unique to our community. The pervasive challenges in SCD care, coupled with its medical complexities, may seem insurmountable, but our survey and qualitative results provide us with a road map for the way forward.

Acknowledgments: The authors thank the adolescents and adults with sickle cell disease, the providers, and the community stakeholders who completed the interviews and surveys. The authors also acknowledge the SCCCI co-investigators for their contributions to this project, including Michael Bell, MD, Ward Hagar, MD, Christine Hoehner, FNP, Kimberly Major, MSW, Anne Marsh, MD, Lynne Neumayr, MD, and Ted Wun, MD. We also thank Kamilah Bailey, Jameelah Hodge, Jennifer Kim, Michael Rowland, Adria Stauber, Amber Fearon, and Shanda Robertson, and the Sickle Cell Data Collection Program for their contributions.

Corresponding author: Marsha J. Treadwell, PhD, University of California San Francisco Benioff Children’s Hospital Oakland, 747 52nd St., Oakland, CA 94609; [email protected].

Financial disclosures: None.

Funding/support: This work was supported by grant # 1U01HL134007 from the National Heart, Lung, and Blood Institute to the University of California San Francisco Benioff Children’s Hospital Oakland.

The American College of Physicians and the American Academy of Family Physicians recently authored a guideline regarding the treatment of acute, non–low back, musculoskeletal injuries in adults in the outpatient setting. While their recommendations mirror what most clinicians currently do in their medical practices, they don’t address the multiple components of pain that include sensory, emotional, cognitive, and behavioral processes in addition to the physical discomfort.

According to the authors, musculoskeletal injuries result in more than 65 million medical visits a year with an annual estimated cost of $176.1 billion in 2010.

In summary, the guideline, which was published in the Annals of Internal Medicine, is based on a review of the best available evidence. The research reviewed by the guideline authors showed favorable results with topical NSAIDs, oral NSAIDs, oral acetaminophen, acupressure, and transcutaneous electrical nerve stimulation in reducing pain and/or improving function. The guideline authors “recommend that clinicians treat patients with acute pain from non–low back, musculoskeletal injuries with topical [NSAIDs] with or without gel as first-line therapy to reduce or relieve symptoms, including pain; improve physical function; and improve the patient’s treatment satisfaction (Grade: strong recommendation; moderate-certainty evidence).” Additionally, the guideline recommends against treating acute pain from non–low back, musculoskeletal injuries with opioids, including tramadol (Grade: conditional recommendation; low-certainty evidence).

The guideline also mentions improving function in relation to decreasing pain, which can be multifactorial.

Treating pain requires a multipronged approach. Many patients require more than one therapy to treat their pain, such as NSAIDs plus physical therapy. The ACP and AAFP did not make any recommendations for combination therapies in this guideline.

When physical therapy is needed

Nonopioid pain medications can do a great job of reducing a patient’s physical discomfort, which the evidence for these guideline demonstrates. However, much of the dysfunction caused by musculoskeletal injuries will not improve by reducing the pain alone. Physical therapy, exercise, and mobilization did not show a significant benefit in reducing symptoms in the systematic review and meta-analysis of randomized trials that appeared alongside the guideline. The type of pain, however, was not evaluated in relation to the effectiveness of these treatments. A fractured bone, for example, may heal just fine with casting and pain management, without the need for additional therapies. However, the muscles surrounding that bone can atrophy and become weak from not being used. Physical therapy may be needed to restrengthen those muscles. Therefore, a multifaceted approach is often needed, even for uncomplicated conditions.

Mental pain often comes with physical pain, and this is an aspect of care that is often neglected. It can be quite devastating for patients to not be able to do the things they were previously able to do. While this is easily recognized in professional athletes when they can no longer play, it is not so readily apparent with a mother who is just trying to take care of her kids. As doctors, especially those of us in family medicine, we should be addressing more than just physical pain.

Patients can also do activities that exacerbate their pain. As doctors, we need to be asking questions that help us determine whether a patient’s pain is caused by a particular action. Maybe that increase in shoulder pain is due to nothing more than lifting something heavy rather than a failure in a prescribed medication. Pain diaries are helpful, and clinicians don’t use them often enough.
 

How pain affects mental health

Acute injuries can also lead to disability. Many patients become quite distressed about being unable to work. They often need Famiy & Medical Leave Act forms filled out, and this task usually falls to the primary care doctor. In addition to assessing the pain, we need to be evaluating, at each visit, a patient’s level of functioning and their ability to do their job.

Every patient responds to pain differently, and it is important to evaluate patients’ mindsets regarding theirs. A patient may be in severe pain and may try to ignore it for a variety of reasons. A patient may “catastrophize” their pain, believing only the worst outcome will happen to them. Helping patients set appropriate expectations and having a positive mindset can help.

Overall, the new recommendations are a great tool as a guideline, but they are not complete enough to be the only ones used in managing acute, non–low back, musculoskeletal pain in adults.

They are very important for clinicians who may be prescribing opioid medications for patients with this type of pain. Amid an opioid crisis, it is the responsibility of every doctor to prescribe these medications appropriately. The evidence clearly shows they provide little benefit and place patients at risk of addiction.

We should all be following these recommendations as the baseline of care for acute pain. However, we need to delve deeper and manage all the components involved. We would be ignoring very real suffering in our patients if we limited our focus to only the physical discomfort.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Rutgers RWJ Medical School.

SOURCE: Ann Intern Med. 2020 Aug 18. doi: 10.7326/M19-3602.

The American College of Physicians and the American Academy of Family Physicians recently authored a guideline regarding the treatment of acute, non–low back, musculoskeletal injuries in adults in the outpatient setting. While their recommendations mirror what most clinicians currently do in their medical practices, they don’t address the multiple components of pain that include sensory, emotional, cognitive, and behavioral processes in addition to the physical discomfort.

According to the authors, musculoskeletal injuries result in more than 65 million medical visits a year with an annual estimated cost of $176.1 billion in 2010.

In summary, the guideline, which was published in the Annals of Internal Medicine, is based on a review of the best available evidence. The research reviewed by the guideline authors showed favorable results with topical NSAIDs, oral NSAIDs, oral acetaminophen, acupressure, and transcutaneous electrical nerve stimulation in reducing pain and/or improving function. The guideline authors “recommend that clinicians treat patients with acute pain from non–low back, musculoskeletal injuries with topical [NSAIDs] with or without gel as first-line therapy to reduce or relieve symptoms, including pain; improve physical function; and improve the patient’s treatment satisfaction (Grade: strong recommendation; moderate-certainty evidence).” Additionally, the guideline recommends against treating acute pain from non–low back, musculoskeletal injuries with opioids, including tramadol (Grade: conditional recommendation; low-certainty evidence).

The guideline also mentions improving function in relation to decreasing pain, which can be multifactorial.

Treating pain requires a multipronged approach. Many patients require more than one therapy to treat their pain, such as NSAIDs plus physical therapy. The ACP and AAFP did not make any recommendations for combination therapies in this guideline.

When physical therapy is needed

Nonopioid pain medications can do a great job of reducing a patient’s physical discomfort, which the evidence for these guideline demonstrates. However, much of the dysfunction caused by musculoskeletal injuries will not improve by reducing the pain alone. Physical therapy, exercise, and mobilization did not show a significant benefit in reducing symptoms in the systematic review and meta-analysis of randomized trials that appeared alongside the guideline. The type of pain, however, was not evaluated in relation to the effectiveness of these treatments. A fractured bone, for example, may heal just fine with casting and pain management, without the need for additional therapies. However, the muscles surrounding that bone can atrophy and become weak from not being used. Physical therapy may be needed to restrengthen those muscles. Therefore, a multifaceted approach is often needed, even for uncomplicated conditions.

Mental pain often comes with physical pain, and this is an aspect of care that is often neglected. It can be quite devastating for patients to not be able to do the things they were previously able to do. While this is easily recognized in professional athletes when they can no longer play, it is not so readily apparent with a mother who is just trying to take care of her kids. As doctors, especially those of us in family medicine, we should be addressing more than just physical pain.

Patients can also do activities that exacerbate their pain. As doctors, we need to be asking questions that help us determine whether a patient’s pain is caused by a particular action. Maybe that increase in shoulder pain is due to nothing more than lifting something heavy rather than a failure in a prescribed medication. Pain diaries are helpful, and clinicians don’t use them often enough.
 

How pain affects mental health

Acute injuries can also lead to disability. Many patients become quite distressed about being unable to work. They often need Famiy & Medical Leave Act forms filled out, and this task usually falls to the primary care doctor. In addition to assessing the pain, we need to be evaluating, at each visit, a patient’s level of functioning and their ability to do their job.

Every patient responds to pain differently, and it is important to evaluate patients’ mindsets regarding theirs. A patient may be in severe pain and may try to ignore it for a variety of reasons. A patient may “catastrophize” their pain, believing only the worst outcome will happen to them. Helping patients set appropriate expectations and having a positive mindset can help.

Overall, the new recommendations are a great tool as a guideline, but they are not complete enough to be the only ones used in managing acute, non–low back, musculoskeletal pain in adults.

They are very important for clinicians who may be prescribing opioid medications for patients with this type of pain. Amid an opioid crisis, it is the responsibility of every doctor to prescribe these medications appropriately. The evidence clearly shows they provide little benefit and place patients at risk of addiction.

We should all be following these recommendations as the baseline of care for acute pain. However, we need to delve deeper and manage all the components involved. We would be ignoring very real suffering in our patients if we limited our focus to only the physical discomfort.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Rutgers RWJ Medical School.

SOURCE: Ann Intern Med. 2020 Aug 18. doi: 10.7326/M19-3602.

The American College of Physicians and the American Academy of Family Physicians recently authored a guideline regarding the treatment of acute, non–low back, musculoskeletal injuries in adults in the outpatient setting. While their recommendations mirror what most clinicians currently do in their medical practices, they don’t address the multiple components of pain that include sensory, emotional, cognitive, and behavioral processes in addition to the physical discomfort.

According to the authors, musculoskeletal injuries result in more than 65 million medical visits a year with an annual estimated cost of $176.1 billion in 2010.

In summary, the guideline, which was published in the Annals of Internal Medicine, is based on a review of the best available evidence. The research reviewed by the guideline authors showed favorable results with topical NSAIDs, oral NSAIDs, oral acetaminophen, acupressure, and transcutaneous electrical nerve stimulation in reducing pain and/or improving function. The guideline authors “recommend that clinicians treat patients with acute pain from non–low back, musculoskeletal injuries with topical [NSAIDs] with or without gel as first-line therapy to reduce or relieve symptoms, including pain; improve physical function; and improve the patient’s treatment satisfaction (Grade: strong recommendation; moderate-certainty evidence).” Additionally, the guideline recommends against treating acute pain from non–low back, musculoskeletal injuries with opioids, including tramadol (Grade: conditional recommendation; low-certainty evidence).

The guideline also mentions improving function in relation to decreasing pain, which can be multifactorial.

Treating pain requires a multipronged approach. Many patients require more than one therapy to treat their pain, such as NSAIDs plus physical therapy. The ACP and AAFP did not make any recommendations for combination therapies in this guideline.

When physical therapy is needed

Nonopioid pain medications can do a great job of reducing a patient’s physical discomfort, which the evidence for these guideline demonstrates. However, much of the dysfunction caused by musculoskeletal injuries will not improve by reducing the pain alone. Physical therapy, exercise, and mobilization did not show a significant benefit in reducing symptoms in the systematic review and meta-analysis of randomized trials that appeared alongside the guideline. The type of pain, however, was not evaluated in relation to the effectiveness of these treatments. A fractured bone, for example, may heal just fine with casting and pain management, without the need for additional therapies. However, the muscles surrounding that bone can atrophy and become weak from not being used. Physical therapy may be needed to restrengthen those muscles. Therefore, a multifaceted approach is often needed, even for uncomplicated conditions.

Mental pain often comes with physical pain, and this is an aspect of care that is often neglected. It can be quite devastating for patients to not be able to do the things they were previously able to do. While this is easily recognized in professional athletes when they can no longer play, it is not so readily apparent with a mother who is just trying to take care of her kids. As doctors, especially those of us in family medicine, we should be addressing more than just physical pain.

Patients can also do activities that exacerbate their pain. As doctors, we need to be asking questions that help us determine whether a patient’s pain is caused by a particular action. Maybe that increase in shoulder pain is due to nothing more than lifting something heavy rather than a failure in a prescribed medication. Pain diaries are helpful, and clinicians don’t use them often enough.
 

How pain affects mental health

Acute injuries can also lead to disability. Many patients become quite distressed about being unable to work. They often need Famiy & Medical Leave Act forms filled out, and this task usually falls to the primary care doctor. In addition to assessing the pain, we need to be evaluating, at each visit, a patient’s level of functioning and their ability to do their job.

Every patient responds to pain differently, and it is important to evaluate patients’ mindsets regarding theirs. A patient may be in severe pain and may try to ignore it for a variety of reasons. A patient may “catastrophize” their pain, believing only the worst outcome will happen to them. Helping patients set appropriate expectations and having a positive mindset can help.

Overall, the new recommendations are a great tool as a guideline, but they are not complete enough to be the only ones used in managing acute, non–low back, musculoskeletal pain in adults.

They are very important for clinicians who may be prescribing opioid medications for patients with this type of pain. Amid an opioid crisis, it is the responsibility of every doctor to prescribe these medications appropriately. The evidence clearly shows they provide little benefit and place patients at risk of addiction.

We should all be following these recommendations as the baseline of care for acute pain. However, we need to delve deeper and manage all the components involved. We would be ignoring very real suffering in our patients if we limited our focus to only the physical discomfort.
 

Dr. Girgis practices family medicine in South River, N.J., and is a clinical assistant professor of family medicine at Rutgers RWJ Medical School.

SOURCE: Ann Intern Med. 2020 Aug 18. doi: 10.7326/M19-3602.

The long-awaited postmarketing studies of the abuse-deterrent formulation (ADF) of OxyContin (Perdue Pharma) received mixed reviews from a Food and Drug Administration joint advisory committee.

After a 2-day discussion of new research submitted by Perdue, as well as other relevant published data, most members of the Drug Safety and Risk Management and Anesthetic and Analgesic Drug Products advisory committees came to the conclusion that the reformulated drug “meaningfully” reduced abuse via intranasal administration and intravenous injection, but not overall opioid abuse or overdose.

The reformulated OxyContin “was the first out of the gate,” and “has the greatest market penetration of any ADF” so “it gives us the greatest opportunity to measure change before and after reformulation,” said committee member Traci C. Green, PhD, MSc, professor and director of the Opioid Policy Research Collaborative at Brandeis University, Waltham, Mass.

The FDA approved the original formulation of OxyContin (oxycodone hydrochloride), a mu-receptor opioid agonist, in December 1995 for the management of pain requiring daily round-the-clock opioid treatment in cases where other treatments were inadequate. It approved an ADF version of the product in April 2010.

The updated formulation incorporates polyethylene oxide, an inactive polymer that makes the tablet harder and more crush resistant. The tablet turns into a gel or glue-like substance when wet.

The new formulation is bioequivalent to the original formulation, so no additional clinical efficacy and safety studies were conducted.

At the request of the FDA, the company carried out four postmarketing studies, which the FDA also reviewed.

• A National Addictions Vigilance Intervention and Prevention Program study that included 66,897 assessments in patients undergoing evaluation for substance use or entering an opioid addiction program. Results showed a drop in up to 52% of self-reported past 30-day OxyContin injection and snorting versus comparators, including extended-release morphine and immediate-release hydrocodone.
• An analysis of 308,465 calls to U.S. poison centers showing a reduction of up to 28% for calls regarding intentional OxyContin-related exposures immediately following the drug’s reformulation. However, the FDA analysis concluded it is unclear whether the decline was attributable to the drug’s reformulation or co-occurring trends.
• A study of 63,528 individuals entering methadone clinics or treatment programs that showed a reduction of up to 27% in OxyContin abuse versus comparators. There was no information on route of abuse. Here, the FDA analysis determined the results were mixed and didn’t provide compelling evidence.
• A claims-based analysis of patients who were dispensed an opioid (297,836 OxyContin; 659,673 a comparator) that showed no evidence that the updated product affected the rate of fatal and nonfatal opioid overdoses.

During the meeting, committee members heard that opioid use in the United States peaked in 2012, with 260 million prescriptions dispensed, then declined by 41% by 2019. ADFs accounted for only 2% of prescriptions in 2019. They also heard that results of a wide variety of studies and surveys support the conclusion that misuse, abuse, and diversion of OxyContin decreased after it was reformulated.

Ultimately, the joint committee voted 20 to 7 (with 1 abstention) that the reformulated drug reduced nonoral abuse. Most members who voted in favor cited the NAVIPPRO study as a reason for their decision, but few found the strength of the evidence better than moderate.

Meeting chair Sonia Hernandez-Diaz, MD, professor of epidemiology, Harvard School of Public Health, Boston, noted the reduction in abuse may, in part, be a result of the overall reduction in opioid use.

Jon E. Zibbell, PhD, senior public health scientist, behavioral health research division, RTI International, Atlanta, who voted “no,” was disappointed there was not more data.

“We had a bunch of years for this and so many of us could have done some amazing studies” related to how abuse changed post reformulation, he said.

As for overall abuse deterrence, the committee believed the evidence was less compelling. Only two members voted that the reformulated version of the drug reduced overall abuse and only one member voted that the reformulated tablets reduced opioid overdose.

Members generally agreed that all of the studies had limitations, including retrospective designs, confounding, and potential misclassifications. Many noted the challenge of assessing abuse pre- and post reformulation given the evolving situation.

For instance, at the time the reformulated drug was launched, public health initiatives targeting opioid abuse were introduced, more treatment centers were opening, and there was a crackdown on “pill-mill” doctors.

In addition, prescribing and consumption habits were changing. Some doctors may have switched only “at-risk” patients to the reformulated opioid and there may have been “self-selection” among patients – with some potentially opting for another drug such as immediate-release oxycodone.

During the meeting, there was discussion about how to interpret a “meaningful” abuse reduction. However, there was no consensus of a percentage the reduction had to reach in order to be deemed meaningful.

Another issue discussed was the term “abuse deterrent,” which some members believed was stigmatizing and should be changed to crush resistant.

There was also concern that prescribers might consider the ADF a “safe” or less addictive opioid. Michael Sprintz, DO, clinical assistant professor, division of geriatric and palliative medicine, University of Texas Health Science Center, Houston, said ADFs might provide physicians with “a false sense of security.”

Dr. Sprintz, also founder of the Sprintz Center for Pain and Recovery, noted the importance of pain medicine physicians understanding addiction and addiction specialists understanding pain management.

Other committee members voiced concern that the reformulation results in patients switching from intravenous and intranasal abuse to oral abuse. Committed abusers can still swallow multiple pills.

Some members noted that reformulated OxyContin coincided with increased transition to heroin, which is relatively cheap and readily available. However, they recognized that proving causality is difficult.

The committee was reminded that the reformulated drug provides a significant barrier against, but doesn’t altogether eliminate, opioid abuse. With hot water and the right tools, the tablets can still be manipulated.

In addition, the reformulated drug will not solve the U.S. opioid epidemic, which requires a multifaceted approach. The opioid crisis, said Wilson Compton, MD, deputy director at the National Institute on Drug Abuse, has resulted in a “skyrocketing” of deaths linked to “tremendously potent” forms of fentanyl, emerging stimulant use issues, and the possible increase in drug overdoses linked to COVID-19.

A version of this article originally appeared on Medscape.com.

The long-awaited postmarketing studies of the abuse-deterrent formulation (ADF) of OxyContin (Perdue Pharma) received mixed reviews from a Food and Drug Administration joint advisory committee.

After a 2-day discussion of new research submitted by Perdue, as well as other relevant published data, most members of the Drug Safety and Risk Management and Anesthetic and Analgesic Drug Products advisory committees came to the conclusion that the reformulated drug “meaningfully” reduced abuse via intranasal administration and intravenous injection, but not overall opioid abuse or overdose.

The reformulated OxyContin “was the first out of the gate,” and “has the greatest market penetration of any ADF” so “it gives us the greatest opportunity to measure change before and after reformulation,” said committee member Traci C. Green, PhD, MSc, professor and director of the Opioid Policy Research Collaborative at Brandeis University, Waltham, Mass.

The FDA approved the original formulation of OxyContin (oxycodone hydrochloride), a mu-receptor opioid agonist, in December 1995 for the management of pain requiring daily round-the-clock opioid treatment in cases where other treatments were inadequate. It approved an ADF version of the product in April 2010.

The updated formulation incorporates polyethylene oxide, an inactive polymer that makes the tablet harder and more crush resistant. The tablet turns into a gel or glue-like substance when wet.

The new formulation is bioequivalent to the original formulation, so no additional clinical efficacy and safety studies were conducted.

At the request of the FDA, the company carried out four postmarketing studies, which the FDA also reviewed.

• A National Addictions Vigilance Intervention and Prevention Program study that included 66,897 assessments in patients undergoing evaluation for substance use or entering an opioid addiction program. Results showed a drop in up to 52% of self-reported past 30-day OxyContin injection and snorting versus comparators, including extended-release morphine and immediate-release hydrocodone.
• An analysis of 308,465 calls to U.S. poison centers showing a reduction of up to 28% for calls regarding intentional OxyContin-related exposures immediately following the drug’s reformulation. However, the FDA analysis concluded it is unclear whether the decline was attributable to the drug’s reformulation or co-occurring trends.
• A study of 63,528 individuals entering methadone clinics or treatment programs that showed a reduction of up to 27% in OxyContin abuse versus comparators. There was no information on route of abuse. Here, the FDA analysis determined the results were mixed and didn’t provide compelling evidence.
• A claims-based analysis of patients who were dispensed an opioid (297,836 OxyContin; 659,673 a comparator) that showed no evidence that the updated product affected the rate of fatal and nonfatal opioid overdoses.

During the meeting, committee members heard that opioid use in the United States peaked in 2012, with 260 million prescriptions dispensed, then declined by 41% by 2019. ADFs accounted for only 2% of prescriptions in 2019. They also heard that results of a wide variety of studies and surveys support the conclusion that misuse, abuse, and diversion of OxyContin decreased after it was reformulated.

Ultimately, the joint committee voted 20 to 7 (with 1 abstention) that the reformulated drug reduced nonoral abuse. Most members who voted in favor cited the NAVIPPRO study as a reason for their decision, but few found the strength of the evidence better than moderate.

Meeting chair Sonia Hernandez-Diaz, MD, professor of epidemiology, Harvard School of Public Health, Boston, noted the reduction in abuse may, in part, be a result of the overall reduction in opioid use.

Jon E. Zibbell, PhD, senior public health scientist, behavioral health research division, RTI International, Atlanta, who voted “no,” was disappointed there was not more data.

“We had a bunch of years for this and so many of us could have done some amazing studies” related to how abuse changed post reformulation, he said.

As for overall abuse deterrence, the committee believed the evidence was less compelling. Only two members voted that the reformulated version of the drug reduced overall abuse and only one member voted that the reformulated tablets reduced opioid overdose.

Members generally agreed that all of the studies had limitations, including retrospective designs, confounding, and potential misclassifications. Many noted the challenge of assessing abuse pre- and post reformulation given the evolving situation.

For instance, at the time the reformulated drug was launched, public health initiatives targeting opioid abuse were introduced, more treatment centers were opening, and there was a crackdown on “pill-mill” doctors.

In addition, prescribing and consumption habits were changing. Some doctors may have switched only “at-risk” patients to the reformulated opioid and there may have been “self-selection” among patients – with some potentially opting for another drug such as immediate-release oxycodone.

During the meeting, there was discussion about how to interpret a “meaningful” abuse reduction. However, there was no consensus of a percentage the reduction had to reach in order to be deemed meaningful.

Another issue discussed was the term “abuse deterrent,” which some members believed was stigmatizing and should be changed to crush resistant.

There was also concern that prescribers might consider the ADF a “safe” or less addictive opioid. Michael Sprintz, DO, clinical assistant professor, division of geriatric and palliative medicine, University of Texas Health Science Center, Houston, said ADFs might provide physicians with “a false sense of security.”

Dr. Sprintz, also founder of the Sprintz Center for Pain and Recovery, noted the importance of pain medicine physicians understanding addiction and addiction specialists understanding pain management.

Other committee members voiced concern that the reformulation results in patients switching from intravenous and intranasal abuse to oral abuse. Committed abusers can still swallow multiple pills.

Some members noted that reformulated OxyContin coincided with increased transition to heroin, which is relatively cheap and readily available. However, they recognized that proving causality is difficult.

The committee was reminded that the reformulated drug provides a significant barrier against, but doesn’t altogether eliminate, opioid abuse. With hot water and the right tools, the tablets can still be manipulated.

In addition, the reformulated drug will not solve the U.S. opioid epidemic, which requires a multifaceted approach. The opioid crisis, said Wilson Compton, MD, deputy director at the National Institute on Drug Abuse, has resulted in a “skyrocketing” of deaths linked to “tremendously potent” forms of fentanyl, emerging stimulant use issues, and the possible increase in drug overdoses linked to COVID-19.

A version of this article originally appeared on Medscape.com.

The long-awaited postmarketing studies of the abuse-deterrent formulation (ADF) of OxyContin (Perdue Pharma) received mixed reviews from a Food and Drug Administration joint advisory committee.

After a 2-day discussion of new research submitted by Perdue, as well as other relevant published data, most members of the Drug Safety and Risk Management and Anesthetic and Analgesic Drug Products advisory committees came to the conclusion that the reformulated drug “meaningfully” reduced abuse via intranasal administration and intravenous injection, but not overall opioid abuse or overdose.

The reformulated OxyContin “was the first out of the gate,” and “has the greatest market penetration of any ADF” so “it gives us the greatest opportunity to measure change before and after reformulation,” said committee member Traci C. Green, PhD, MSc, professor and director of the Opioid Policy Research Collaborative at Brandeis University, Waltham, Mass.

The FDA approved the original formulation of OxyContin (oxycodone hydrochloride), a mu-receptor opioid agonist, in December 1995 for the management of pain requiring daily round-the-clock opioid treatment in cases where other treatments were inadequate. It approved an ADF version of the product in April 2010.

The updated formulation incorporates polyethylene oxide, an inactive polymer that makes the tablet harder and more crush resistant. The tablet turns into a gel or glue-like substance when wet.

The new formulation is bioequivalent to the original formulation, so no additional clinical efficacy and safety studies were conducted.

At the request of the FDA, the company carried out four postmarketing studies, which the FDA also reviewed.

• A National Addictions Vigilance Intervention and Prevention Program study that included 66,897 assessments in patients undergoing evaluation for substance use or entering an opioid addiction program. Results showed a drop in up to 52% of self-reported past 30-day OxyContin injection and snorting versus comparators, including extended-release morphine and immediate-release hydrocodone.
• An analysis of 308,465 calls to U.S. poison centers showing a reduction of up to 28% for calls regarding intentional OxyContin-related exposures immediately following the drug’s reformulation. However, the FDA analysis concluded it is unclear whether the decline was attributable to the drug’s reformulation or co-occurring trends.
• A study of 63,528 individuals entering methadone clinics or treatment programs that showed a reduction of up to 27% in OxyContin abuse versus comparators. There was no information on route of abuse. Here, the FDA analysis determined the results were mixed and didn’t provide compelling evidence.
• A claims-based analysis of patients who were dispensed an opioid (297,836 OxyContin; 659,673 a comparator) that showed no evidence that the updated product affected the rate of fatal and nonfatal opioid overdoses.

During the meeting, committee members heard that opioid use in the United States peaked in 2012, with 260 million prescriptions dispensed, then declined by 41% by 2019. ADFs accounted for only 2% of prescriptions in 2019. They also heard that results of a wide variety of studies and surveys support the conclusion that misuse, abuse, and diversion of OxyContin decreased after it was reformulated.

Ultimately, the joint committee voted 20 to 7 (with 1 abstention) that the reformulated drug reduced nonoral abuse. Most members who voted in favor cited the NAVIPPRO study as a reason for their decision, but few found the strength of the evidence better than moderate.

Meeting chair Sonia Hernandez-Diaz, MD, professor of epidemiology, Harvard School of Public Health, Boston, noted the reduction in abuse may, in part, be a result of the overall reduction in opioid use.

Jon E. Zibbell, PhD, senior public health scientist, behavioral health research division, RTI International, Atlanta, who voted “no,” was disappointed there was not more data.

“We had a bunch of years for this and so many of us could have done some amazing studies” related to how abuse changed post reformulation, he said.

As for overall abuse deterrence, the committee believed the evidence was less compelling. Only two members voted that the reformulated version of the drug reduced overall abuse and only one member voted that the reformulated tablets reduced opioid overdose.

Members generally agreed that all of the studies had limitations, including retrospective designs, confounding, and potential misclassifications. Many noted the challenge of assessing abuse pre- and post reformulation given the evolving situation.

For instance, at the time the reformulated drug was launched, public health initiatives targeting opioid abuse were introduced, more treatment centers were opening, and there was a crackdown on “pill-mill” doctors.

In addition, prescribing and consumption habits were changing. Some doctors may have switched only “at-risk” patients to the reformulated opioid and there may have been “self-selection” among patients – with some potentially opting for another drug such as immediate-release oxycodone.

During the meeting, there was discussion about how to interpret a “meaningful” abuse reduction. However, there was no consensus of a percentage the reduction had to reach in order to be deemed meaningful.

Another issue discussed was the term “abuse deterrent,” which some members believed was stigmatizing and should be changed to crush resistant.

There was also concern that prescribers might consider the ADF a “safe” or less addictive opioid. Michael Sprintz, DO, clinical assistant professor, division of geriatric and palliative medicine, University of Texas Health Science Center, Houston, said ADFs might provide physicians with “a false sense of security.”

Dr. Sprintz, also founder of the Sprintz Center for Pain and Recovery, noted the importance of pain medicine physicians understanding addiction and addiction specialists understanding pain management.

Other committee members voiced concern that the reformulation results in patients switching from intravenous and intranasal abuse to oral abuse. Committed abusers can still swallow multiple pills.

Some members noted that reformulated OxyContin coincided with increased transition to heroin, which is relatively cheap and readily available. However, they recognized that proving causality is difficult.

The committee was reminded that the reformulated drug provides a significant barrier against, but doesn’t altogether eliminate, opioid abuse. With hot water and the right tools, the tablets can still be manipulated.

In addition, the reformulated drug will not solve the U.S. opioid epidemic, which requires a multifaceted approach. The opioid crisis, said Wilson Compton, MD, deputy director at the National Institute on Drug Abuse, has resulted in a “skyrocketing” of deaths linked to “tremendously potent” forms of fentanyl, emerging stimulant use issues, and the possible increase in drug overdoses linked to COVID-19.

A version of this article originally appeared on Medscape.com.

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; [email protected]

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; [email protected]

THE CASE

A 4-year-old girl was triaged to the Pediatric Emergency Department (PED) Fast Track, complaining of pain and limited movement in both arms. For an unknown reason, she had attempted to lift a heavy, 3-person sofa several hours earlier.

Her prior medical history included left nursemaid elbow (NME) at both 15 months and 33 months of age. Neither event had a known mechanism of injury. In both episodes, it was noted in the medical record that the child was not using her arm, “was holding it funny,” and was complaining of pain. Each time, she presented about 24 hours after symptom onset.

During the physical exam in the PED, the patient showed no signs of acute distress. She held both arms close to her body, with a slight flexion at the elbows, and her hands were pronated. She could not pinpoint the location of her discomfort and described diffuse pain in her forearms, elbows, and upper arms. Examination revealed no localized pain or tenderness in her hands, wrists, or clavicles. Radial pulses were easily palpated, and capillary refill was less than 2 seconds. There was no swelling or bruising. The rest of her physical exam was normal.

DIAGNOSIS

The patient was given a diagnosis of self-inflicted bilateral nursemaid elbows (BNME). Reductions were performed by individually stabilizing the elbows and hyper-pronating the forearms, with palpable clicks felt at the proximal radius. Even though a palpable click was felt, this motion was immediately followed by supination of the forearm and flexion at the elbow. The patient tolerated the procedures well and was using both arms normally within 10 minutes. She was discharged home shortly thereafter.

DISCUSSION

BNME is an uncommon diagnosis; a literature review of reported cases indicates none were self-inflicted.^1-4 However, NME is a common injury and is easily reduced. The classic mechanism of injury for NME involves the elbow in extension, while the forearm is pronated, and a sudden brisk axial traction is applied. This combination of motions causes the annular ligament to slip over the head of the radius and become displaced downward into the radiohumeral joint, where it becomes entrapped. In this case, the patient apparently exerted enough longitudinal traction while trying to lift the couch to produce the injury.

NME occurs most commonly in the left arm of girls between the ages of 4 months and 7 years and peaks at around the age of 2 years.⁵ A 2014 study by Irie et al⁶ corroborated the findings on left-side predominance and increased incidence with age, noting that frequency of injury peaked at 6 months in those younger than 1 year of age and at 2 years for those 1 year or older. However, the researchers found no significant sex difference.⁶

NME is radiographically indistinguishable from a healthy elbow.⁷ To prevent unnecessary expense and radiation exposure in young children, prereduction radiographs should only be used to rule out the possibility of fracture or other injury.⁷ Krul et al⁸ recommend restricting x-ray use to cases with an unclear history or those that are due to trauma other than an arm pull.

Continue to: Methods of reduction

Methods of reduction. Once NME is diagnosed, there are 2 methods of reduction: hyper-pronation and supination-flexion. Reduction is best performed with the child sitting in the parent’s lap with the injured arm facing the examiner.

Nursemaid’s elbow is radiographically indistinguishable from a healthy elbow.

Success rates for both methods of NME reduction are statistically similar; however, first-attempt success rates are significantly higher with the hyper-pronation method than with supination-flexion.⁹ Furthermore, physicians have deemed the hyper-­pronation method significantly easier to perform than supination-flexion.⁹ A Cochrane review by Krul et al¹⁰ concluded that the hyper-­pronation method may result in lower failure rates than supination-flexion, but due to limited evidence, the researchers were unable to draw any conclusions on other outcomes, such as pain. Green et al¹¹ noted that hyper-pronation is perceived by parents of children with NME as being less painful. For these reasons, hyper-pronation should be utilized as the first method of reduction, followed by supination-flexion if the former does not work.¹²

Additional management. In a limited study of 50 children with pulled-elbow injuries, ultrasound revealed that 78% had an intact yet interposed radial annular ligament and 22% had a tear in the radial annular ligament.¹³ The authors propose that if, after appropriate reduction methods are attempted, no pop is felt, or there is no prompt clinical improvement, and ultrasound is not available to assess the integrity of the annular ligament, the child should be placed in a splint for 7 days and referred for orthopedic intervention.¹³

Our patient returned to the PED 3 days later, complaining of pain and an inability to move her left arm after her older sibling pulled her by her outstretched arms. She was once again diagnosed with NME, the injury was reduced, and she was using the arm within minutes. She has not presented to either the PED or the pediatric clinic with a similar complaint since. Discarding outliers, NME recurrence rates fall within a range of 23.7% to 32.9%.^14,15

THE TAKEAWAY

Pre-reduction x-rays are not warranted in cases of NME unless there is suspicion for fracture or another injury. The 2 reduction methods, hyper-pronation and supination-flexion, are easily mastered. Any reduction should be quick, easy, and as painless as possible. Hyper-pronation should be utilized first, as this maneuver seems to be the more successful and is perceived by parents as being less painful. However, it is always most helpful to be proficient in both methods. If, after appropriate attempts at reduction, the child has not regained the use of the arm, 7 days of splinting is recommended, along with an orthopedic referral.

CORRESPONDENCE
Robert N. Anderson, DNP, APRN, (F)NP-C, ENP-BC, Vanderbilt Health, 512 Autumn Springs Court, Suite 100 C, Franklin, TN 37067; [email protected]

Since the early 1990s, modern treatments have steadily reduced overall cancer mortality from primary tumors.¹ Consequently, more people are at risk of metastatic bone disease, with subsequent pain and pathologic fractures^1,2 and death from metastasis.³ Patients who have bone metastases present with a variety of signs and symptoms including pain, fractures, and metabolic derangements. The primary care approach to work-up and diagnosis described in this article enables prompt treatment, either surgical or nonsurgical, to maintain a high quality of life for patients.

Primary tumors determine types of metastases and prognosis

Metastasis, a complex pathologic process in which cancerous cells migrate to distant organs, implant, and grow,³ is a poor prognostic indicator in cancer patients. Bone is the third most common site of metastasis, behind the liver and lungs.⁴ While the true prevalence of metastatic bone cancer is unknown, studies have estimated it to be > 280,000 cases in the United States.⁵

Bone metastases interfere with normal bone metabolism and turnover in several different characteristic patterns. These changes—radiographically defined as osteoblastic, osteolytic, or mixed lesions—are determined by the primary tumor type.

• Osteoblastic lesions, comprised of new, disorganized bone formation, often occur secondary to prostate cancer, small cell lung cancer, and carcinoid malignancies, among others.
• Osteolytic lesions, in which bone is destroyed, are more common with breast cancer, renal cell carcinoma, melanoma, and multiple myeloma.
• Mixed lesions, in which areas of bone destruction and growth are simultaneously found, occur with some GI cancers and a few breast cancers.^6,7

Most bone metastases result from carcinomas, of which up to 50% eventually spread to bone, although this process can take 10 to 15 years.^8,9 The likelihood of bone metastasis depends on the primary tumor and its stage. Breast and prostate cancer account for most skeletal metastases, although these lesions are often asymptomatic.^6,9 Other malignancies, such as ovarian and gastrointestinal, metastasize to bone much less frequently.^7,10 Virtually any cancer at an advanced stage can spread to bone. These metastases are usually multifocal and incurable, with the patient’s prognosis varying from a few months to years.^6,11,12

Factors that influence prognosis. Metastatic bone disease arising from melanoma and lung cancers has the shortest life expectancy of roughly 6 months from initial diagnosis; metastasis following prostate, breast, and thyroid cancers has the longest, usually 2 to 4 years.¹¹TABLE 1¹³ shows survival estimates from a large Danish population at various time points following bone metastasis diagnosis for several primary cancer types.

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer—even if such a history is remote. It’s important.

When surgical intervention for bony metastasis is required, prognosis is generally poorer, likely due to more advanced disease. The overall 1-year survival following surgery varies, but several large studies have found a rate of around 40% when considering all primary tumors.^14,15 The most common metastases, from breast and prostate cancers, have 1-year survivals of around 50% and 30%, respectively, following surgical intervention.^16-18

What you’re likely to see on presentation

Bone metastases are one of the leading causes of morbidity in cancer patients from resultant pain, pathologic fractures, metabolic derangements, and reduced activities of daily living.^8,19 The most common cause of cancer pain is bone involvement.⁶ Patients report pain that is usually worse at night, poorly localized, and not alleviated with rest. They often mistakenly relate the pain to an injury.²⁰ The pathophysiology of bone pain is not completely understood but is likely multifactorial and includes inflammatory and mechanical processes.^7,21 Spine involvement can lead to stenosis or nerve root compression, with symptoms dependent on level and severity of nerve or cord compromise.²⁰ Overall, the most common site of bone metastasis is the thoracic spine, followed by the ribs, pelvis, and proximal long bones.²⁰

Continue to: Pathologic fractures

Pathologic fractures occur frequently in cancer patients. Bone destruction leads to a loss of mechanical support which, in turn, causes microfractures and pain. These microfractures can proliferate and coalesce, causing a pathologic fracture, often in weight-bearing bones.⁶ Breast cancer with lytic lesions is the single leading cause of all pathologic fractures.²² Lung cancer with its short survival time and prostate cancer with blastic lesions are less common causes.²³ In the appendicular skeleton, the vast majority of these fractures occur in the femur and humerus.¹¹

Symptomatic metabolic derangements. The most common metabolic disorder is hypercalcemia, found predominantly in patients with hematologic malignancies, squamous cell lung cancer, renal cell cancer, and breast cancer.^6,7,12,24 The clinical presentation is nonspecific and can include polyuria, polydipsia, fatigue, constipation, and confusion. The prevalence is estimated to be 13% in breast cancer, 4% in lung cancers, and 1% in prostate cancer, although results in individual studies vary.¹² The pathophysiology is multifactorial and often includes osteolytic lesions and an increased circulating level of parathyroid hormone–related peptide, although other mechanisms contribute.^25,26 Ultimately, severe hypercalcemia may be fatal secondary to renal failure and cardiac arrhythmias.^6,7,12 Paraneoplastic hypercalcemia independently decreases survival; 1 study found the median survival to be 10 to 12 weeks.¹¹

Primary care work-up and diagnosis

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer. Even if such a history is remote, it is important—­particularly so if the patient received chemotherapy or radiation, which can lead to secondary cancers such as leukemia or sarcoma.²⁰ If a primary site of malignancy is unknown, pursue a general review of systems. Clues to the primary site of disease could be a history of chest pain, shortness of breath, hemoptysis, heat/cold intolerance, or changes in bowel/bladder habits. Also ask about risk factors such as smoking, chemical exposure, and sun exposure.

Pointers on radiographic imaging. If you suspect a destructive bone lesion, order appropriate radiographic imaging. Arrange for plain radiographs with at least 2 views of the specific area of interest that include the entire bone along with the joints above and below. Importantly, the entire bone must be imaged before any surgical procedure to avoid periprosthetic fractures from undetected bone metastases around hardware.²⁰ Keep in mind that plain films can miss early lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) may be needed if suspicion of a pathologic process is still strong and especially if a primary malignancy is known.²⁷

Working back to a primary diagnosis

If imaging confirms a suspicious lesion and the patient has no known primary tumor, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan, and refer the patient to an oncologist. If the bone lesion is painful, initiate protected weight-bearing and additionally refer the patient to an orthopedic surgeon.

Continue to: Appropriate laboratory evaluation

Appropriate laboratory evaluation entails a complete blood count; metabolic panel that includes serum calcium and phosphorus, vitamin D, alkaline phosphatase, thyroid-stimulating hormone, and parathyroid hormone; and serum protein electrophoresis to rule out multiple myeloma.^7,11 Tumor markers are useful to monitor a patient’s response to cancer treatment or to determine recurrence, but they play only a limited role in the initial work-up of an unknown bone tumor.²⁸

Further imaging. A CT scan with intravenous contrast of the chest, abdomen, and pelvis is done to screen for visceral malignancy; however, 15% of bone lesions in patients with an unknown primary lesion never have a source identified.²⁹ Bone scans can be useful in identifying the extent of a single lesion seen on plain films and to assess for additional asymptomatic lesions. Additional imaging—eg, CT or MRI of the lesion, or positron emission tomography (PET)—can be left to the discretion of the oncologist or surgeon.

Order plain radiographs if you suspect a bone lesion. Request at least 2 views of the area that include the entire bone with the joints above and below.

CT scans have significantly higher sensitivity than radiographs and offer better visualization of bone quality, bone destruction, and soft-tissue extension.³⁰ MRI can be used to assess changes in bone marrow and soft-tissue involvement. PET scans, which detect tumors by quantifying metabolic activity, remain controversial. PET is superior to bone scans in detecting bone metastases from lung and breast cancers, but worse in renal and prostate cancers due to slow growth of metastases.^31-33

Caveat. Do not assume that a bone lesion is metastatic. Delayed diagnosis of a primary bone tumor can lead to significant changes in clinical course and patient outcome.³⁴ If any doubt exists as to the type of lesion, arrange for a biopsy using proper technique and delay bone fixation until a histologic diagnosis is complete.³⁵ Biopsy may be performed via image-guided fine-needle aspiration, core biopsy, or open incisional biopsy.

Treatment options

Metastatic bone disease is typically managed nonsurgically with radiation, chemo- or immunotherapies, hormone suppression, bone-modifying agents, or ablation.³⁶ An overview of the cancer treatment guidelines for bone metastasis from the 2017 National Comprehensive Cancer Network is shown in TABLE 2.³⁶

Continue to: Radiotherapy

Radiotherapy can take the form of external-beam or radioisotope radiation. With localized irradiation, most patients who have painful lesions experience at least partial relief, often within a few weeks.^12,37 It may be used postoperatively, as well, to decrease the chances of disease progession.²⁰

Systemic therapies include chemo- and hormone therapies. Chemotherapy effectiveness is highly dependent on the primary tumor type. For example, renal cell carcinoma and melanoma are often resistant, while lymphoma and germ-cell tumors may be eliminated and sometimes even cured.⁷ Hormone therapy can be highly effective in selective cancers, primarily breast and prostate cancers. Immunotherapy options may also be used to specifically target bone metastasis sites.

Bone-modifying agents include bisphosphonates and denosumab (Prolia, Xgeva). These are generally initiated at the discretion of the oncologist, but primary care physicians should be familiar with their use. Bisphosphonates, which includes zoledronic acid, pamidronate, and other agents, are analogues of pyrophosphate that inhibit bone demineralization.³⁸ These agents target bone resorption through incorporation into osteoclasts and have been effective in the treatment of hypercalcemia and bone lesions.^6,12,39 Not only do they reduce the incidence of all skeleton-related events, including pathologic fractures and pain, they also appear to have antitumor activity with prolonged survival in certain cancers.^7,12

Denosumab, which has a much shorter half-life than bisphosphonates, is a monoclonal antibody that targets the gene RANKL, a key activator of osteoclasts, and thereby prevents the development of osteoclasts and related bone resorption.⁴⁰

Radiofrequency ablation or cryoablation, using image-guided needle placement, specifically targets individual bone lesions, destroying tumor cells with extreme heat or cold, respectively. This has been shown to reduce pain and opioid consumption.⁴¹

Continue to: Managing pain

Pain management can be difficult, especially as patients live longer and undergo additional treatments such as surgery, radiation, and chemotherapy, each with the potential to produce chronic pain.⁴² A multidisciplinary team with a stepwise and multimodal approach can improve the patient’s function and comfort while decreasing drug adverse effects.⁴³

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs, acetaminophen, and tramadol may provide effective relief. For more severe pain, narcotics are often required on a fixed-dose schedule along with breakthrough options such as short-acting hydromorphone, oxycodone, or transmucosal fentanyl.^42-44 Opioid adverse effects such as constipation and nausea/vomiting must be managed with laxatives and metoclopramide/antidopaminergics, respectively.

Other important non-narcotic therapies are corticosteroids, tricyclic antidepressants, gabapentin, neuroleptics, and nerve blocks.⁴⁵ Physical therapy and acupuncture may also be useful, depending on the patient’s needs and desires. Despite the wide range of options, most patients continue to have a significant amount of pain that can impact daily activities and even cause them to feel that their quality of life was not an important factor in physician decision making.⁴⁶

Surgery options

Surgical intervention for metastatic bone disease differs from its use in primary bone tumors in that clinical indications are not clearly defined. In general, surgery for metastatic disease is used in patients who have pathologic fractures, a risk of pathologic fracture, or uncontrolled cancer-induced bone pain. Keep in mind that the overarching goal of surgery is to reduce morbidity, not mortality, although exceptions exist. Metastatic renal cell carcinoma is one such exception: improved survival may be achieved via aggressive surgical resection for solitary or oligometastatic lesions.⁴⁷

Before deciding on surgery, engage the patient in goals-of-care discussions and take into account factors specific to the individual, as operative complications can be devasting. Risk of postoperative infection is high, given that these patients are often immunocompromised and that irradiated tissue is prone to wound healing issues.⁸ Complications may require a pause in chemotherapy and a subsequent decrease in life expectancy.

Continue to: Another factor in surgical decision making...

Another factor in surgical decision making is that newer systemic therapies are leading to longer survival for those with various types of metastatic cancer.⁴⁸ Older methods of fixation designed to last a few years may now fail during the patient’s prolonged ­lifespan. As novel therapies continue to improve survival and complicate surgical indications, it may be prudent for the surgical management of metastatic bone disease to be handled by fellowship-trained orthopedic oncologists.

Factors that affect timing. Surgical intervention ideally occurs before the development of a pathologic fracture. Outcomes research has shown that intervention before fracture leads to reduced blood loss and length of hospital stay with improved functional recovery and survival.^12,49 Despite these improved outcomes, an adequate scoring system to guide surgical intervention has yet to be developed. Mirels’ criteria are cited most often, yet this scoring system fails to account for many important considerations such as primary tumor type, life expectancy, and other factors.^50,51

If a patient with no known primary tumor has a confirmed bone lesion, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan.

Given the deleterious effects of fractures in cancer patients and the inadequacy of closed reduction and immobilization, surgical intervention is often warranted.⁵² Surgical technology has continued to progress; however, intramedullary nailing, plating, and endoprostheses are still the most commonly used methods.⁵³

Intramedullary nailing is commonly used in the prophylactic treatment of pathologic lesions and fractures of long bones in patients whose expected survival is as little as 6 to 12 weeks.⁵⁴ Plate and screw fixation is a viable alternative to intramedullary nailing when tumor resection is desired. Endoprostheses replacement is used when a tumor involves joint surfaces or if biological reconstruction cannot be achieved by nailing or plating.

Explicit communication with patients is critical

Of vital importance is your participation with patients and families in shared decision making throughout the diagnostic and treatment process, ensuring clear communication. Misunderstandings about cancer stages and prognoses are not uncommon and are sometimes due to insufficient explanation.^55,56 Additionally, expectations of survival and adverse effects of treatment often differ greatly between physicians and patients, which can lead to patient dissatisfaction.⁵⁷

Continue to: Finally, the long-term care...

Finally, the long-term care of patients with metastatic cancers necessarily involves multidisciplinary teams, which further complicates communication. To ensure that patients are receiving an appropriate course of treatment, evaluate their health literacy, confirm their understanding of the disease, and acknowledge their desires.

CORRESPONDENCE
Kyle Sweeney, MD, University of Kansas Medical Center, Department of Orthopedic Surgery, 3901 Rainbow Boulevard, MS 3017, Kansas City, KS 66160; [email protected].

Since the early 1990s, modern treatments have steadily reduced overall cancer mortality from primary tumors.¹ Consequently, more people are at risk of metastatic bone disease, with subsequent pain and pathologic fractures^1,2 and death from metastasis.³ Patients who have bone metastases present with a variety of signs and symptoms including pain, fractures, and metabolic derangements. The primary care approach to work-up and diagnosis described in this article enables prompt treatment, either surgical or nonsurgical, to maintain a high quality of life for patients.

Primary tumors determine types of metastases and prognosis

Metastasis, a complex pathologic process in which cancerous cells migrate to distant organs, implant, and grow,³ is a poor prognostic indicator in cancer patients. Bone is the third most common site of metastasis, behind the liver and lungs.⁴ While the true prevalence of metastatic bone cancer is unknown, studies have estimated it to be > 280,000 cases in the United States.⁵

Bone metastases interfere with normal bone metabolism and turnover in several different characteristic patterns. These changes—radiographically defined as osteoblastic, osteolytic, or mixed lesions—are determined by the primary tumor type.

• Osteoblastic lesions, comprised of new, disorganized bone formation, often occur secondary to prostate cancer, small cell lung cancer, and carcinoid malignancies, among others.
• Osteolytic lesions, in which bone is destroyed, are more common with breast cancer, renal cell carcinoma, melanoma, and multiple myeloma.
• Mixed lesions, in which areas of bone destruction and growth are simultaneously found, occur with some GI cancers and a few breast cancers.^6,7

Most bone metastases result from carcinomas, of which up to 50% eventually spread to bone, although this process can take 10 to 15 years.^8,9 The likelihood of bone metastasis depends on the primary tumor and its stage. Breast and prostate cancer account for most skeletal metastases, although these lesions are often asymptomatic.^6,9 Other malignancies, such as ovarian and gastrointestinal, metastasize to bone much less frequently.^7,10 Virtually any cancer at an advanced stage can spread to bone. These metastases are usually multifocal and incurable, with the patient’s prognosis varying from a few months to years.^6,11,12

Factors that influence prognosis. Metastatic bone disease arising from melanoma and lung cancers has the shortest life expectancy of roughly 6 months from initial diagnosis; metastasis following prostate, breast, and thyroid cancers has the longest, usually 2 to 4 years.¹¹TABLE 1¹³ shows survival estimates from a large Danish population at various time points following bone metastasis diagnosis for several primary cancer types.

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer—even if such a history is remote. It’s important.

When surgical intervention for bony metastasis is required, prognosis is generally poorer, likely due to more advanced disease. The overall 1-year survival following surgery varies, but several large studies have found a rate of around 40% when considering all primary tumors.^14,15 The most common metastases, from breast and prostate cancers, have 1-year survivals of around 50% and 30%, respectively, following surgical intervention.^16-18

What you’re likely to see on presentation

Bone metastases are one of the leading causes of morbidity in cancer patients from resultant pain, pathologic fractures, metabolic derangements, and reduced activities of daily living.^8,19 The most common cause of cancer pain is bone involvement.⁶ Patients report pain that is usually worse at night, poorly localized, and not alleviated with rest. They often mistakenly relate the pain to an injury.²⁰ The pathophysiology of bone pain is not completely understood but is likely multifactorial and includes inflammatory and mechanical processes.^7,21 Spine involvement can lead to stenosis or nerve root compression, with symptoms dependent on level and severity of nerve or cord compromise.²⁰ Overall, the most common site of bone metastasis is the thoracic spine, followed by the ribs, pelvis, and proximal long bones.²⁰

Continue to: Pathologic fractures

Pathologic fractures occur frequently in cancer patients. Bone destruction leads to a loss of mechanical support which, in turn, causes microfractures and pain. These microfractures can proliferate and coalesce, causing a pathologic fracture, often in weight-bearing bones.⁶ Breast cancer with lytic lesions is the single leading cause of all pathologic fractures.²² Lung cancer with its short survival time and prostate cancer with blastic lesions are less common causes.²³ In the appendicular skeleton, the vast majority of these fractures occur in the femur and humerus.¹¹

Symptomatic metabolic derangements. The most common metabolic disorder is hypercalcemia, found predominantly in patients with hematologic malignancies, squamous cell lung cancer, renal cell cancer, and breast cancer.^6,7,12,24 The clinical presentation is nonspecific and can include polyuria, polydipsia, fatigue, constipation, and confusion. The prevalence is estimated to be 13% in breast cancer, 4% in lung cancers, and 1% in prostate cancer, although results in individual studies vary.¹² The pathophysiology is multifactorial and often includes osteolytic lesions and an increased circulating level of parathyroid hormone–related peptide, although other mechanisms contribute.^25,26 Ultimately, severe hypercalcemia may be fatal secondary to renal failure and cardiac arrhythmias.^6,7,12 Paraneoplastic hypercalcemia independently decreases survival; 1 study found the median survival to be 10 to 12 weeks.¹¹

Primary care work-up and diagnosis

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer. Even if such a history is remote, it is important—­particularly so if the patient received chemotherapy or radiation, which can lead to secondary cancers such as leukemia or sarcoma.²⁰ If a primary site of malignancy is unknown, pursue a general review of systems. Clues to the primary site of disease could be a history of chest pain, shortness of breath, hemoptysis, heat/cold intolerance, or changes in bowel/bladder habits. Also ask about risk factors such as smoking, chemical exposure, and sun exposure.

Pointers on radiographic imaging. If you suspect a destructive bone lesion, order appropriate radiographic imaging. Arrange for plain radiographs with at least 2 views of the specific area of interest that include the entire bone along with the joints above and below. Importantly, the entire bone must be imaged before any surgical procedure to avoid periprosthetic fractures from undetected bone metastases around hardware.²⁰ Keep in mind that plain films can miss early lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) may be needed if suspicion of a pathologic process is still strong and especially if a primary malignancy is known.²⁷

Working back to a primary diagnosis

If imaging confirms a suspicious lesion and the patient has no known primary tumor, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan, and refer the patient to an oncologist. If the bone lesion is painful, initiate protected weight-bearing and additionally refer the patient to an orthopedic surgeon.

Continue to: Appropriate laboratory evaluation

Appropriate laboratory evaluation entails a complete blood count; metabolic panel that includes serum calcium and phosphorus, vitamin D, alkaline phosphatase, thyroid-stimulating hormone, and parathyroid hormone; and serum protein electrophoresis to rule out multiple myeloma.^7,11 Tumor markers are useful to monitor a patient’s response to cancer treatment or to determine recurrence, but they play only a limited role in the initial work-up of an unknown bone tumor.²⁸

Further imaging. A CT scan with intravenous contrast of the chest, abdomen, and pelvis is done to screen for visceral malignancy; however, 15% of bone lesions in patients with an unknown primary lesion never have a source identified.²⁹ Bone scans can be useful in identifying the extent of a single lesion seen on plain films and to assess for additional asymptomatic lesions. Additional imaging—eg, CT or MRI of the lesion, or positron emission tomography (PET)—can be left to the discretion of the oncologist or surgeon.

Order plain radiographs if you suspect a bone lesion. Request at least 2 views of the area that include the entire bone with the joints above and below.

CT scans have significantly higher sensitivity than radiographs and offer better visualization of bone quality, bone destruction, and soft-tissue extension.³⁰ MRI can be used to assess changes in bone marrow and soft-tissue involvement. PET scans, which detect tumors by quantifying metabolic activity, remain controversial. PET is superior to bone scans in detecting bone metastases from lung and breast cancers, but worse in renal and prostate cancers due to slow growth of metastases.^31-33

Caveat. Do not assume that a bone lesion is metastatic. Delayed diagnosis of a primary bone tumor can lead to significant changes in clinical course and patient outcome.³⁴ If any doubt exists as to the type of lesion, arrange for a biopsy using proper technique and delay bone fixation until a histologic diagnosis is complete.³⁵ Biopsy may be performed via image-guided fine-needle aspiration, core biopsy, or open incisional biopsy.

Treatment options

Metastatic bone disease is typically managed nonsurgically with radiation, chemo- or immunotherapies, hormone suppression, bone-modifying agents, or ablation.³⁶ An overview of the cancer treatment guidelines for bone metastasis from the 2017 National Comprehensive Cancer Network is shown in TABLE 2.³⁶

Continue to: Radiotherapy

Radiotherapy can take the form of external-beam or radioisotope radiation. With localized irradiation, most patients who have painful lesions experience at least partial relief, often within a few weeks.^12,37 It may be used postoperatively, as well, to decrease the chances of disease progession.²⁰

Systemic therapies include chemo- and hormone therapies. Chemotherapy effectiveness is highly dependent on the primary tumor type. For example, renal cell carcinoma and melanoma are often resistant, while lymphoma and germ-cell tumors may be eliminated and sometimes even cured.⁷ Hormone therapy can be highly effective in selective cancers, primarily breast and prostate cancers. Immunotherapy options may also be used to specifically target bone metastasis sites.

Bone-modifying agents include bisphosphonates and denosumab (Prolia, Xgeva). These are generally initiated at the discretion of the oncologist, but primary care physicians should be familiar with their use. Bisphosphonates, which includes zoledronic acid, pamidronate, and other agents, are analogues of pyrophosphate that inhibit bone demineralization.³⁸ These agents target bone resorption through incorporation into osteoclasts and have been effective in the treatment of hypercalcemia and bone lesions.^6,12,39 Not only do they reduce the incidence of all skeleton-related events, including pathologic fractures and pain, they also appear to have antitumor activity with prolonged survival in certain cancers.^7,12

Denosumab, which has a much shorter half-life than bisphosphonates, is a monoclonal antibody that targets the gene RANKL, a key activator of osteoclasts, and thereby prevents the development of osteoclasts and related bone resorption.⁴⁰

Radiofrequency ablation or cryoablation, using image-guided needle placement, specifically targets individual bone lesions, destroying tumor cells with extreme heat or cold, respectively. This has been shown to reduce pain and opioid consumption.⁴¹

Continue to: Managing pain

Pain management can be difficult, especially as patients live longer and undergo additional treatments such as surgery, radiation, and chemotherapy, each with the potential to produce chronic pain.⁴² A multidisciplinary team with a stepwise and multimodal approach can improve the patient’s function and comfort while decreasing drug adverse effects.⁴³

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs, acetaminophen, and tramadol may provide effective relief. For more severe pain, narcotics are often required on a fixed-dose schedule along with breakthrough options such as short-acting hydromorphone, oxycodone, or transmucosal fentanyl.^42-44 Opioid adverse effects such as constipation and nausea/vomiting must be managed with laxatives and metoclopramide/antidopaminergics, respectively.

Other important non-narcotic therapies are corticosteroids, tricyclic antidepressants, gabapentin, neuroleptics, and nerve blocks.⁴⁵ Physical therapy and acupuncture may also be useful, depending on the patient’s needs and desires. Despite the wide range of options, most patients continue to have a significant amount of pain that can impact daily activities and even cause them to feel that their quality of life was not an important factor in physician decision making.⁴⁶

Surgery options

Surgical intervention for metastatic bone disease differs from its use in primary bone tumors in that clinical indications are not clearly defined. In general, surgery for metastatic disease is used in patients who have pathologic fractures, a risk of pathologic fracture, or uncontrolled cancer-induced bone pain. Keep in mind that the overarching goal of surgery is to reduce morbidity, not mortality, although exceptions exist. Metastatic renal cell carcinoma is one such exception: improved survival may be achieved via aggressive surgical resection for solitary or oligometastatic lesions.⁴⁷

Before deciding on surgery, engage the patient in goals-of-care discussions and take into account factors specific to the individual, as operative complications can be devasting. Risk of postoperative infection is high, given that these patients are often immunocompromised and that irradiated tissue is prone to wound healing issues.⁸ Complications may require a pause in chemotherapy and a subsequent decrease in life expectancy.

Continue to: Another factor in surgical decision making...

Another factor in surgical decision making is that newer systemic therapies are leading to longer survival for those with various types of metastatic cancer.⁴⁸ Older methods of fixation designed to last a few years may now fail during the patient’s prolonged ­lifespan. As novel therapies continue to improve survival and complicate surgical indications, it may be prudent for the surgical management of metastatic bone disease to be handled by fellowship-trained orthopedic oncologists.

Factors that affect timing. Surgical intervention ideally occurs before the development of a pathologic fracture. Outcomes research has shown that intervention before fracture leads to reduced blood loss and length of hospital stay with improved functional recovery and survival.^12,49 Despite these improved outcomes, an adequate scoring system to guide surgical intervention has yet to be developed. Mirels’ criteria are cited most often, yet this scoring system fails to account for many important considerations such as primary tumor type, life expectancy, and other factors.^50,51

If a patient with no known primary tumor has a confirmed bone lesion, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan.

Given the deleterious effects of fractures in cancer patients and the inadequacy of closed reduction and immobilization, surgical intervention is often warranted.⁵² Surgical technology has continued to progress; however, intramedullary nailing, plating, and endoprostheses are still the most commonly used methods.⁵³

Intramedullary nailing is commonly used in the prophylactic treatment of pathologic lesions and fractures of long bones in patients whose expected survival is as little as 6 to 12 weeks.⁵⁴ Plate and screw fixation is a viable alternative to intramedullary nailing when tumor resection is desired. Endoprostheses replacement is used when a tumor involves joint surfaces or if biological reconstruction cannot be achieved by nailing or plating.

Explicit communication with patients is critical

Of vital importance is your participation with patients and families in shared decision making throughout the diagnostic and treatment process, ensuring clear communication. Misunderstandings about cancer stages and prognoses are not uncommon and are sometimes due to insufficient explanation.^55,56 Additionally, expectations of survival and adverse effects of treatment often differ greatly between physicians and patients, which can lead to patient dissatisfaction.⁵⁷

Continue to: Finally, the long-term care...

Finally, the long-term care of patients with metastatic cancers necessarily involves multidisciplinary teams, which further complicates communication. To ensure that patients are receiving an appropriate course of treatment, evaluate their health literacy, confirm their understanding of the disease, and acknowledge their desires.

CORRESPONDENCE
Kyle Sweeney, MD, University of Kansas Medical Center, Department of Orthopedic Surgery, 3901 Rainbow Boulevard, MS 3017, Kansas City, KS 66160; [email protected].

Since the early 1990s, modern treatments have steadily reduced overall cancer mortality from primary tumors.¹ Consequently, more people are at risk of metastatic bone disease, with subsequent pain and pathologic fractures^1,2 and death from metastasis.³ Patients who have bone metastases present with a variety of signs and symptoms including pain, fractures, and metabolic derangements. The primary care approach to work-up and diagnosis described in this article enables prompt treatment, either surgical or nonsurgical, to maintain a high quality of life for patients.

Primary tumors determine types of metastases and prognosis

Metastasis, a complex pathologic process in which cancerous cells migrate to distant organs, implant, and grow,³ is a poor prognostic indicator in cancer patients. Bone is the third most common site of metastasis, behind the liver and lungs.⁴ While the true prevalence of metastatic bone cancer is unknown, studies have estimated it to be > 280,000 cases in the United States.⁵

Bone metastases interfere with normal bone metabolism and turnover in several different characteristic patterns. These changes—radiographically defined as osteoblastic, osteolytic, or mixed lesions—are determined by the primary tumor type.

• Osteoblastic lesions, comprised of new, disorganized bone formation, often occur secondary to prostate cancer, small cell lung cancer, and carcinoid malignancies, among others.
• Osteolytic lesions, in which bone is destroyed, are more common with breast cancer, renal cell carcinoma, melanoma, and multiple myeloma.
• Mixed lesions, in which areas of bone destruction and growth are simultaneously found, occur with some GI cancers and a few breast cancers.^6,7

Most bone metastases result from carcinomas, of which up to 50% eventually spread to bone, although this process can take 10 to 15 years.^8,9 The likelihood of bone metastasis depends on the primary tumor and its stage. Breast and prostate cancer account for most skeletal metastases, although these lesions are often asymptomatic.^6,9 Other malignancies, such as ovarian and gastrointestinal, metastasize to bone much less frequently.^7,10 Virtually any cancer at an advanced stage can spread to bone. These metastases are usually multifocal and incurable, with the patient’s prognosis varying from a few months to years.^6,11,12

Factors that influence prognosis. Metastatic bone disease arising from melanoma and lung cancers has the shortest life expectancy of roughly 6 months from initial diagnosis; metastasis following prostate, breast, and thyroid cancers has the longest, usually 2 to 4 years.¹¹TABLE 1¹³ shows survival estimates from a large Danish population at various time points following bone metastasis diagnosis for several primary cancer types.

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer—even if such a history is remote. It’s important.

When surgical intervention for bony metastasis is required, prognosis is generally poorer, likely due to more advanced disease. The overall 1-year survival following surgery varies, but several large studies have found a rate of around 40% when considering all primary tumors.^14,15 The most common metastases, from breast and prostate cancers, have 1-year survivals of around 50% and 30%, respectively, following surgical intervention.^16-18

What you’re likely to see on presentation

Bone metastases are one of the leading causes of morbidity in cancer patients from resultant pain, pathologic fractures, metabolic derangements, and reduced activities of daily living.^8,19 The most common cause of cancer pain is bone involvement.⁶ Patients report pain that is usually worse at night, poorly localized, and not alleviated with rest. They often mistakenly relate the pain to an injury.²⁰ The pathophysiology of bone pain is not completely understood but is likely multifactorial and includes inflammatory and mechanical processes.^7,21 Spine involvement can lead to stenosis or nerve root compression, with symptoms dependent on level and severity of nerve or cord compromise.²⁰ Overall, the most common site of bone metastasis is the thoracic spine, followed by the ribs, pelvis, and proximal long bones.²⁰

Continue to: Pathologic fractures

Pathologic fractures occur frequently in cancer patients. Bone destruction leads to a loss of mechanical support which, in turn, causes microfractures and pain. These microfractures can proliferate and coalesce, causing a pathologic fracture, often in weight-bearing bones.⁶ Breast cancer with lytic lesions is the single leading cause of all pathologic fractures.²² Lung cancer with its short survival time and prostate cancer with blastic lesions are less common causes.²³ In the appendicular skeleton, the vast majority of these fractures occur in the femur and humerus.¹¹

Symptomatic metabolic derangements. The most common metabolic disorder is hypercalcemia, found predominantly in patients with hematologic malignancies, squamous cell lung cancer, renal cell cancer, and breast cancer.^6,7,12,24 The clinical presentation is nonspecific and can include polyuria, polydipsia, fatigue, constipation, and confusion. The prevalence is estimated to be 13% in breast cancer, 4% in lung cancers, and 1% in prostate cancer, although results in individual studies vary.¹² The pathophysiology is multifactorial and often includes osteolytic lesions and an increased circulating level of parathyroid hormone–related peptide, although other mechanisms contribute.^25,26 Ultimately, severe hypercalcemia may be fatal secondary to renal failure and cardiac arrhythmias.^6,7,12 Paraneoplastic hypercalcemia independently decreases survival; 1 study found the median survival to be 10 to 12 weeks.¹¹

Primary care work-up and diagnosis

When a patient presents with signs and symptoms suggestive of metastatic bone disease, inquire about a history of cancer. Even if such a history is remote, it is important—­particularly so if the patient received chemotherapy or radiation, which can lead to secondary cancers such as leukemia or sarcoma.²⁰ If a primary site of malignancy is unknown, pursue a general review of systems. Clues to the primary site of disease could be a history of chest pain, shortness of breath, hemoptysis, heat/cold intolerance, or changes in bowel/bladder habits. Also ask about risk factors such as smoking, chemical exposure, and sun exposure.

Pointers on radiographic imaging. If you suspect a destructive bone lesion, order appropriate radiographic imaging. Arrange for plain radiographs with at least 2 views of the specific area of interest that include the entire bone along with the joints above and below. Importantly, the entire bone must be imaged before any surgical procedure to avoid periprosthetic fractures from undetected bone metastases around hardware.²⁰ Keep in mind that plain films can miss early lesions, and computed tomography (CT) or magnetic resonance imaging (MRI) may be needed if suspicion of a pathologic process is still strong and especially if a primary malignancy is known.²⁷

Working back to a primary diagnosis

If imaging confirms a suspicious lesion and the patient has no known primary tumor, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan, and refer the patient to an oncologist. If the bone lesion is painful, initiate protected weight-bearing and additionally refer the patient to an orthopedic surgeon.

Continue to: Appropriate laboratory evaluation

Appropriate laboratory evaluation entails a complete blood count; metabolic panel that includes serum calcium and phosphorus, vitamin D, alkaline phosphatase, thyroid-stimulating hormone, and parathyroid hormone; and serum protein electrophoresis to rule out multiple myeloma.^7,11 Tumor markers are useful to monitor a patient’s response to cancer treatment or to determine recurrence, but they play only a limited role in the initial work-up of an unknown bone tumor.²⁸

Further imaging. A CT scan with intravenous contrast of the chest, abdomen, and pelvis is done to screen for visceral malignancy; however, 15% of bone lesions in patients with an unknown primary lesion never have a source identified.²⁹ Bone scans can be useful in identifying the extent of a single lesion seen on plain films and to assess for additional asymptomatic lesions. Additional imaging—eg, CT or MRI of the lesion, or positron emission tomography (PET)—can be left to the discretion of the oncologist or surgeon.

Order plain radiographs if you suspect a bone lesion. Request at least 2 views of the area that include the entire bone with the joints above and below.

CT scans have significantly higher sensitivity than radiographs and offer better visualization of bone quality, bone destruction, and soft-tissue extension.³⁰ MRI can be used to assess changes in bone marrow and soft-tissue involvement. PET scans, which detect tumors by quantifying metabolic activity, remain controversial. PET is superior to bone scans in detecting bone metastases from lung and breast cancers, but worse in renal and prostate cancers due to slow growth of metastases.^31-33

Caveat. Do not assume that a bone lesion is metastatic. Delayed diagnosis of a primary bone tumor can lead to significant changes in clinical course and patient outcome.³⁴ If any doubt exists as to the type of lesion, arrange for a biopsy using proper technique and delay bone fixation until a histologic diagnosis is complete.³⁵ Biopsy may be performed via image-guided fine-needle aspiration, core biopsy, or open incisional biopsy.

Treatment options

Metastatic bone disease is typically managed nonsurgically with radiation, chemo- or immunotherapies, hormone suppression, bone-modifying agents, or ablation.³⁶ An overview of the cancer treatment guidelines for bone metastasis from the 2017 National Comprehensive Cancer Network is shown in TABLE 2.³⁶

Continue to: Radiotherapy

Radiotherapy can take the form of external-beam or radioisotope radiation. With localized irradiation, most patients who have painful lesions experience at least partial relief, often within a few weeks.^12,37 It may be used postoperatively, as well, to decrease the chances of disease progession.²⁰

Systemic therapies include chemo- and hormone therapies. Chemotherapy effectiveness is highly dependent on the primary tumor type. For example, renal cell carcinoma and melanoma are often resistant, while lymphoma and germ-cell tumors may be eliminated and sometimes even cured.⁷ Hormone therapy can be highly effective in selective cancers, primarily breast and prostate cancers. Immunotherapy options may also be used to specifically target bone metastasis sites.

Bone-modifying agents include bisphosphonates and denosumab (Prolia, Xgeva). These are generally initiated at the discretion of the oncologist, but primary care physicians should be familiar with their use. Bisphosphonates, which includes zoledronic acid, pamidronate, and other agents, are analogues of pyrophosphate that inhibit bone demineralization.³⁸ These agents target bone resorption through incorporation into osteoclasts and have been effective in the treatment of hypercalcemia and bone lesions.^6,12,39 Not only do they reduce the incidence of all skeleton-related events, including pathologic fractures and pain, they also appear to have antitumor activity with prolonged survival in certain cancers.^7,12

Denosumab, which has a much shorter half-life than bisphosphonates, is a monoclonal antibody that targets the gene RANKL, a key activator of osteoclasts, and thereby prevents the development of osteoclasts and related bone resorption.⁴⁰

Radiofrequency ablation or cryoablation, using image-guided needle placement, specifically targets individual bone lesions, destroying tumor cells with extreme heat or cold, respectively. This has been shown to reduce pain and opioid consumption.⁴¹

Continue to: Managing pain

Pain management can be difficult, especially as patients live longer and undergo additional treatments such as surgery, radiation, and chemotherapy, each with the potential to produce chronic pain.⁴² A multidisciplinary team with a stepwise and multimodal approach can improve the patient’s function and comfort while decreasing drug adverse effects.⁴³

For mild-to-moderate pain, nonsteroidal anti-inflammatory drugs, acetaminophen, and tramadol may provide effective relief. For more severe pain, narcotics are often required on a fixed-dose schedule along with breakthrough options such as short-acting hydromorphone, oxycodone, or transmucosal fentanyl.^42-44 Opioid adverse effects such as constipation and nausea/vomiting must be managed with laxatives and metoclopramide/antidopaminergics, respectively.

Other important non-narcotic therapies are corticosteroids, tricyclic antidepressants, gabapentin, neuroleptics, and nerve blocks.⁴⁵ Physical therapy and acupuncture may also be useful, depending on the patient’s needs and desires. Despite the wide range of options, most patients continue to have a significant amount of pain that can impact daily activities and even cause them to feel that their quality of life was not an important factor in physician decision making.⁴⁶

Surgery options

Surgical intervention for metastatic bone disease differs from its use in primary bone tumors in that clinical indications are not clearly defined. In general, surgery for metastatic disease is used in patients who have pathologic fractures, a risk of pathologic fracture, or uncontrolled cancer-induced bone pain. Keep in mind that the overarching goal of surgery is to reduce morbidity, not mortality, although exceptions exist. Metastatic renal cell carcinoma is one such exception: improved survival may be achieved via aggressive surgical resection for solitary or oligometastatic lesions.⁴⁷

Before deciding on surgery, engage the patient in goals-of-care discussions and take into account factors specific to the individual, as operative complications can be devasting. Risk of postoperative infection is high, given that these patients are often immunocompromised and that irradiated tissue is prone to wound healing issues.⁸ Complications may require a pause in chemotherapy and a subsequent decrease in life expectancy.

Continue to: Another factor in surgical decision making...

Another factor in surgical decision making is that newer systemic therapies are leading to longer survival for those with various types of metastatic cancer.⁴⁸ Older methods of fixation designed to last a few years may now fail during the patient’s prolonged ­lifespan. As novel therapies continue to improve survival and complicate surgical indications, it may be prudent for the surgical management of metastatic bone disease to be handled by fellowship-trained orthopedic oncologists.

Factors that affect timing. Surgical intervention ideally occurs before the development of a pathologic fracture. Outcomes research has shown that intervention before fracture leads to reduced blood loss and length of hospital stay with improved functional recovery and survival.^12,49 Despite these improved outcomes, an adequate scoring system to guide surgical intervention has yet to be developed. Mirels’ criteria are cited most often, yet this scoring system fails to account for many important considerations such as primary tumor type, life expectancy, and other factors.^50,51

If a patient with no known primary tumor has a confirmed bone lesion, order labs, a CT scan with contrast of the chest, abdomen, and pelvis, and a bone scan.

Given the deleterious effects of fractures in cancer patients and the inadequacy of closed reduction and immobilization, surgical intervention is often warranted.⁵² Surgical technology has continued to progress; however, intramedullary nailing, plating, and endoprostheses are still the most commonly used methods.⁵³

Intramedullary nailing is commonly used in the prophylactic treatment of pathologic lesions and fractures of long bones in patients whose expected survival is as little as 6 to 12 weeks.⁵⁴ Plate and screw fixation is a viable alternative to intramedullary nailing when tumor resection is desired. Endoprostheses replacement is used when a tumor involves joint surfaces or if biological reconstruction cannot be achieved by nailing or plating.

Explicit communication with patients is critical

Of vital importance is your participation with patients and families in shared decision making throughout the diagnostic and treatment process, ensuring clear communication. Misunderstandings about cancer stages and prognoses are not uncommon and are sometimes due to insufficient explanation.^55,56 Additionally, expectations of survival and adverse effects of treatment often differ greatly between physicians and patients, which can lead to patient dissatisfaction.⁵⁷

Continue to: Finally, the long-term care...

Finally, the long-term care of patients with metastatic cancers necessarily involves multidisciplinary teams, which further complicates communication. To ensure that patients are receiving an appropriate course of treatment, evaluate their health literacy, confirm their understanding of the disease, and acknowledge their desires.

CORRESPONDENCE
Kyle Sweeney, MD, University of Kansas Medical Center, Department of Orthopedic Surgery, 3901 Rainbow Boulevard, MS 3017, Kansas City, KS 66160; [email protected].

One high school student out of every seven ever has either misused a prescription pain medicine or taken one without a prescription, according to an analysis from the Centers for Disease Control and Prevention.

That type of opioid use/misuse, reported by 14.3% of respondents to the 2019 Youth Risk Behavior Survey, was more common among females (16.1%) than males (12.4%) and even more prevalent among nonheterosexuals and those who are unsure about their sexual identity, Christopher M. Jones, PharmD, DrPH, and associates at the CDC said in the Morbidity and Mortality Weekly Report.

The YRBS data show that 18.5% of gay or lesbian students had, at some point in their lives, used a prescription opioid differently than a physician had told them to or taken one without a prescription. That figure was slightly higher (19.1%) for those unsure of their sexual identity, considerably higher (25.4%) for bisexuals, and lower for heterosexuals (12.7%), they reported.

The pattern for current use/misuse of opioids, defined as use one or more times in the 30 days before the survey, was similar to ever use but somewhat less pronounced in 2019. Prevalence was 7.2% for all students in grades 9-12, 8.3% for females, and 6.1% for males. By sexual identity, prevalence was 6.4% for heterosexuals, 7.6% for gays or lesbians, 11.5% for those unsure about their sexual identity, and 13.1% for bisexuals, based on the YRBS data.

This increased misuse of opioids among sexual minority youths, “even after controlling for other demographic and substance use characteristics ... emphasizes the importance of identifying tailored prevention strategies to address disparities among this vulnerable population,” the CDC researchers wrote.

[email protected]

SOURCE: Jones CM et al. MMWR Suppl. 2020 Aug 21;69(1):38-46.

One high school student out of every seven ever has either misused a prescription pain medicine or taken one without a prescription, according to an analysis from the Centers for Disease Control and Prevention.

That type of opioid use/misuse, reported by 14.3% of respondents to the 2019 Youth Risk Behavior Survey, was more common among females (16.1%) than males (12.4%) and even more prevalent among nonheterosexuals and those who are unsure about their sexual identity, Christopher M. Jones, PharmD, DrPH, and associates at the CDC said in the Morbidity and Mortality Weekly Report.

The YRBS data show that 18.5% of gay or lesbian students had, at some point in their lives, used a prescription opioid differently than a physician had told them to or taken one without a prescription. That figure was slightly higher (19.1%) for those unsure of their sexual identity, considerably higher (25.4%) for bisexuals, and lower for heterosexuals (12.7%), they reported.

The pattern for current use/misuse of opioids, defined as use one or more times in the 30 days before the survey, was similar to ever use but somewhat less pronounced in 2019. Prevalence was 7.2% for all students in grades 9-12, 8.3% for females, and 6.1% for males. By sexual identity, prevalence was 6.4% for heterosexuals, 7.6% for gays or lesbians, 11.5% for those unsure about their sexual identity, and 13.1% for bisexuals, based on the YRBS data.

This increased misuse of opioids among sexual minority youths, “even after controlling for other demographic and substance use characteristics ... emphasizes the importance of identifying tailored prevention strategies to address disparities among this vulnerable population,” the CDC researchers wrote.

[email protected]

SOURCE: Jones CM et al. MMWR Suppl. 2020 Aug 21;69(1):38-46.

One high school student out of every seven ever has either misused a prescription pain medicine or taken one without a prescription, according to an analysis from the Centers for Disease Control and Prevention.

That type of opioid use/misuse, reported by 14.3% of respondents to the 2019 Youth Risk Behavior Survey, was more common among females (16.1%) than males (12.4%) and even more prevalent among nonheterosexuals and those who are unsure about their sexual identity, Christopher M. Jones, PharmD, DrPH, and associates at the CDC said in the Morbidity and Mortality Weekly Report.

The YRBS data show that 18.5% of gay or lesbian students had, at some point in their lives, used a prescription opioid differently than a physician had told them to or taken one without a prescription. That figure was slightly higher (19.1%) for those unsure of their sexual identity, considerably higher (25.4%) for bisexuals, and lower for heterosexuals (12.7%), they reported.

The pattern for current use/misuse of opioids, defined as use one or more times in the 30 days before the survey, was similar to ever use but somewhat less pronounced in 2019. Prevalence was 7.2% for all students in grades 9-12, 8.3% for females, and 6.1% for males. By sexual identity, prevalence was 6.4% for heterosexuals, 7.6% for gays or lesbians, 11.5% for those unsure about their sexual identity, and 13.1% for bisexuals, based on the YRBS data.

This increased misuse of opioids among sexual minority youths, “even after controlling for other demographic and substance use characteristics ... emphasizes the importance of identifying tailored prevention strategies to address disparities among this vulnerable population,” the CDC researchers wrote.

[email protected]

SOURCE: Jones CM et al. MMWR Suppl. 2020 Aug 21;69(1):38-46.

CASE A 73-year-old woman presents to your clinic with 1 year of gradual-onset left knee pain. The pain is worse at the medial knee and at the beginning and end of the day, with some mild improvement after activity in the morning. The patient has already tried oral acetaminophen, an over-the-counter menthol cream, and a soft elastic knee brace, but these interventions have helped only minimally.

On physical exam, there is no obvious deformity of the knee. There is a bit of small joint effusion without redness or warmth. There is mild tenderness to palpation of the medial joint line. Radiographic findings include osteophytes of the medial and lateral tibial plateaus and medial and lateral femoral condyles with mild joint-space narrowing of the medial compartment, consistent with mild osteoarthritis.

How would you manage this patient’s care?

The knee is the most common joint to be affected by osteoarthritis (OA) and accounts for the majority of the disease’s total burden.¹ More than 19% of American adults ages ≥ 45 years have knee OA,^1,2 and more than half of the people with symptomatic knee OA in the United States are younger than 65 years of age.³ Longer lifespan and increasing rates of obesity are thought to be driving the increasing prevalence of knee OA, although this remains debated.¹ Risk factors for knee OA are outlined in TABLE.^1,4-8

Diagnosis: Radiographs are helpful, not essential

The diagnosis of knee OA is relatively straightforward. Gradual onset of knee joint pain is present most days, with pain worse after activity and better with rest. Patients are usually middle-aged or older and/or have a distant history of knee joint injury. Other signs, symptoms, and physical exam findings associated with knee OA include: morning stiffness < 30 minutes, crepitus, instability, range-of-motion deficit, varus or valgus deformity, bony exostosis, joint-line tenderness, joint swelling/effusion, and the absence of erythema/warmth.^1,9,10

Although radiographs are not necessary to diagnose knee OA, they can be helpful in confirming the diagnosis by assessing the degree and location of OA and ruling out other pathology. Standing, weight-bearing radiographs are particularly helpful for assessing the degree of joint-space narrowing. In addition to joint-space narrowing, radiographic findings indicative of knee OA include marginal osteophytes, subchondral sclerosis, and subchondral cysts. (See FIGURE 1.)

Keep in mind that radiographs are less sensitive for early OA, that the degree of OA seen on radiographs does not correlate well with symptoms, and that radiographic evidence of OA is a common incidental finding—especially in elderly individuals.¹¹ Although not routinely utilized for knee OA diagnosis, magnetic resonance imaging (MRI) can be used to assess for earlier stages of the disease and to rule out pathology associated with the soft tissue and cartilage that is not directly associated with OA.

Continue to: Management

Because there is no cure for OA, the primary goals of treatment are to decrease pain, improve function of the joint, and slow progression of the disease. As a result, a multifaceted treatment approach is usually undertaken that includes weight reduction and exercise therapy and may include pharmacotherapy, depending on the degree of symptoms. ­FIGURE 2 contains a summary of the stepwise management of knee OA.

Weight management can slow progression of the disease

Obesity is a causative factor in knee OA.^12,13 Patients with knee OA who achieve and maintain an appropriate body weight can potentially slow progression of the disease.^13,14 One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.¹⁵

Specific methods of weight reduction are beyond the scope of this article; however, one randomized controlled trial (RCT) involving 399 overweight and obese adults with knee OA found that individuals who participated in a dietary intervention or a combined diet and exercise intervention achieved more weight loss than those who undertook exercise alone.¹⁶ Additionally, the diet group had greater reductions in knee compression forces compared to the exercise group, and the combined diet and exercise group had less pain and better function than both the diet group and the exercise group.¹⁶ This would suggest that both diet and exercise interventions should be employed in the treatment of knee OA, not only for weight management, but also for knee joint health.

What kind of exercise? Evidence exists to support the utilization of various forms of exercise. In general, land-based therapeutic exercise improves knee pain, physical function, and quality of life, but these benefits often last less than 1 year because people often fail to maintain exercise programs for the long term.¹⁷

Specific therapies such as yoga, Tai Chi, balance training, and aquatic exercise have shown some minor improvement in symptoms related to knee OA.^18-22 Weight-bearing strength training, non–weight-­bearing strength training, and aerobic exercise have all been shown to be effective for short-term pain relief in knee OA, with non–weight-bearing strength training being the most effective.²³

Continue to: Strengthening of the upper leg muscles...

Strengthening of the upper leg muscles is thought to be one of the factors involved in reducing pain associated with knee OA.²⁴ Strength training, Tai Chi, and aerobic exercise have also been shown to decrease fall risk in the elderly with knee OA.²⁵ In general, lower impact activities (eg, walking, swimming, biking, yoga) are preferred over higher impact activities (eg, running, jumping) in order to lessen pain with exercise.^26-28

Knee orthoses: Many forms and mixed findings

Knee braces come in many forms, including soft braces (eg, elastic sleeves, simple hinged braces) and unloading braces. Many of these braces have been purported to help with knee OA although the evidence remains mixed, with a lack of high-quality trials. A systematic review of RCTs comparing various knee braces, foot orthotics, and conservative treatment for the management of medial compartment OA concluded that the optimal choice for orthosis remains unclear, and long-term evidence is lacking.²⁹

The medial unloading (valgus) knee brace is often used to treat medial compartment OA and varus malalignment of the knee by applying a valgus force, thereby reducing the load on the medial compartment. One recent systematic review concluded that medial unloading braces improve pain from medial compartment OA, but whether they improve function and stiffness is unclear.³⁰ Another study showed that compared to conservative treatment alone, valgus knee bracing has some benefit in decreasing pain and improving knee function.³¹ Additionally, an 8-year prospective study found that the valgus unloading brace can delay the time before patients need to undergo knee arthroplasty.³² However, another prospective study examining the efficacy of valgus bracing at 2.7 years and 11.2 years showed short-term but not long-term benefit.³³

Soft knee braces include a variety of elastic sleeves and simple hinged knee braces. These braces are available commercially at most pharmacies and athletic retail stores. Soft braces are thought to improve pain by a thermal and compressive effect, and to provide stability to the knee joint. One systematic review concluded that soft knee braces have a moderate effect on pain and a small-to-moderate effect on self-reported physical function.³⁴ A small trial showed that soft knee braces reduced pain and dynamic instability in individuals with knee OA.³⁵

One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.

In summary, many types of soft knee braces exist, but the evidence for recommending them individually or collectively is limited, as high-quality trials are lacking. However, the available evidence does suggest some mild benefit with regard to pain and function with no concern for adverse effects.

Continue to: Pharmacotherapy

Pharmacotherapy: Oral agents

Acetaminophen. Although people commonly use this over-the-counter analgesic for knee OA pain, recent meta-analyses have shown that acetaminophen provides little to no benefit.^36,37 Furthermore, although many believe acetaminophen causes fewer adverse effects than oral nonsteroidal anti-inflammatory drugs (NSAIDs), liver, gastrointestinal, and renal complications are not uncommon with long-term acetaminophen use. Nevertheless, a trial of acetaminophen may be beneficial in patients with cardiovascular disease or who are taking oral anticoagulants.

Oral NSAIDs. Many studies have concluded that NSAIDs are more effective at controlling pain from knee OA than acetaminophen.^37,38 They are among the most commonly prescribed treatments for knee OA, but patients and their physicians should be cautious about long-term use because of potential cardiac, renal, gastrointestinal, and other adverse effects. Although evidence regarding optimal frequency of use is scarce, oral NSAIDs should be used intermittently and at the minimal effective dose in order to decrease the risk of adverse events.

One recent meta-analysis of RCTs concluded that diclofenac at a dose of 150 mg/d is the most effective NSAID for improving pain and function associated with knee OA.³⁷ Another recent systematic review and meta-analysis analyzing multiple pharmacologic treatments found an association between celecoxib and decreased pain from knee OA.³⁹ However, this study also concluded that uncertainty surrounded all of the estimates of effect size for change in pain compared to placebo for all of the pharmacologic treatments included in the study.³⁹

A meta-analysis of RCTs comparing celecoxib to no treatment, placebo, naproxen, and diclofenac concluded that celecoxib is slightly better than placebo and the aforementioned NSAIDs in reducing pain and improving function in general OA. However, the authors had reservations regarding pharmaceutical industry involvement in the studies and overall limited data.⁴⁰

With all of that said, the American Academy of Orthopaedic Surgeons (AAOS) recommends strongly for the use of oral NSAIDs in the management of knee OA.⁴¹

Continue to: Glucosamine and chondroitin

Glucosamine and chondroitin. Glucosamine and chondroitin are supplements that have gained popularity in the treatment of knee OA. These constituents are found naturally in articular cartilage, which explains the rationale for their use. Glucosamine and chondroitin (or a combination of the 2) are associated with few adverse effects, but the evidence to support their use in knee OA management is mixed.

One large double-blind RCT (the Glucosamine/Chondroitin Arthritis Intervention Trial [GAIT]) concluded that glucosamine, chondroitin, or the combination of the 2 did not have a significant effect on reducing pain from knee OA compared to placebo and did not slow structural joint disease.⁴² However, this same study found that in a subset of patients with moderate-to-severe knee OA, the combination of glucosamine and chondroitin was mildly effective in reducing pain.⁴²

Multiple studies have shown either no benefit, inconsistent results, or limited benefit of glucosamine and chondroitin in the treatment of knee OA, with the patented crystalline form of glucosamine showing the most efficacy.^43-47 The AAOS and the American College of Rheumatology (ACR) do not recommend glucosamine and chondroitin for knee OA management.^10,41

In summary, the evidence for glucosamine, chondroitin, or a combination of the 2 for knee OA is mixed with likely limited benefit, but because they are associated with few adverse effects, patients may be offered a 3- to 6-month trial of these supplements if other effective options are exhausted.

Injections

Limited-quality evidence suggests that oral NSAIDs and intra-articular (IA) hyaluronic acid (HA) injections are equally efficacious for knee OA pain.^38,48 There is insufficient evidence directly comparing oral NSAIDs with IA corticosteroid (CS) injections.

Continue to: HA is found naturally...

HA is found naturally in articular cartilage, which explains the rationale behind its use. A network meta-analysis performed by the American Medical Society for Sports Medicine concluded that knee OA is more likely to respond to IAHA than to IACS or IA placebo, leading the society to recommend the use of IAHA in knee OA management, especially for patients > 60 years with mild-to-moderate knee OA.⁹ Conversely, the AAOS does not recommend the use of IAHA, and the ACR does not recommend for or against the use of IAHA.^10,41

Platelet-rich plasma therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.

IACSs are commonly used to provide pain relief in those with moderate-to-severe knee OA. There is evidence that a single IACS injection provides mild pain relief for up to 6 weeks.⁴⁹ However, there is some concern that repetitive IACS injections may speed cartilage loss. A 2-year randomized double-blind placebo-controlled trial comparing the effectiveness of repetitive IA triamcinolone vs saline in knee OA found no difference in pain severity and concluded that there was greater cartilage volume loss in the triamcinolone group.⁵⁰

AAOS does not recommend for or against the use of IACSs, whereas the ACR does recommend for the use of IACSs.^10,41 Given the available evidence, conservative use of IACS injections remains an option for patients with refractory moderate-to-severe knee OA.

Topicals

Topical analgesics are often utilized for knee OA because of their efficacy, tolerability, low risk of adverse effects, and ease of use. They are generally recommended over oral NSAIDs in the elderly and in individuals at risk for cardiac, renal, and gastrointestinal complications from oral NSAIDs.

Extendedrelease IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.

One review found that topical diclofenac and topical ketoprofen were comparable to the oral forms of these medications.⁵¹ One RCT concluded that topical and oral diclofenac were equally efficacious in treating knee OA symptoms, although topical diclofenac was associated with significantly fewer gastrointestinal adverse effects.⁵² In multiple randomized trials, topical diclofenac has shown efficacy compared to placebo.^53-55 A recent systematic review and meta-analysis of RCTs concluded that topical NSAIDs were safe and effective for treating general OA compared to placebo, with diclofenac patches most effective for pain relief and piroxicam most effective for functional improvement.⁵⁶

Continue to: Topical capsaicin has shown...

Topical capsaicin has shown some efficacy in treating pain associated with knee OA.⁵⁷ One meta-analysis of RCTs concluded that topical NSAIDs and capsaicin may be equally efficacious for OA-associated pain relief, although none of the RCTs directly compared the two.⁵⁸ The major limitation of capsaicin is a patient-reported mild-to-moderate burning sensation with application that may decrease compliance.

Emerging treatments: IA PRP & extended-release IA triamcinolone acetonide

IA platelet-rich plasma (PRP) has been investigated for efficacy in treating knee OA. PRP is thought to decrease inflammation in the joint, although its exact mechanism remains unknown.⁵⁹ Multiple studies have shown some benefit of PRP in reducing pain and improving function in individuals with knee OA, but nearly all of these studies have failed to show a clear benefit of PRP over HA injections.^59-63 Additionally, the authors of most of these studies mention a high risk of bias. PRP therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.

Extended-release (ER) IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.^64-66 The ER version tolerability did not differ from placebo and also showed prolonged synovial presence, lower systemic absorption, and lower blood glucose elevations compared with standard triamcinolone.^64-66

Surgical intervention: A last resort

Select patients with severe pain and disability from knee OA that is refractory to conservative management options should be referred for consideration of knee arthroplasty. Age, weight, OA location, and degree of OA are all considered with respect to knee arthroplasty timing and technique.

There is good evidence that arthroscopy with debridement, on the other hand, is no more effective than conservative management.⁶⁷

Continue to: Unicompartmental or "partial"...

Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.

CASE After reviewing the therapeutic options with your patient, you agree that she will undergo a course of physical therapy and try using topical diclofenac along with a hinged knee brace. Because of the patient’s age and co-morbidities of cardiovascular disease and mild chronic kidney disease, oral NSAIDs are avoided at this time.

Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.

The patient returns to the office in 2 months reporting mild improvement in her pain. To provide additional pain relief, an ­ultrasound-guided IA steroid injection is attempted. The patient also continues home physical therapy, activity modification, topical diclofenac, and use of a hinged knee brace.

She returns to the office 2 months later, reporting continued improvement in her pain. No further intervention is undertaken at this time.

CORRESPONDENCE
Ryan A. Sprouse, MD, CAQSM, West Virginia University School of Medicine–Eastern Campus, WVU Medicine Orthopaedics and Sports Medicine, 912 Somerset Boulevard, Charles Town, WV 25414; [email protected].

CASE A 73-year-old woman presents to your clinic with 1 year of gradual-onset left knee pain. The pain is worse at the medial knee and at the beginning and end of the day, with some mild improvement after activity in the morning. The patient has already tried oral acetaminophen, an over-the-counter menthol cream, and a soft elastic knee brace, but these interventions have helped only minimally.

On physical exam, there is no obvious deformity of the knee. There is a bit of small joint effusion without redness or warmth. There is mild tenderness to palpation of the medial joint line. Radiographic findings include osteophytes of the medial and lateral tibial plateaus and medial and lateral femoral condyles with mild joint-space narrowing of the medial compartment, consistent with mild osteoarthritis.

How would you manage this patient’s care?

The knee is the most common joint to be affected by osteoarthritis (OA) and accounts for the majority of the disease’s total burden.¹ More than 19% of American adults ages ≥ 45 years have knee OA,^1,2 and more than half of the people with symptomatic knee OA in the United States are younger than 65 years of age.³ Longer lifespan and increasing rates of obesity are thought to be driving the increasing prevalence of knee OA, although this remains debated.¹ Risk factors for knee OA are outlined in TABLE.^1,4-8

Diagnosis: Radiographs are helpful, not essential

The diagnosis of knee OA is relatively straightforward. Gradual onset of knee joint pain is present most days, with pain worse after activity and better with rest. Patients are usually middle-aged or older and/or have a distant history of knee joint injury. Other signs, symptoms, and physical exam findings associated with knee OA include: morning stiffness < 30 minutes, crepitus, instability, range-of-motion deficit, varus or valgus deformity, bony exostosis, joint-line tenderness, joint swelling/effusion, and the absence of erythema/warmth.^1,9,10

Although radiographs are not necessary to diagnose knee OA, they can be helpful in confirming the diagnosis by assessing the degree and location of OA and ruling out other pathology. Standing, weight-bearing radiographs are particularly helpful for assessing the degree of joint-space narrowing. In addition to joint-space narrowing, radiographic findings indicative of knee OA include marginal osteophytes, subchondral sclerosis, and subchondral cysts. (See FIGURE 1.)

Keep in mind that radiographs are less sensitive for early OA, that the degree of OA seen on radiographs does not correlate well with symptoms, and that radiographic evidence of OA is a common incidental finding—especially in elderly individuals.¹¹ Although not routinely utilized for knee OA diagnosis, magnetic resonance imaging (MRI) can be used to assess for earlier stages of the disease and to rule out pathology associated with the soft tissue and cartilage that is not directly associated with OA.

Continue to: Management

Because there is no cure for OA, the primary goals of treatment are to decrease pain, improve function of the joint, and slow progression of the disease. As a result, a multifaceted treatment approach is usually undertaken that includes weight reduction and exercise therapy and may include pharmacotherapy, depending on the degree of symptoms. ­FIGURE 2 contains a summary of the stepwise management of knee OA.

Weight management can slow progression of the disease

Obesity is a causative factor in knee OA.^12,13 Patients with knee OA who achieve and maintain an appropriate body weight can potentially slow progression of the disease.^13,14 One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.¹⁵

Specific methods of weight reduction are beyond the scope of this article; however, one randomized controlled trial (RCT) involving 399 overweight and obese adults with knee OA found that individuals who participated in a dietary intervention or a combined diet and exercise intervention achieved more weight loss than those who undertook exercise alone.¹⁶ Additionally, the diet group had greater reductions in knee compression forces compared to the exercise group, and the combined diet and exercise group had less pain and better function than both the diet group and the exercise group.¹⁶ This would suggest that both diet and exercise interventions should be employed in the treatment of knee OA, not only for weight management, but also for knee joint health.

What kind of exercise? Evidence exists to support the utilization of various forms of exercise. In general, land-based therapeutic exercise improves knee pain, physical function, and quality of life, but these benefits often last less than 1 year because people often fail to maintain exercise programs for the long term.¹⁷

Specific therapies such as yoga, Tai Chi, balance training, and aquatic exercise have shown some minor improvement in symptoms related to knee OA.^18-22 Weight-bearing strength training, non–weight-­bearing strength training, and aerobic exercise have all been shown to be effective for short-term pain relief in knee OA, with non–weight-bearing strength training being the most effective.²³

Continue to: Strengthening of the upper leg muscles...

Strengthening of the upper leg muscles is thought to be one of the factors involved in reducing pain associated with knee OA.²⁴ Strength training, Tai Chi, and aerobic exercise have also been shown to decrease fall risk in the elderly with knee OA.²⁵ In general, lower impact activities (eg, walking, swimming, biking, yoga) are preferred over higher impact activities (eg, running, jumping) in order to lessen pain with exercise.^26-28

Knee orthoses: Many forms and mixed findings

Knee braces come in many forms, including soft braces (eg, elastic sleeves, simple hinged braces) and unloading braces. Many of these braces have been purported to help with knee OA although the evidence remains mixed, with a lack of high-quality trials. A systematic review of RCTs comparing various knee braces, foot orthotics, and conservative treatment for the management of medial compartment OA concluded that the optimal choice for orthosis remains unclear, and long-term evidence is lacking.²⁹

The medial unloading (valgus) knee brace is often used to treat medial compartment OA and varus malalignment of the knee by applying a valgus force, thereby reducing the load on the medial compartment. One recent systematic review concluded that medial unloading braces improve pain from medial compartment OA, but whether they improve function and stiffness is unclear.³⁰ Another study showed that compared to conservative treatment alone, valgus knee bracing has some benefit in decreasing pain and improving knee function.³¹ Additionally, an 8-year prospective study found that the valgus unloading brace can delay the time before patients need to undergo knee arthroplasty.³² However, another prospective study examining the efficacy of valgus bracing at 2.7 years and 11.2 years showed short-term but not long-term benefit.³³

Soft knee braces include a variety of elastic sleeves and simple hinged knee braces. These braces are available commercially at most pharmacies and athletic retail stores. Soft braces are thought to improve pain by a thermal and compressive effect, and to provide stability to the knee joint. One systematic review concluded that soft knee braces have a moderate effect on pain and a small-to-moderate effect on self-reported physical function.³⁴ A small trial showed that soft knee braces reduced pain and dynamic instability in individuals with knee OA.³⁵

One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.

In summary, many types of soft knee braces exist, but the evidence for recommending them individually or collectively is limited, as high-quality trials are lacking. However, the available evidence does suggest some mild benefit with regard to pain and function with no concern for adverse effects.

Continue to: Pharmacotherapy

Pharmacotherapy: Oral agents

Acetaminophen. Although people commonly use this over-the-counter analgesic for knee OA pain, recent meta-analyses have shown that acetaminophen provides little to no benefit.^36,37 Furthermore, although many believe acetaminophen causes fewer adverse effects than oral nonsteroidal anti-inflammatory drugs (NSAIDs), liver, gastrointestinal, and renal complications are not uncommon with long-term acetaminophen use. Nevertheless, a trial of acetaminophen may be beneficial in patients with cardiovascular disease or who are taking oral anticoagulants.

Oral NSAIDs. Many studies have concluded that NSAIDs are more effective at controlling pain from knee OA than acetaminophen.^37,38 They are among the most commonly prescribed treatments for knee OA, but patients and their physicians should be cautious about long-term use because of potential cardiac, renal, gastrointestinal, and other adverse effects. Although evidence regarding optimal frequency of use is scarce, oral NSAIDs should be used intermittently and at the minimal effective dose in order to decrease the risk of adverse events.

One recent meta-analysis of RCTs concluded that diclofenac at a dose of 150 mg/d is the most effective NSAID for improving pain and function associated with knee OA.³⁷ Another recent systematic review and meta-analysis analyzing multiple pharmacologic treatments found an association between celecoxib and decreased pain from knee OA.³⁹ However, this study also concluded that uncertainty surrounded all of the estimates of effect size for change in pain compared to placebo for all of the pharmacologic treatments included in the study.³⁹

A meta-analysis of RCTs comparing celecoxib to no treatment, placebo, naproxen, and diclofenac concluded that celecoxib is slightly better than placebo and the aforementioned NSAIDs in reducing pain and improving function in general OA. However, the authors had reservations regarding pharmaceutical industry involvement in the studies and overall limited data.⁴⁰

With all of that said, the American Academy of Orthopaedic Surgeons (AAOS) recommends strongly for the use of oral NSAIDs in the management of knee OA.⁴¹

Continue to: Glucosamine and chondroitin

Glucosamine and chondroitin. Glucosamine and chondroitin are supplements that have gained popularity in the treatment of knee OA. These constituents are found naturally in articular cartilage, which explains the rationale for their use. Glucosamine and chondroitin (or a combination of the 2) are associated with few adverse effects, but the evidence to support their use in knee OA management is mixed.

One large double-blind RCT (the Glucosamine/Chondroitin Arthritis Intervention Trial [GAIT]) concluded that glucosamine, chondroitin, or the combination of the 2 did not have a significant effect on reducing pain from knee OA compared to placebo and did not slow structural joint disease.⁴² However, this same study found that in a subset of patients with moderate-to-severe knee OA, the combination of glucosamine and chondroitin was mildly effective in reducing pain.⁴²

Multiple studies have shown either no benefit, inconsistent results, or limited benefit of glucosamine and chondroitin in the treatment of knee OA, with the patented crystalline form of glucosamine showing the most efficacy.^43-47 The AAOS and the American College of Rheumatology (ACR) do not recommend glucosamine and chondroitin for knee OA management.^10,41

In summary, the evidence for glucosamine, chondroitin, or a combination of the 2 for knee OA is mixed with likely limited benefit, but because they are associated with few adverse effects, patients may be offered a 3- to 6-month trial of these supplements if other effective options are exhausted.

Injections

Limited-quality evidence suggests that oral NSAIDs and intra-articular (IA) hyaluronic acid (HA) injections are equally efficacious for knee OA pain.^38,48 There is insufficient evidence directly comparing oral NSAIDs with IA corticosteroid (CS) injections.

Continue to: HA is found naturally...

HA is found naturally in articular cartilage, which explains the rationale behind its use. A network meta-analysis performed by the American Medical Society for Sports Medicine concluded that knee OA is more likely to respond to IAHA than to IACS or IA placebo, leading the society to recommend the use of IAHA in knee OA management, especially for patients > 60 years with mild-to-moderate knee OA.⁹ Conversely, the AAOS does not recommend the use of IAHA, and the ACR does not recommend for or against the use of IAHA.^10,41

Platelet-rich plasma therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.

IACSs are commonly used to provide pain relief in those with moderate-to-severe knee OA. There is evidence that a single IACS injection provides mild pain relief for up to 6 weeks.⁴⁹ However, there is some concern that repetitive IACS injections may speed cartilage loss. A 2-year randomized double-blind placebo-controlled trial comparing the effectiveness of repetitive IA triamcinolone vs saline in knee OA found no difference in pain severity and concluded that there was greater cartilage volume loss in the triamcinolone group.⁵⁰

AAOS does not recommend for or against the use of IACSs, whereas the ACR does recommend for the use of IACSs.^10,41 Given the available evidence, conservative use of IACS injections remains an option for patients with refractory moderate-to-severe knee OA.

Topicals

Topical analgesics are often utilized for knee OA because of their efficacy, tolerability, low risk of adverse effects, and ease of use. They are generally recommended over oral NSAIDs in the elderly and in individuals at risk for cardiac, renal, and gastrointestinal complications from oral NSAIDs.

Extendedrelease IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.

One review found that topical diclofenac and topical ketoprofen were comparable to the oral forms of these medications.⁵¹ One RCT concluded that topical and oral diclofenac were equally efficacious in treating knee OA symptoms, although topical diclofenac was associated with significantly fewer gastrointestinal adverse effects.⁵² In multiple randomized trials, topical diclofenac has shown efficacy compared to placebo.^53-55 A recent systematic review and meta-analysis of RCTs concluded that topical NSAIDs were safe and effective for treating general OA compared to placebo, with diclofenac patches most effective for pain relief and piroxicam most effective for functional improvement.⁵⁶

Continue to: Topical capsaicin has shown...

Topical capsaicin has shown some efficacy in treating pain associated with knee OA.⁵⁷ One meta-analysis of RCTs concluded that topical NSAIDs and capsaicin may be equally efficacious for OA-associated pain relief, although none of the RCTs directly compared the two.⁵⁸ The major limitation of capsaicin is a patient-reported mild-to-moderate burning sensation with application that may decrease compliance.

Emerging treatments: IA PRP & extended-release IA triamcinolone acetonide

IA platelet-rich plasma (PRP) has been investigated for efficacy in treating knee OA. PRP is thought to decrease inflammation in the joint, although its exact mechanism remains unknown.⁵⁹ Multiple studies have shown some benefit of PRP in reducing pain and improving function in individuals with knee OA, but nearly all of these studies have failed to show a clear benefit of PRP over HA injections.^59-63 Additionally, the authors of most of these studies mention a high risk of bias. PRP therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.

Extended-release (ER) IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.^64-66 The ER version tolerability did not differ from placebo and also showed prolonged synovial presence, lower systemic absorption, and lower blood glucose elevations compared with standard triamcinolone.^64-66

Surgical intervention: A last resort

Select patients with severe pain and disability from knee OA that is refractory to conservative management options should be referred for consideration of knee arthroplasty. Age, weight, OA location, and degree of OA are all considered with respect to knee arthroplasty timing and technique.

There is good evidence that arthroscopy with debridement, on the other hand, is no more effective than conservative management.⁶⁷

Continue to: Unicompartmental or "partial"...

Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.

CASE After reviewing the therapeutic options with your patient, you agree that she will undergo a course of physical therapy and try using topical diclofenac along with a hinged knee brace. Because of the patient’s age and co-morbidities of cardiovascular disease and mild chronic kidney disease, oral NSAIDs are avoided at this time.

Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.

The patient returns to the office in 2 months reporting mild improvement in her pain. To provide additional pain relief, an ­ultrasound-guided IA steroid injection is attempted. The patient also continues home physical therapy, activity modification, topical diclofenac, and use of a hinged knee brace.

She returns to the office 2 months later, reporting continued improvement in her pain. No further intervention is undertaken at this time.

CORRESPONDENCE
Ryan A. Sprouse, MD, CAQSM, West Virginia University School of Medicine–Eastern Campus, WVU Medicine Orthopaedics and Sports Medicine, 912 Somerset Boulevard, Charles Town, WV 25414; [email protected].

CASE A 73-year-old woman presents to your clinic with 1 year of gradual-onset left knee pain. The pain is worse at the medial knee and at the beginning and end of the day, with some mild improvement after activity in the morning. The patient has already tried oral acetaminophen, an over-the-counter menthol cream, and a soft elastic knee brace, but these interventions have helped only minimally.

On physical exam, there is no obvious deformity of the knee. There is a bit of small joint effusion without redness or warmth. There is mild tenderness to palpation of the medial joint line. Radiographic findings include osteophytes of the medial and lateral tibial plateaus and medial and lateral femoral condyles with mild joint-space narrowing of the medial compartment, consistent with mild osteoarthritis.

How would you manage this patient’s care?

The knee is the most common joint to be affected by osteoarthritis (OA) and accounts for the majority of the disease’s total burden.¹ More than 19% of American adults ages ≥ 45 years have knee OA,^1,2 and more than half of the people with symptomatic knee OA in the United States are younger than 65 years of age.³ Longer lifespan and increasing rates of obesity are thought to be driving the increasing prevalence of knee OA, although this remains debated.¹ Risk factors for knee OA are outlined in TABLE.^1,4-8

Diagnosis: Radiographs are helpful, not essential

The diagnosis of knee OA is relatively straightforward. Gradual onset of knee joint pain is present most days, with pain worse after activity and better with rest. Patients are usually middle-aged or older and/or have a distant history of knee joint injury. Other signs, symptoms, and physical exam findings associated with knee OA include: morning stiffness < 30 minutes, crepitus, instability, range-of-motion deficit, varus or valgus deformity, bony exostosis, joint-line tenderness, joint swelling/effusion, and the absence of erythema/warmth.^1,9,10

Although radiographs are not necessary to diagnose knee OA, they can be helpful in confirming the diagnosis by assessing the degree and location of OA and ruling out other pathology. Standing, weight-bearing radiographs are particularly helpful for assessing the degree of joint-space narrowing. In addition to joint-space narrowing, radiographic findings indicative of knee OA include marginal osteophytes, subchondral sclerosis, and subchondral cysts. (See FIGURE 1.)

Keep in mind that radiographs are less sensitive for early OA, that the degree of OA seen on radiographs does not correlate well with symptoms, and that radiographic evidence of OA is a common incidental finding—especially in elderly individuals.¹¹ Although not routinely utilized for knee OA diagnosis, magnetic resonance imaging (MRI) can be used to assess for earlier stages of the disease and to rule out pathology associated with the soft tissue and cartilage that is not directly associated with OA.

Continue to: Management

Because there is no cure for OA, the primary goals of treatment are to decrease pain, improve function of the joint, and slow progression of the disease. As a result, a multifaceted treatment approach is usually undertaken that includes weight reduction and exercise therapy and may include pharmacotherapy, depending on the degree of symptoms. ­FIGURE 2 contains a summary of the stepwise management of knee OA.

Weight management can slow progression of the disease

Obesity is a causative factor in knee OA.^12,13 Patients with knee OA who achieve and maintain an appropriate body weight can potentially slow progression of the disease.^13,14 One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.¹⁵

Specific methods of weight reduction are beyond the scope of this article; however, one randomized controlled trial (RCT) involving 399 overweight and obese adults with knee OA found that individuals who participated in a dietary intervention or a combined diet and exercise intervention achieved more weight loss than those who undertook exercise alone.¹⁶ Additionally, the diet group had greater reductions in knee compression forces compared to the exercise group, and the combined diet and exercise group had less pain and better function than both the diet group and the exercise group.¹⁶ This would suggest that both diet and exercise interventions should be employed in the treatment of knee OA, not only for weight management, but also for knee joint health.

What kind of exercise? Evidence exists to support the utilization of various forms of exercise. In general, land-based therapeutic exercise improves knee pain, physical function, and quality of life, but these benefits often last less than 1 year because people often fail to maintain exercise programs for the long term.¹⁷

Specific therapies such as yoga, Tai Chi, balance training, and aquatic exercise have shown some minor improvement in symptoms related to knee OA.^18-22 Weight-bearing strength training, non–weight-­bearing strength training, and aerobic exercise have all been shown to be effective for short-term pain relief in knee OA, with non–weight-bearing strength training being the most effective.²³

Continue to: Strengthening of the upper leg muscles...

Strengthening of the upper leg muscles is thought to be one of the factors involved in reducing pain associated with knee OA.²⁴ Strength training, Tai Chi, and aerobic exercise have also been shown to decrease fall risk in the elderly with knee OA.²⁵ In general, lower impact activities (eg, walking, swimming, biking, yoga) are preferred over higher impact activities (eg, running, jumping) in order to lessen pain with exercise.^26-28

Knee orthoses: Many forms and mixed findings

Knee braces come in many forms, including soft braces (eg, elastic sleeves, simple hinged braces) and unloading braces. Many of these braces have been purported to help with knee OA although the evidence remains mixed, with a lack of high-quality trials. A systematic review of RCTs comparing various knee braces, foot orthotics, and conservative treatment for the management of medial compartment OA concluded that the optimal choice for orthosis remains unclear, and long-term evidence is lacking.²⁹

The medial unloading (valgus) knee brace is often used to treat medial compartment OA and varus malalignment of the knee by applying a valgus force, thereby reducing the load on the medial compartment. One recent systematic review concluded that medial unloading braces improve pain from medial compartment OA, but whether they improve function and stiffness is unclear.³⁰ Another study showed that compared to conservative treatment alone, valgus knee bracing has some benefit in decreasing pain and improving knee function.³¹ Additionally, an 8-year prospective study found that the valgus unloading brace can delay the time before patients need to undergo knee arthroplasty.³² However, another prospective study examining the efficacy of valgus bracing at 2.7 years and 11.2 years showed short-term but not long-term benefit.³³

Soft knee braces include a variety of elastic sleeves and simple hinged knee braces. These braces are available commercially at most pharmacies and athletic retail stores. Soft braces are thought to improve pain by a thermal and compressive effect, and to provide stability to the knee joint. One systematic review concluded that soft knee braces have a moderate effect on pain and a small-to-moderate effect on self-reported physical function.³⁴ A small trial showed that soft knee braces reduced pain and dynamic instability in individuals with knee OA.³⁵

One pound of weight loss can lead to a 4-fold reduction in the load exerted on the knee per step.

In summary, many types of soft knee braces exist, but the evidence for recommending them individually or collectively is limited, as high-quality trials are lacking. However, the available evidence does suggest some mild benefit with regard to pain and function with no concern for adverse effects.

Continue to: Pharmacotherapy

Pharmacotherapy: Oral agents

Acetaminophen. Although people commonly use this over-the-counter analgesic for knee OA pain, recent meta-analyses have shown that acetaminophen provides little to no benefit.^36,37 Furthermore, although many believe acetaminophen causes fewer adverse effects than oral nonsteroidal anti-inflammatory drugs (NSAIDs), liver, gastrointestinal, and renal complications are not uncommon with long-term acetaminophen use. Nevertheless, a trial of acetaminophen may be beneficial in patients with cardiovascular disease or who are taking oral anticoagulants.

Oral NSAIDs. Many studies have concluded that NSAIDs are more effective at controlling pain from knee OA than acetaminophen.^37,38 They are among the most commonly prescribed treatments for knee OA, but patients and their physicians should be cautious about long-term use because of potential cardiac, renal, gastrointestinal, and other adverse effects. Although evidence regarding optimal frequency of use is scarce, oral NSAIDs should be used intermittently and at the minimal effective dose in order to decrease the risk of adverse events.

One recent meta-analysis of RCTs concluded that diclofenac at a dose of 150 mg/d is the most effective NSAID for improving pain and function associated with knee OA.³⁷ Another recent systematic review and meta-analysis analyzing multiple pharmacologic treatments found an association between celecoxib and decreased pain from knee OA.³⁹ However, this study also concluded that uncertainty surrounded all of the estimates of effect size for change in pain compared to placebo for all of the pharmacologic treatments included in the study.³⁹

A meta-analysis of RCTs comparing celecoxib to no treatment, placebo, naproxen, and diclofenac concluded that celecoxib is slightly better than placebo and the aforementioned NSAIDs in reducing pain and improving function in general OA. However, the authors had reservations regarding pharmaceutical industry involvement in the studies and overall limited data.⁴⁰

With all of that said, the American Academy of Orthopaedic Surgeons (AAOS) recommends strongly for the use of oral NSAIDs in the management of knee OA.⁴¹

Continue to: Glucosamine and chondroitin

Glucosamine and chondroitin. Glucosamine and chondroitin are supplements that have gained popularity in the treatment of knee OA. These constituents are found naturally in articular cartilage, which explains the rationale for their use. Glucosamine and chondroitin (or a combination of the 2) are associated with few adverse effects, but the evidence to support their use in knee OA management is mixed.

One large double-blind RCT (the Glucosamine/Chondroitin Arthritis Intervention Trial [GAIT]) concluded that glucosamine, chondroitin, or the combination of the 2 did not have a significant effect on reducing pain from knee OA compared to placebo and did not slow structural joint disease.⁴² However, this same study found that in a subset of patients with moderate-to-severe knee OA, the combination of glucosamine and chondroitin was mildly effective in reducing pain.⁴²

Multiple studies have shown either no benefit, inconsistent results, or limited benefit of glucosamine and chondroitin in the treatment of knee OA, with the patented crystalline form of glucosamine showing the most efficacy.^43-47 The AAOS and the American College of Rheumatology (ACR) do not recommend glucosamine and chondroitin for knee OA management.^10,41

In summary, the evidence for glucosamine, chondroitin, or a combination of the 2 for knee OA is mixed with likely limited benefit, but because they are associated with few adverse effects, patients may be offered a 3- to 6-month trial of these supplements if other effective options are exhausted.

Injections

Limited-quality evidence suggests that oral NSAIDs and intra-articular (IA) hyaluronic acid (HA) injections are equally efficacious for knee OA pain.^38,48 There is insufficient evidence directly comparing oral NSAIDs with IA corticosteroid (CS) injections.

Continue to: HA is found naturally...

HA is found naturally in articular cartilage, which explains the rationale behind its use. A network meta-analysis performed by the American Medical Society for Sports Medicine concluded that knee OA is more likely to respond to IAHA than to IACS or IA placebo, leading the society to recommend the use of IAHA in knee OA management, especially for patients > 60 years with mild-to-moderate knee OA.⁹ Conversely, the AAOS does not recommend the use of IAHA, and the ACR does not recommend for or against the use of IAHA.^10,41

Platelet-rich plasma therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.

IACSs are commonly used to provide pain relief in those with moderate-to-severe knee OA. There is evidence that a single IACS injection provides mild pain relief for up to 6 weeks.⁴⁹ However, there is some concern that repetitive IACS injections may speed cartilage loss. A 2-year randomized double-blind placebo-controlled trial comparing the effectiveness of repetitive IA triamcinolone vs saline in knee OA found no difference in pain severity and concluded that there was greater cartilage volume loss in the triamcinolone group.⁵⁰

AAOS does not recommend for or against the use of IACSs, whereas the ACR does recommend for the use of IACSs.^10,41 Given the available evidence, conservative use of IACS injections remains an option for patients with refractory moderate-to-severe knee OA.

Topicals

Topical analgesics are often utilized for knee OA because of their efficacy, tolerability, low risk of adverse effects, and ease of use. They are generally recommended over oral NSAIDs in the elderly and in individuals at risk for cardiac, renal, and gastrointestinal complications from oral NSAIDs.

Extendedrelease IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.

One review found that topical diclofenac and topical ketoprofen were comparable to the oral forms of these medications.⁵¹ One RCT concluded that topical and oral diclofenac were equally efficacious in treating knee OA symptoms, although topical diclofenac was associated with significantly fewer gastrointestinal adverse effects.⁵² In multiple randomized trials, topical diclofenac has shown efficacy compared to placebo.^53-55 A recent systematic review and meta-analysis of RCTs concluded that topical NSAIDs were safe and effective for treating general OA compared to placebo, with diclofenac patches most effective for pain relief and piroxicam most effective for functional improvement.⁵⁶

Continue to: Topical capsaicin has shown...

Topical capsaicin has shown some efficacy in treating pain associated with knee OA.⁵⁷ One meta-analysis of RCTs concluded that topical NSAIDs and capsaicin may be equally efficacious for OA-associated pain relief, although none of the RCTs directly compared the two.⁵⁸ The major limitation of capsaicin is a patient-reported mild-to-moderate burning sensation with application that may decrease compliance.

Emerging treatments: IA PRP & extended-release IA triamcinolone acetonide

IA platelet-rich plasma (PRP) has been investigated for efficacy in treating knee OA. PRP is thought to decrease inflammation in the joint, although its exact mechanism remains unknown.⁵⁹ Multiple studies have shown some benefit of PRP in reducing pain and improving function in individuals with knee OA, but nearly all of these studies have failed to show a clear benefit of PRP over HA injections.^59-63 Additionally, the authors of most of these studies mention a high risk of bias. PRP therapy is expensive and generally is not covered by insurance companies, which precludes its use for many people.

Extended-release (ER) IA triamcinolone acetonide (Zilretta) has shown some superiority to standard IA triamcinolone acetonide in both degree and duration of pain relief for knee OA.^64-66 The ER version tolerability did not differ from placebo and also showed prolonged synovial presence, lower systemic absorption, and lower blood glucose elevations compared with standard triamcinolone.^64-66

Surgical intervention: A last resort

Select patients with severe pain and disability from knee OA that is refractory to conservative management options should be referred for consideration of knee arthroplasty. Age, weight, OA location, and degree of OA are all considered with respect to knee arthroplasty timing and technique.

There is good evidence that arthroscopy with debridement, on the other hand, is no more effective than conservative management.⁶⁷

Continue to: Unicompartmental or "partial"...

Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.

CASE After reviewing the therapeutic options with your patient, you agree that she will undergo a course of physical therapy and try using topical diclofenac along with a hinged knee brace. Because of the patient’s age and co-morbidities of cardiovascular disease and mild chronic kidney disease, oral NSAIDs are avoided at this time.

Unicompartmental or “partial” knee replacements are reserved for select cases when 1 knee compartment has a significantly higher degree of degenerative change.

The patient returns to the office in 2 months reporting mild improvement in her pain. To provide additional pain relief, an ­ultrasound-guided IA steroid injection is attempted. The patient also continues home physical therapy, activity modification, topical diclofenac, and use of a hinged knee brace.

She returns to the office 2 months later, reporting continued improvement in her pain. No further intervention is undertaken at this time.

CORRESPONDENCE
Ryan A. Sprouse, MD, CAQSM, West Virginia University School of Medicine–Eastern Campus, WVU Medicine Orthopaedics and Sports Medicine, 912 Somerset Boulevard, Charles Town, WV 25414; [email protected].

A 15-year-old girl was brought to the Family Medicine Clinic in Somaliland, Africa, for evaluation of intermittent abdominal pain and watery diarrhea of 12 years’ duration. Over the previous 2 months, her symptoms had worsened and included vomiting and weight loss. She denied fever, melena, or hematemesis.

Physical examination revealed a thin female with a normal abdominal exam and numerous hyperpigmented macules on the lips, buccal mucosa, fingers, and toes (FIGURE 1). Her family reported that the black spots on her lips had been there since birth. There was no known family history of similar symptoms or black spots.

Her hemoglobin was 10 g/dL (reference range, 12–15 g/dL). A probable diagnosis was discussed with the family, and they elected to travel to India for further evaluation due to limited diagnostic resources in their location. In India, computed tomography (CT) and ultrasonography showed duodenojejunal intussusception. Upper gastrointestinal (GI) endoscopy revealed multiple polyps from the lower stomach to the jejunum of the small bowel; colonoscopy was normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Our patient was given a diagnosis of Peutz-Jeghers syndrome (PJS) based on the characteristic pigmented mucocutaneous macules and numerous polyps in the stomach and small bowel. PJS is an autosomal dominant syndrome characterized by mucocutaneous pigmentation, polyposis of the GI tract, and increased cancer risk. The prevalence is approximately 1 in 100,000.¹ Genetic testing for the STK11 gene mutation, which is found in 70% of familial cases and 30% to 67% of sporadic cases, is not required for diagnosis.¹

What you’ll see. The bluish brown to black spots of PJS often are apparent at birth or in early infancy. They are most common on the lips, buccal mucosa, perioral region, palms, and soles.

When PeutzJeghers syndrome is suspected, the entire GI tract should be investigated.

The polyps may cause bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction.² Intussusception is the most frequent cause of morbidity in childhood for PJS patients.^3,4 Recurrent attacks of abdominal pain likely result from recurring transient episodes of incomplete intussusception. The polyps usually are benign, but patients are at increased risk of GI and non-GI malignancies such as breast, pancreas, lung, and reproductive tract cancers.¹ Most cancers associated with PJS occur during adulthood.²

Other possible causes of hyperpigmentation

PJS can be differentiated from other causes of hyperpigmentation by clinical presentation and/or genetic testing.

Laugier-Hunziker syndrome manifests with macular hyperpigmentation of the lips and buccal mucosa and pigmented bands on the nails in young or middle-aged adults. It is not associated with intestinal polyps.

Continue to: Cronkhite-Canada syndrome

Cronkhite-Canada syndrome consists of acral and oral pigmented macules and GI polyps as well as generalized darkening of the skin, extensive alopecia, loss of taste, and nail dystrophy.

Familial lentiginosis syndromes such as Noonan syndrome and NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, ephelides) have other systemic signs such as cardiac abnormalities, and the pigmentation is not as clearly perioral.

Albright syndrome manifests with oral pigmented macules but also is associated with precocious puberty and polyostotic fibrous dysplasia.

Addison disease may cause multiple hyperpigmented macules but has other systemic involvement; adrenocorticotropic hormone levels are elevated.

Juvenile polyposis syndrome manifests with GI polyps but is not associated with mucosal pigmentation.

Continue to: Use these 4 criteria to make the diagnosis

Use these 4 criteria to make the diagnosis

The diagnosis of PJS is made using the following criteria: (1) two or more histologically confirmed PJS polyps, (2) any number of PJS polyps and a family history of PJS, (3) characteristic mucocutaneous pigmentation and a family history of PJS, or (4) any number of PJS polyps and characteristic mucocutaneous pigmentation.²

When PJS is suspected, the entire GI tract should be investigated. The hamartomatous polyps may be found from the stomach to the anal canal, but the small bowel most commonly is involved. The polyps may occur in early childhood, with one study of 14 children reporting a median age of 4.5 years.⁵ Polyp biopsy will show smooth muscle arborization. When possible, those who meet clinical criteria for PJS should undergo genetic testing for a STK11 gene mutation. PJS may occur due to de novo mutations in patients with no family history.⁶

Long-term management involves surveillance for polyps and cancer

Screening guidelines for polyps vary. Some suggest starting screening at age 8 to 10 years with esophagogastroduodenoscopy or capsule endoscopy and if negative, colonoscopy at age 18. Others suggest starting screening at 4 to 5 years of age.⁵ The recommendation is to remove polyps if technically feasible.³ Surveillance for Sertoli cell tumors (sex cord stromal tumors) should be done before puberty, and evaluation of other organs at risk of malignancy should begin by the end of adolescence.

The pigmented macules do not require treatment. Macules on the lips may disappear with time, while those on the buccal mucosa persist. The lip lesions can be lightened with chemical peels or laser.

Our patient underwent laparotomy, which revealed a grossly dilated and gangrenous small bowel segment. Intussusception was not present and was thought to have spontaneously reduced. Resection and anastomosis of the affected small bowel was performed. The patient’s postoperative course was uneventful, and her diarrhea and abdominal pain resolved. We recommended follow-up in her home city with primary care and a GI specialist and explained the need for surveillance of her condition.

CORRESPONDENCE
Josette R. McMichael, MD, Department of Dermatology, Emory University, 1525 Clifton Road NE, 1st Floor, Atlanta, GA 30322; [email protected]

A 15-year-old girl was brought to the Family Medicine Clinic in Somaliland, Africa, for evaluation of intermittent abdominal pain and watery diarrhea of 12 years’ duration. Over the previous 2 months, her symptoms had worsened and included vomiting and weight loss. She denied fever, melena, or hematemesis.

Physical examination revealed a thin female with a normal abdominal exam and numerous hyperpigmented macules on the lips, buccal mucosa, fingers, and toes (FIGURE 1). Her family reported that the black spots on her lips had been there since birth. There was no known family history of similar symptoms or black spots.

Her hemoglobin was 10 g/dL (reference range, 12–15 g/dL). A probable diagnosis was discussed with the family, and they elected to travel to India for further evaluation due to limited diagnostic resources in their location. In India, computed tomography (CT) and ultrasonography showed duodenojejunal intussusception. Upper gastrointestinal (GI) endoscopy revealed multiple polyps from the lower stomach to the jejunum of the small bowel; colonoscopy was normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Our patient was given a diagnosis of Peutz-Jeghers syndrome (PJS) based on the characteristic pigmented mucocutaneous macules and numerous polyps in the stomach and small bowel. PJS is an autosomal dominant syndrome characterized by mucocutaneous pigmentation, polyposis of the GI tract, and increased cancer risk. The prevalence is approximately 1 in 100,000.¹ Genetic testing for the STK11 gene mutation, which is found in 70% of familial cases and 30% to 67% of sporadic cases, is not required for diagnosis.¹

What you’ll see. The bluish brown to black spots of PJS often are apparent at birth or in early infancy. They are most common on the lips, buccal mucosa, perioral region, palms, and soles.

When PeutzJeghers syndrome is suspected, the entire GI tract should be investigated.

The polyps may cause bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction.² Intussusception is the most frequent cause of morbidity in childhood for PJS patients.^3,4 Recurrent attacks of abdominal pain likely result from recurring transient episodes of incomplete intussusception. The polyps usually are benign, but patients are at increased risk of GI and non-GI malignancies such as breast, pancreas, lung, and reproductive tract cancers.¹ Most cancers associated with PJS occur during adulthood.²

Other possible causes of hyperpigmentation

PJS can be differentiated from other causes of hyperpigmentation by clinical presentation and/or genetic testing.

Laugier-Hunziker syndrome manifests with macular hyperpigmentation of the lips and buccal mucosa and pigmented bands on the nails in young or middle-aged adults. It is not associated with intestinal polyps.

Continue to: Cronkhite-Canada syndrome

Cronkhite-Canada syndrome consists of acral and oral pigmented macules and GI polyps as well as generalized darkening of the skin, extensive alopecia, loss of taste, and nail dystrophy.

Familial lentiginosis syndromes such as Noonan syndrome and NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, ephelides) have other systemic signs such as cardiac abnormalities, and the pigmentation is not as clearly perioral.

Albright syndrome manifests with oral pigmented macules but also is associated with precocious puberty and polyostotic fibrous dysplasia.

Addison disease may cause multiple hyperpigmented macules but has other systemic involvement; adrenocorticotropic hormone levels are elevated.

Juvenile polyposis syndrome manifests with GI polyps but is not associated with mucosal pigmentation.

Continue to: Use these 4 criteria to make the diagnosis

Use these 4 criteria to make the diagnosis

The diagnosis of PJS is made using the following criteria: (1) two or more histologically confirmed PJS polyps, (2) any number of PJS polyps and a family history of PJS, (3) characteristic mucocutaneous pigmentation and a family history of PJS, or (4) any number of PJS polyps and characteristic mucocutaneous pigmentation.²

When PJS is suspected, the entire GI tract should be investigated. The hamartomatous polyps may be found from the stomach to the anal canal, but the small bowel most commonly is involved. The polyps may occur in early childhood, with one study of 14 children reporting a median age of 4.5 years.⁵ Polyp biopsy will show smooth muscle arborization. When possible, those who meet clinical criteria for PJS should undergo genetic testing for a STK11 gene mutation. PJS may occur due to de novo mutations in patients with no family history.⁶

Long-term management involves surveillance for polyps and cancer

Screening guidelines for polyps vary. Some suggest starting screening at age 8 to 10 years with esophagogastroduodenoscopy or capsule endoscopy and if negative, colonoscopy at age 18. Others suggest starting screening at 4 to 5 years of age.⁵ The recommendation is to remove polyps if technically feasible.³ Surveillance for Sertoli cell tumors (sex cord stromal tumors) should be done before puberty, and evaluation of other organs at risk of malignancy should begin by the end of adolescence.

The pigmented macules do not require treatment. Macules on the lips may disappear with time, while those on the buccal mucosa persist. The lip lesions can be lightened with chemical peels or laser.

Our patient underwent laparotomy, which revealed a grossly dilated and gangrenous small bowel segment. Intussusception was not present and was thought to have spontaneously reduced. Resection and anastomosis of the affected small bowel was performed. The patient’s postoperative course was uneventful, and her diarrhea and abdominal pain resolved. We recommended follow-up in her home city with primary care and a GI specialist and explained the need for surveillance of her condition.

CORRESPONDENCE
Josette R. McMichael, MD, Department of Dermatology, Emory University, 1525 Clifton Road NE, 1st Floor, Atlanta, GA 30322; [email protected]

A 15-year-old girl was brought to the Family Medicine Clinic in Somaliland, Africa, for evaluation of intermittent abdominal pain and watery diarrhea of 12 years’ duration. Over the previous 2 months, her symptoms had worsened and included vomiting and weight loss. She denied fever, melena, or hematemesis.

Physical examination revealed a thin female with a normal abdominal exam and numerous hyperpigmented macules on the lips, buccal mucosa, fingers, and toes (FIGURE 1). Her family reported that the black spots on her lips had been there since birth. There was no known family history of similar symptoms or black spots.

Her hemoglobin was 10 g/dL (reference range, 12–15 g/dL). A probable diagnosis was discussed with the family, and they elected to travel to India for further evaluation due to limited diagnostic resources in their location. In India, computed tomography (CT) and ultrasonography showed duodenojejunal intussusception. Upper gastrointestinal (GI) endoscopy revealed multiple polyps from the lower stomach to the jejunum of the small bowel; colonoscopy was normal.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Our patient was given a diagnosis of Peutz-Jeghers syndrome (PJS) based on the characteristic pigmented mucocutaneous macules and numerous polyps in the stomach and small bowel. PJS is an autosomal dominant syndrome characterized by mucocutaneous pigmentation, polyposis of the GI tract, and increased cancer risk. The prevalence is approximately 1 in 100,000.¹ Genetic testing for the STK11 gene mutation, which is found in 70% of familial cases and 30% to 67% of sporadic cases, is not required for diagnosis.¹

What you’ll see. The bluish brown to black spots of PJS often are apparent at birth or in early infancy. They are most common on the lips, buccal mucosa, perioral region, palms, and soles.

When PeutzJeghers syndrome is suspected, the entire GI tract should be investigated.

The polyps may cause bleeding, anemia, and abdominal pain due to intussusception, obstruction, or infarction.² Intussusception is the most frequent cause of morbidity in childhood for PJS patients.^3,4 Recurrent attacks of abdominal pain likely result from recurring transient episodes of incomplete intussusception. The polyps usually are benign, but patients are at increased risk of GI and non-GI malignancies such as breast, pancreas, lung, and reproductive tract cancers.¹ Most cancers associated with PJS occur during adulthood.²

Other possible causes of hyperpigmentation

PJS can be differentiated from other causes of hyperpigmentation by clinical presentation and/or genetic testing.

Laugier-Hunziker syndrome manifests with macular hyperpigmentation of the lips and buccal mucosa and pigmented bands on the nails in young or middle-aged adults. It is not associated with intestinal polyps.

Continue to: Cronkhite-Canada syndrome

Cronkhite-Canada syndrome consists of acral and oral pigmented macules and GI polyps as well as generalized darkening of the skin, extensive alopecia, loss of taste, and nail dystrophy.

Familial lentiginosis syndromes such as Noonan syndrome and NAME syndrome (nevi, atrial myxoma, myxoid neurofibroma, ephelides) have other systemic signs such as cardiac abnormalities, and the pigmentation is not as clearly perioral.

Albright syndrome manifests with oral pigmented macules but also is associated with precocious puberty and polyostotic fibrous dysplasia.

Addison disease may cause multiple hyperpigmented macules but has other systemic involvement; adrenocorticotropic hormone levels are elevated.

Juvenile polyposis syndrome manifests with GI polyps but is not associated with mucosal pigmentation.

Continue to: Use these 4 criteria to make the diagnosis

Use these 4 criteria to make the diagnosis

The diagnosis of PJS is made using the following criteria: (1) two or more histologically confirmed PJS polyps, (2) any number of PJS polyps and a family history of PJS, (3) characteristic mucocutaneous pigmentation and a family history of PJS, or (4) any number of PJS polyps and characteristic mucocutaneous pigmentation.²

When PJS is suspected, the entire GI tract should be investigated. The hamartomatous polyps may be found from the stomach to the anal canal, but the small bowel most commonly is involved. The polyps may occur in early childhood, with one study of 14 children reporting a median age of 4.5 years.⁵ Polyp biopsy will show smooth muscle arborization. When possible, those who meet clinical criteria for PJS should undergo genetic testing for a STK11 gene mutation. PJS may occur due to de novo mutations in patients with no family history.⁶

Long-term management involves surveillance for polyps and cancer

Screening guidelines for polyps vary. Some suggest starting screening at age 8 to 10 years with esophagogastroduodenoscopy or capsule endoscopy and if negative, colonoscopy at age 18. Others suggest starting screening at 4 to 5 years of age.⁵ The recommendation is to remove polyps if technically feasible.³ Surveillance for Sertoli cell tumors (sex cord stromal tumors) should be done before puberty, and evaluation of other organs at risk of malignancy should begin by the end of adolescence.

The pigmented macules do not require treatment. Macules on the lips may disappear with time, while those on the buccal mucosa persist. The lip lesions can be lightened with chemical peels or laser.

Our patient underwent laparotomy, which revealed a grossly dilated and gangrenous small bowel segment. Intussusception was not present and was thought to have spontaneously reduced. Resection and anastomosis of the affected small bowel was performed. The patient’s postoperative course was uneventful, and her diarrhea and abdominal pain resolved. We recommended follow-up in her home city with primary care and a GI specialist and explained the need for surveillance of her condition.

CORRESPONDENCE
Josette R. McMichael, MD, Department of Dermatology, Emory University, 1525 Clifton Road NE, 1st Floor, Atlanta, GA 30322; [email protected]