Hospital Medicine

Alarm fatigue is a patient safety hazard in hospitals¹ that occurs when exposure to high rates of alarms leads clinicians to ignore or delay their responses to the alarms.^2,3 To date, most studies of physiologic monitor alarms in hospitalized children have used data from single institutions and often only a few units within each institution.⁴ These limited studies have found that alarms in pediatric units are rarely actionable.² They have also shown that physiologic monitor alarms occur frequently in children’s hospitals and that alarm rates can vary widely within a single institution,⁵ but the extent of variation between children’s hospitals is unknown. In this study, we aimed to describe and compare physiologic monitor alarm characteristics and the proportion of patients monitored in the inpatient units of 5 children’s hospitals.

We performed a cross-sectional study using a point-prevalence design of physiologic monitor alarms and monitoring during a 24-hour period at 5 large, freestanding tertiary-care children’s hospitals. At the time of the study, each hospital had an alarm management committee in place and was working to address alarm fatigue. Each hospital’s institutional review board reviewed and approved the study.

We collected 24 consecutive hours of data from the inpatient units of each hospital between March 24, 2015, and May 1, 2015. Each hospital selected the data collection date within that window based on the availability of staff to perform data collection.⁶ We excluded emergency departments, procedural areas, and inpatient psychiatry and rehabilitation units. By using existing central alarm-collection software that interfaced with bedside physiologic monitors, we collected data on audible alarms generated for apnea, arrhythmia, low and high oxygen saturation, heart rate, respiratory rate, blood pressure, and exhaled carbon dioxide. Bedside alarm systems and alarm collection software differed between centers; therefore, alarm types that were not consistently collected at every institution (eg, alarms for electrode and device malfunction, ventilators, intracranial and central venous pressure monitors, and temperatures probes) were excluded. To estimate alarm rates and to account for fluctuations in hospital census throughout the day,⁷ we collected census (to calculate the number of alarms per patient day) and the number of monitored patients (to calculate the number of alarms per monitored-patient day, including only monitored patients in the denominator) on each unit at 3 time points, 8 hours apart. Patients were considered continuously monitored if they had presence of a waveform and data for pulse oximetry, respiratory rate, and/or heart rate at the time of data collection. We then determined the rate of alarms by unit type—medical-surgical unit (MSU), neonatal intensive care unit (NICU), or pediatric intensive care unit (PICU)—and the alarm types. Based on prior literature demonstrating up to 95% of alarms contributed by a minority of patients on a single unit,⁸ we also calculated the percentage of alarms contributed by beds in the highest quartile of alarms. We also assessed the percentage of patients monitored by unit type. The Supplementary Appendix shows the alarm parameter thresholds in use at the time of the study.

Physiologic monitor alarm rates and the proportion of patients monitored varied widely between unit types and among the tertiary-care children’s hospitals in our study. We found that among MSUs, the hospital with the lowest proportion of beds monitored had the highest alarm rate, with over triple the rate seen at the hospital with the lowest alarm rate. Regardless of unit type, a small subgroup of patients at each hospital contributed a disproportionate share of alarms. These findings are concerning because of the patient morbidity and mortality associated with alarm fatigue¹ and the studies suggesting that higher alarm rates may lead to delays in response to potentially critical alarms.²

We previously described alarm rates at a single children’s hospital and found that alarm rates were high both in and outside of the ICU areas.⁵ This study supports those findings and goes further to show that alarm rates on some MSUs approached rates seen in the ICU areas at other centers.⁴ However, our results should be considered in the context of several limitations. First, the 5 study hospitals utilized different bedside monitors, equipment, and software to collect alarm data. It is possible that this impacted how alarms were counted, though there were no technical specifications to suggest that results should have been biased in a specific way. Second, our data did not reflect alarm validity (ie, whether an alarm accurately reflected the physiologic state of the patient) or factors outside of the number of patients monitored—such as practices around ICU admission and transfer as well as monitor practices such as lead changes, the type of leads employed, and the degree to which alarm parameter thresholds could be customized, which may have also affected alarm rates. Finally, we excluded alarm types that were not consistently collected at all hospitals. We were also unable to capture alarms from other alarm-generating devices, including ventilators and infusion pumps, which have also been identified as sources of alarm-related safety issues in hospitals.^9-11 This suggests that the alarm rates reported here underestimate the total number of audible alarms experienced by staff and by hospitalized patients and families.

While our data collection was limited in scope, the striking differences in alarm rates between hospitals and between similar units in the same hospitals suggest that unit- and hospital-level factors—including default alarm parameter threshold settings, types of monitors used, and monitoring practices such as the degree to which alarm parameters are customized to the patient’s physiologic state—likely contribute to the variability. It is also important to note that while there were clear outlier hospitals, no single hospital had the lowest alarm rate across all unit types. And while we found that a small number of patients contributed disproportionately to alarms, monitoring fewer patients overall was not consistently associated with lower alarm rates. While it is difficult to draw conclusions based on a limited study, these findings suggest that solutions to meaningfully lower alarm rates may be multifaceted. Standardization of care in multiple areas of medicine has shown the potential to decrease unnecessary utilization of testing and therapies while maintaining good patient outcomes.^12-15 Our findings suggest that the concept of positive deviance,¹⁶ by which some organizations produce better outcomes than others despite similar limitations, may help identify successful alarm reduction strategies for further testing. Larger quantitative studies of alarm rates and ethnographic or qualitative studies of monitoring practices may reveal practices and policies that are associated with lower alarm rates with similar or improved monitoring outcomes.

We found wide variability in physiologic monitor alarm rates and the proportion of patients monitored across 5 children’s hospitals. Because alarm fatigue remains a pressing patient safety concern, further study of the features of high-performing (low-alarm) hospital systems may help identify barriers and facilitators of safe, effective monitoring and develop targeted interventions to reduce alarms.

The authors thank Melinda Egan, Matt MacMurchy, and Shannon Stemler for their assistance with data collection.

Disclosure

Dr. Bonafide is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL116427. Dr. Brady is supported by the Agency for Healthcare Research and Quality under Award Number K08HS23827. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Agency for Healthcare Research and Quality. There was no external funding obtained for this study. The authors have no conflicts of interest to disclose.

Alarm fatigue is a patient safety hazard in hospitals¹ that occurs when exposure to high rates of alarms leads clinicians to ignore or delay their responses to the alarms.^2,3 To date, most studies of physiologic monitor alarms in hospitalized children have used data from single institutions and often only a few units within each institution.⁴ These limited studies have found that alarms in pediatric units are rarely actionable.² They have also shown that physiologic monitor alarms occur frequently in children’s hospitals and that alarm rates can vary widely within a single institution,⁵ but the extent of variation between children’s hospitals is unknown. In this study, we aimed to describe and compare physiologic monitor alarm characteristics and the proportion of patients monitored in the inpatient units of 5 children’s hospitals.

We performed a cross-sectional study using a point-prevalence design of physiologic monitor alarms and monitoring during a 24-hour period at 5 large, freestanding tertiary-care children’s hospitals. At the time of the study, each hospital had an alarm management committee in place and was working to address alarm fatigue. Each hospital’s institutional review board reviewed and approved the study.

We collected 24 consecutive hours of data from the inpatient units of each hospital between March 24, 2015, and May 1, 2015. Each hospital selected the data collection date within that window based on the availability of staff to perform data collection.⁶ We excluded emergency departments, procedural areas, and inpatient psychiatry and rehabilitation units. By using existing central alarm-collection software that interfaced with bedside physiologic monitors, we collected data on audible alarms generated for apnea, arrhythmia, low and high oxygen saturation, heart rate, respiratory rate, blood pressure, and exhaled carbon dioxide. Bedside alarm systems and alarm collection software differed between centers; therefore, alarm types that were not consistently collected at every institution (eg, alarms for electrode and device malfunction, ventilators, intracranial and central venous pressure monitors, and temperatures probes) were excluded. To estimate alarm rates and to account for fluctuations in hospital census throughout the day,⁷ we collected census (to calculate the number of alarms per patient day) and the number of monitored patients (to calculate the number of alarms per monitored-patient day, including only monitored patients in the denominator) on each unit at 3 time points, 8 hours apart. Patients were considered continuously monitored if they had presence of a waveform and data for pulse oximetry, respiratory rate, and/or heart rate at the time of data collection. We then determined the rate of alarms by unit type—medical-surgical unit (MSU), neonatal intensive care unit (NICU), or pediatric intensive care unit (PICU)—and the alarm types. Based on prior literature demonstrating up to 95% of alarms contributed by a minority of patients on a single unit,⁸ we also calculated the percentage of alarms contributed by beds in the highest quartile of alarms. We also assessed the percentage of patients monitored by unit type. The Supplementary Appendix shows the alarm parameter thresholds in use at the time of the study.

Physiologic monitor alarm rates and the proportion of patients monitored varied widely between unit types and among the tertiary-care children’s hospitals in our study. We found that among MSUs, the hospital with the lowest proportion of beds monitored had the highest alarm rate, with over triple the rate seen at the hospital with the lowest alarm rate. Regardless of unit type, a small subgroup of patients at each hospital contributed a disproportionate share of alarms. These findings are concerning because of the patient morbidity and mortality associated with alarm fatigue¹ and the studies suggesting that higher alarm rates may lead to delays in response to potentially critical alarms.²

We previously described alarm rates at a single children’s hospital and found that alarm rates were high both in and outside of the ICU areas.⁵ This study supports those findings and goes further to show that alarm rates on some MSUs approached rates seen in the ICU areas at other centers.⁴ However, our results should be considered in the context of several limitations. First, the 5 study hospitals utilized different bedside monitors, equipment, and software to collect alarm data. It is possible that this impacted how alarms were counted, though there were no technical specifications to suggest that results should have been biased in a specific way. Second, our data did not reflect alarm validity (ie, whether an alarm accurately reflected the physiologic state of the patient) or factors outside of the number of patients monitored—such as practices around ICU admission and transfer as well as monitor practices such as lead changes, the type of leads employed, and the degree to which alarm parameter thresholds could be customized, which may have also affected alarm rates. Finally, we excluded alarm types that were not consistently collected at all hospitals. We were also unable to capture alarms from other alarm-generating devices, including ventilators and infusion pumps, which have also been identified as sources of alarm-related safety issues in hospitals.^9-11 This suggests that the alarm rates reported here underestimate the total number of audible alarms experienced by staff and by hospitalized patients and families.

While our data collection was limited in scope, the striking differences in alarm rates between hospitals and between similar units in the same hospitals suggest that unit- and hospital-level factors—including default alarm parameter threshold settings, types of monitors used, and monitoring practices such as the degree to which alarm parameters are customized to the patient’s physiologic state—likely contribute to the variability. It is also important to note that while there were clear outlier hospitals, no single hospital had the lowest alarm rate across all unit types. And while we found that a small number of patients contributed disproportionately to alarms, monitoring fewer patients overall was not consistently associated with lower alarm rates. While it is difficult to draw conclusions based on a limited study, these findings suggest that solutions to meaningfully lower alarm rates may be multifaceted. Standardization of care in multiple areas of medicine has shown the potential to decrease unnecessary utilization of testing and therapies while maintaining good patient outcomes.^12-15 Our findings suggest that the concept of positive deviance,¹⁶ by which some organizations produce better outcomes than others despite similar limitations, may help identify successful alarm reduction strategies for further testing. Larger quantitative studies of alarm rates and ethnographic or qualitative studies of monitoring practices may reveal practices and policies that are associated with lower alarm rates with similar or improved monitoring outcomes.

We found wide variability in physiologic monitor alarm rates and the proportion of patients monitored across 5 children’s hospitals. Because alarm fatigue remains a pressing patient safety concern, further study of the features of high-performing (low-alarm) hospital systems may help identify barriers and facilitators of safe, effective monitoring and develop targeted interventions to reduce alarms.

The authors thank Melinda Egan, Matt MacMurchy, and Shannon Stemler for their assistance with data collection.

Disclosure

Dr. Bonafide is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL116427. Dr. Brady is supported by the Agency for Healthcare Research and Quality under Award Number K08HS23827. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Agency for Healthcare Research and Quality. There was no external funding obtained for this study. The authors have no conflicts of interest to disclose.

Alarm fatigue is a patient safety hazard in hospitals¹ that occurs when exposure to high rates of alarms leads clinicians to ignore or delay their responses to the alarms.^2,3 To date, most studies of physiologic monitor alarms in hospitalized children have used data from single institutions and often only a few units within each institution.⁴ These limited studies have found that alarms in pediatric units are rarely actionable.² They have also shown that physiologic monitor alarms occur frequently in children’s hospitals and that alarm rates can vary widely within a single institution,⁵ but the extent of variation between children’s hospitals is unknown. In this study, we aimed to describe and compare physiologic monitor alarm characteristics and the proportion of patients monitored in the inpatient units of 5 children’s hospitals.

We performed a cross-sectional study using a point-prevalence design of physiologic monitor alarms and monitoring during a 24-hour period at 5 large, freestanding tertiary-care children’s hospitals. At the time of the study, each hospital had an alarm management committee in place and was working to address alarm fatigue. Each hospital’s institutional review board reviewed and approved the study.

We collected 24 consecutive hours of data from the inpatient units of each hospital between March 24, 2015, and May 1, 2015. Each hospital selected the data collection date within that window based on the availability of staff to perform data collection.⁶ We excluded emergency departments, procedural areas, and inpatient psychiatry and rehabilitation units. By using existing central alarm-collection software that interfaced with bedside physiologic monitors, we collected data on audible alarms generated for apnea, arrhythmia, low and high oxygen saturation, heart rate, respiratory rate, blood pressure, and exhaled carbon dioxide. Bedside alarm systems and alarm collection software differed between centers; therefore, alarm types that were not consistently collected at every institution (eg, alarms for electrode and device malfunction, ventilators, intracranial and central venous pressure monitors, and temperatures probes) were excluded. To estimate alarm rates and to account for fluctuations in hospital census throughout the day,⁷ we collected census (to calculate the number of alarms per patient day) and the number of monitored patients (to calculate the number of alarms per monitored-patient day, including only monitored patients in the denominator) on each unit at 3 time points, 8 hours apart. Patients were considered continuously monitored if they had presence of a waveform and data for pulse oximetry, respiratory rate, and/or heart rate at the time of data collection. We then determined the rate of alarms by unit type—medical-surgical unit (MSU), neonatal intensive care unit (NICU), or pediatric intensive care unit (PICU)—and the alarm types. Based on prior literature demonstrating up to 95% of alarms contributed by a minority of patients on a single unit,⁸ we also calculated the percentage of alarms contributed by beds in the highest quartile of alarms. We also assessed the percentage of patients monitored by unit type. The Supplementary Appendix shows the alarm parameter thresholds in use at the time of the study.

Physiologic monitor alarm rates and the proportion of patients monitored varied widely between unit types and among the tertiary-care children’s hospitals in our study. We found that among MSUs, the hospital with the lowest proportion of beds monitored had the highest alarm rate, with over triple the rate seen at the hospital with the lowest alarm rate. Regardless of unit type, a small subgroup of patients at each hospital contributed a disproportionate share of alarms. These findings are concerning because of the patient morbidity and mortality associated with alarm fatigue¹ and the studies suggesting that higher alarm rates may lead to delays in response to potentially critical alarms.²

We previously described alarm rates at a single children’s hospital and found that alarm rates were high both in and outside of the ICU areas.⁵ This study supports those findings and goes further to show that alarm rates on some MSUs approached rates seen in the ICU areas at other centers.⁴ However, our results should be considered in the context of several limitations. First, the 5 study hospitals utilized different bedside monitors, equipment, and software to collect alarm data. It is possible that this impacted how alarms were counted, though there were no technical specifications to suggest that results should have been biased in a specific way. Second, our data did not reflect alarm validity (ie, whether an alarm accurately reflected the physiologic state of the patient) or factors outside of the number of patients monitored—such as practices around ICU admission and transfer as well as monitor practices such as lead changes, the type of leads employed, and the degree to which alarm parameter thresholds could be customized, which may have also affected alarm rates. Finally, we excluded alarm types that were not consistently collected at all hospitals. We were also unable to capture alarms from other alarm-generating devices, including ventilators and infusion pumps, which have also been identified as sources of alarm-related safety issues in hospitals.^9-11 This suggests that the alarm rates reported here underestimate the total number of audible alarms experienced by staff and by hospitalized patients and families.

While our data collection was limited in scope, the striking differences in alarm rates between hospitals and between similar units in the same hospitals suggest that unit- and hospital-level factors—including default alarm parameter threshold settings, types of monitors used, and monitoring practices such as the degree to which alarm parameters are customized to the patient’s physiologic state—likely contribute to the variability. It is also important to note that while there were clear outlier hospitals, no single hospital had the lowest alarm rate across all unit types. And while we found that a small number of patients contributed disproportionately to alarms, monitoring fewer patients overall was not consistently associated with lower alarm rates. While it is difficult to draw conclusions based on a limited study, these findings suggest that solutions to meaningfully lower alarm rates may be multifaceted. Standardization of care in multiple areas of medicine has shown the potential to decrease unnecessary utilization of testing and therapies while maintaining good patient outcomes.^12-15 Our findings suggest that the concept of positive deviance,¹⁶ by which some organizations produce better outcomes than others despite similar limitations, may help identify successful alarm reduction strategies for further testing. Larger quantitative studies of alarm rates and ethnographic or qualitative studies of monitoring practices may reveal practices and policies that are associated with lower alarm rates with similar or improved monitoring outcomes.

We found wide variability in physiologic monitor alarm rates and the proportion of patients monitored across 5 children’s hospitals. Because alarm fatigue remains a pressing patient safety concern, further study of the features of high-performing (low-alarm) hospital systems may help identify barriers and facilitators of safe, effective monitoring and develop targeted interventions to reduce alarms.

The authors thank Melinda Egan, Matt MacMurchy, and Shannon Stemler for their assistance with data collection.

Disclosure

Dr. Bonafide is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL116427. Dr. Brady is supported by the Agency for Healthcare Research and Quality under Award Number K08HS23827. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Agency for Healthcare Research and Quality. There was no external funding obtained for this study. The authors have no conflicts of interest to disclose.

The Indian Health Service (IHS) has announced a new tool to monitor and report information system-wide. The National Accountability Dashboard for Quality (NAD-Q) will allow IHS to report on key performance data in a “succinct and easily viewed display.”

The NAD-Q shows how IHS is functioning in the following key domains for health care systems:

• Quality (efficient, effective, and equitable);
• Accreditation;
• Workforce;
• Patient-centered care;
• Safety; and
• Timely care.

The dashboard will monitor and report on compliance with policy requirements, accreditation standards, and regulations at hospitals and ambulatory health centers. The tool also supports oversight and management, and will allow IHS to make fact-based decisions to ensure quality and safety of care.

The NAD-Q also allows IHS to share with tribes, tribal and urban Indian organizations, and Congress how well it is meeting standards and requirements

The Indian Health Service (IHS) has announced a new tool to monitor and report information system-wide. The National Accountability Dashboard for Quality (NAD-Q) will allow IHS to report on key performance data in a “succinct and easily viewed display.”

The NAD-Q shows how IHS is functioning in the following key domains for health care systems:

• Quality (efficient, effective, and equitable);
• Accreditation;
• Workforce;
• Patient-centered care;
• Safety; and
• Timely care.

The dashboard will monitor and report on compliance with policy requirements, accreditation standards, and regulations at hospitals and ambulatory health centers. The tool also supports oversight and management, and will allow IHS to make fact-based decisions to ensure quality and safety of care.

The NAD-Q also allows IHS to share with tribes, tribal and urban Indian organizations, and Congress how well it is meeting standards and requirements

The Indian Health Service (IHS) has announced a new tool to monitor and report information system-wide. The National Accountability Dashboard for Quality (NAD-Q) will allow IHS to report on key performance data in a “succinct and easily viewed display.”

The NAD-Q shows how IHS is functioning in the following key domains for health care systems:

• Quality (efficient, effective, and equitable);
• Accreditation;
• Workforce;
• Patient-centered care;
• Safety; and
• Timely care.

The dashboard will monitor and report on compliance with policy requirements, accreditation standards, and regulations at hospitals and ambulatory health centers. The tool also supports oversight and management, and will allow IHS to make fact-based decisions to ensure quality and safety of care.

The NAD-Q also allows IHS to share with tribes, tribal and urban Indian organizations, and Congress how well it is meeting standards and requirements

As more hospitalized patients develop infections that are immune to antibiotics, researchers are looking into new preventive therapies. National Institute of Allergy and Infectious-supported researchers are studying monoclonal antibodies and their effects on Pseudomonas aeruginosa (P aeruginosa) and Staphylococcus aureus (S aureus), which are among the antibiotic-resistant bacteria that the World Health Organization says pose the greatest risk to human health.

The monoclonal antibodies can be administered along with standard antibiotic therapy. Monoclonal antibodies have been used in cancer, Ebola, and respiratory syncytial virus but rarely have been used to target bacterial pathogens, National Institute of Health says.

One trial, EVADE, will evaluate the safety of the investigational medicine MEDI3902 and whether it can prevent pneumonia caused by P aeruginosa. The other study, SAATELLITE, will test the safety and efficacy of another investigational medicine, suvratoxumab, against S aureus. The researchers hope to enroll 30 patients from 15 intensive care units.

As more hospitalized patients develop infections that are immune to antibiotics, researchers are looking into new preventive therapies. National Institute of Allergy and Infectious-supported researchers are studying monoclonal antibodies and their effects on Pseudomonas aeruginosa (P aeruginosa) and Staphylococcus aureus (S aureus), which are among the antibiotic-resistant bacteria that the World Health Organization says pose the greatest risk to human health.

The monoclonal antibodies can be administered along with standard antibiotic therapy. Monoclonal antibodies have been used in cancer, Ebola, and respiratory syncytial virus but rarely have been used to target bacterial pathogens, National Institute of Health says.

One trial, EVADE, will evaluate the safety of the investigational medicine MEDI3902 and whether it can prevent pneumonia caused by P aeruginosa. The other study, SAATELLITE, will test the safety and efficacy of another investigational medicine, suvratoxumab, against S aureus. The researchers hope to enroll 30 patients from 15 intensive care units.

As more hospitalized patients develop infections that are immune to antibiotics, researchers are looking into new preventive therapies. National Institute of Allergy and Infectious-supported researchers are studying monoclonal antibodies and their effects on Pseudomonas aeruginosa (P aeruginosa) and Staphylococcus aureus (S aureus), which are among the antibiotic-resistant bacteria that the World Health Organization says pose the greatest risk to human health.

The monoclonal antibodies can be administered along with standard antibiotic therapy. Monoclonal antibodies have been used in cancer, Ebola, and respiratory syncytial virus but rarely have been used to target bacterial pathogens, National Institute of Health says.

One trial, EVADE, will evaluate the safety of the investigational medicine MEDI3902 and whether it can prevent pneumonia caused by P aeruginosa. The other study, SAATELLITE, will test the safety and efficacy of another investigational medicine, suvratoxumab, against S aureus. The researchers hope to enroll 30 patients from 15 intensive care units.

Pain is prevalent among hospitalized patients, occurring in 52%-71% of patients in cross-sectional surveys.^1-3 Opioid administration is also common, with more than half of nonsurgical patients in United States (US) hospitals receiving at least one dose of opioid during hospitalization.⁴ Studies have also begun to define the degree to which hospital prescribing contributes to long-term use. Among opioid-naïve patients admitted to the hospital, 15%-25% fill an opioid prescription in the week after hospital discharge,^5,6 43% of such patients fill another opioid prescription 90 days postdischarge,⁶ and 15% meet the criteria for long-term use at one year.⁷ With about 37 million discharges from US hospitals each year,⁸ these estimates suggest that hospitalization contributes to initiation of long-term opioid use in millions of adults each year.

Additionally, studies in the emergency department and hospital settings demonstrate large variations in prescribing of opioids between providers and hospitals.^4,9 Variation unrelated to patient characteristics highlights areas of clinical uncertainty and the corresponding need for prescribing standards and guidance. To our knowledge, there are no existing guidelines on safe prescribing of opioids in hospitalized patients, aside from guidelines specifically focused on the perioperative, palliative care, or end-of-life settings.

Thus, in the context of the current opioid epidemic, the Society of Hospital Medicine (SHM) sought to develop a consensus statement to assist clinicians practicing medicine in the inpatient setting in safe prescribing of opioids for acute, noncancer pain on the medical services. We define “safe” prescribing as proposed by Aronson: “a process that recommends a medicine appropriate to the patient’s condition and minimizes the risk of undue harm from it.”¹⁰ To inform development of the consensus statement, SHM convened a working group to systematically review existing guidelines on the more general management of acute pain. This article describes the methods and results of our systematic review of existing guidelines for managing acute pain. The Consensus Statement derived from these existing guidelines, applied to the hospital setting, appears in a companion article.

Steps in the systematic review process included: 1) searching for relevant guidelines, 2) applying exclusion criteria, 3) assessing the quality of the guidelines, and 4) synthesizing guideline recommendations to identify issues potentially relevant to medical inpatients with acute pain. Details of the protocol for this systematic review were registered on PROSPERO and can be accessed at https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=71846.

Data Sources and Search Terms

Guideline Inclusion/Exclusion Criteria

We defined guidelines as statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harm of alternative care options, consistent with the National Academies’ definition.¹¹ To be eligible, guidelines had to be published in English and include recommendations on prescribing opioids for acute, noncancer pain. We excluded guidelines focused on chronic pain or palliative care, guidelines derived entirely from another guideline, and guidelines published before 2010, since such guidelines may contain outdated information.¹² Because we were interested in general principles regarding safe use of opioids for managing acute pain, we excluded guidelines that focused exclusively on specific disease processes (eg, cancer, low-back pain, and sickle cell anemia). As we were specifically interested in the management of acute pain in the hospital setting, we also excluded guidelines that focused exclusively on specific nonhospital settings of care (eg, outpatient care clinics and nursing homes). We included guidelines related to care in the emergency department (ED) given the hospital-based location of care and the high degree of similarity in scope of practice and patient population, as most hospitalized adults are admitted through the ED. Finally, we excluded guidelines focusing on management in the intensive care setting (including the post-anesthesia care unit) given the inherent differences in patient population and management options between the intensive and nonintensive care areas of the hospital.

Guideline Quality Assessment

Guideline Synthesis and Analysis

We extracted recommendations from each guideline related to the following topics: 1) deciding when to use opioids, nonopioid medications, and nonmedication-based pain management modalities, 2) best practices in screening/monitoring/education prior to prescribing an opioid and/or during treatment, 3) opioid selection considerations, including selection of dose, duration, and route of administration, 4) strategies to minimize the risk of opioid-related adverse events, and 5) safe practices on discharge.

Role of the Funding Source

The Society of Hospital Medicine provided administrative and material support for the project, but had no role in the design or execution of the scientific evaluation.

Guideline Quality Assessment

See Table 1 for the AGREE II scaled domain scores, and Appendix Table 1 for the ratings on each individual item within a domain. The range of scaled scores for each of the AGREE II domains were as follows: Scope and purpose 52%-89%, stakeholder involvement 30%-81%, rigor of development 46%-81%, clarity of presentation 59%-72%, applicability 10%-57%, and editorial independence 42%-78%. Overall guideline assessment scores ranged from 4 to 5.33 on a scale from 1 to 7. Three of the guidelines (NICE, ACOEM, and WSAMDG)^16,17,19 were recommended for use without modification by 2 out of 3 guideline appraisers, and one of the guidelines (ACEP)¹⁸ was recommended for use with modification by all 3 appraisers. The guideline by NICE¹⁹ was rated the highest both overall (5.33), and on 4 of the 6 AGREE II domains.

Although the guidelines each included a systematic review of the literature, the NICE¹⁹ and WSAMDG¹⁷ guidelines did not include the strength of recommendations or provide clear links between each recommendation and the underlying evidence base. When citations were present, we reviewed them to determine the type of data upon which the recommendations were based and included this information in Table 2. The majority of the recommendations in Table 2 are based on expert opinion alone, or other guidelines.

Guideline Synthesis and Analysis

Table 2 contains a synthesis of the recommendations related to each of our 5 prespecified content areas. Despite the generally low quality of the evidence supporting the recommendations, there were many areas of concordance across guidelines.

Deciding When to Use Opioids, Nonopioid Medications, and Nonmedication-Based Pain Management Modalities

Three out of 4 guidelines recommended restricting opioid use to severe pain or pain that has not responded to nonopioid therapy,^16-18 2 guidelines recommended treating mild to moderate pain with nonopioid medications, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs),^16,17 and 2 guidelines recommended co-prescribing opioids with nonopioid analgesic medications to reduce total opioid requirements and improve pain control.^16,17 Each of these recommendations was supported by at least one randomized controlled trial.

Best Practices in Screening/Monitoring/Education to Occur Prior to Prescribing an Opioid and/or During Treatment

Three guidelines recommended checking prescription drug monitoring programs (PDMPs), all based on expert consensus.^16-18 Only the WSAMDG guideline offered guidance as to the optimal timing to check the PDMP in this setting, specifically recommending to check before prescribing opioids.¹⁷ Two guidelines also recommended helping patients set reasonable expectations about their recovery and educating patients about the risks/side effects of opioid therapy, all based on expert consensus or other guidelines.^17,19

Opioid Selection Considerations, Including Selection of Dose, Duration, and Route of Administration

Three guidelines recommended using the lowest effective dose, supported by expert consensus and observational data in the outpatient setting demonstrating that overdose risk increases with opioid dose.^16-18 Three guidelines recommended using short-acting opioids and/or avoiding use of long-acting/extended-release opioids for acute pain based on expert consensus.^16-18 Two guidelines recommended using as-needed rather than scheduled dosing of opioids based on expert recommendation.^{16, 17}

Strategies to Minimize the Risk of Opioid-Related Adverse Events

Several strategies to minimize the risk of opioid-related adverse events were identified, but most were only recommended by a single guideline. Strategies recommended by more than one guideline included using a recognized opioid dose conversion guide when prescribing, reviewing, or changing opioid prescriptions (based on expert consensus);^16,19 avoiding co-administration of parenteral and oral as-needed opioids, and if as-needed opioids from different routes are necessary, providing a clear indication for use of each (based on expert consensus and other guidelines);^17,19 and avoiding/using caution when co-prescribing opioids with other central nervous system depressant medications^16,17 (supported by observational studies demonstrating increased risk in the outpatient setting).

Safe Practices on Discharge

All 4 of the guidelines recommended prescribing a limited duration of opioids for the acute pain episode; however the maximum recommended duration varied widely from one week to 30 days.^16-19 It is important to note that because these guidelines were not focused on hospitalization specifically, these maximum recommended durations of use reflect the entire acute pain episode (ie, not prescribing on discharge specifically). The guideline with the longest maximum recommended duration was from NICE, based in the United Kingdom, while the US-based guideline development groups uniformly recommended 1 to 2 weeks as the maximum duration of opioid use, including the period of hospitalization.

This systematic review identified only 4 existing guidelines that included recommendations on safe opioid prescribing practices for managing acute, noncancer pain, outside of the context of specific conditions, specific nonhospital settings, or the intensive care setting. Although 2 of the identified guidelines offered sparse recommendations specific to the hospital setting, we found no guidelines that focused exclusively on the period of hospitalization specifically outside of the perioperative period. Furthermore, the guideline recommendations were largely based on expert opinion. Although these factors limit the confidence with which the recommendations can be applied to the hospital setting, they nonetheless represent the best guidance currently available to standardize and improve the safety of prescribing opioids in the hospital setting.

This paucity of guidance specific to patients hospitalized in general, nonintensive care areas of the hospital is important because pain management in this setting differs in a number of ways from pain management in the ambulatory or intensive care unit settings (including the post-anesthesia care unit). First, there are differences in the monitoring strategies that are available in each of these settings (eg, variability in nurse-to-patient ratios, frequency of measuring vital signs, and availability of continuous pulse oximetry/capnography). Second, there are differences in available/feasible routes of medication administration depending on the setting of care. Finally, there are differences in the patients themselves, including severity of illness, baseline and expected functional status, pain severity, and ability to communicate.

Accordingly, to avoid substantial heterogeneity in recommendations obtained from this review, we chose to focus on guidelines most relevant to clinicians practicing medicine in nonintensive care areas of the hospital. This resulted in the exclusion of 2 guidelines intended for anesthesiologists that focused exclusively on perioperative management and included use of advanced management procedures beyond the scope of practice for general internists,^20,21 and one guideline that focused on management in the intensive care unit.²² Within the set of guidelines included in this review, we did include recommendations designated for the postoperative period that we felt were relevant to the care of hospitalized patients more generally. In fact, the ACOEM guideline, which includes postoperative recommendations, specifically noted that these recommendations are mostly comparable to those for treating acute pain more generally.¹⁶

In addition to the lack of guidance specific to the setting in which most hospitalists practice, most of the recommendations in the existing guidelines are based on expert consensus. Guidelines based on expert opinion typically carry a lower strength of recommendation, and, accordingly, should be applied with some caution and accompanied by diligent tracking of outcome metrics, as these recommendations are applied to local health systems. Recommendations may have unintended consequences that are not necessarily apparent at the outset, and the specific circumstances of each patient must be considered when deciding how best to apply recommendations. Additional research will be necessary to track the impact of the recommended prescribing practices on patient outcomes, particularly given that many states have already begun instituting regulations on safe opioid prescribing despite the limited nature of the evidence. Furthermore, although several studies have identified patient- and prescribing-related risk factors for opioid-related adverse events in surgical patient populations, given the differences in patient characteristics and prescribing patterns in these settings, research to understand the risk factors in hospitalized medical patients specifically is important to inform evidence-based, safe prescribing recommendations in this setting.

Despite the largely expert consensus-based nature of the recommendations, we found substantial overlap in the recommendations between the guidelines, spanning our prespecified topics of interest related to safe prescribing. Most guidelines recommended restricting opioid use to severe pain or pain that has not responded to nonopioid therapy, checking PDMPs, using the lowest effective dose, and using short-acting opioids and/or avoiding use of long-acting/extended-release opioids for acute pain. There was less consensus on risk mitigation strategies, where the majority of recommendations were endorsed by only 1 or 2 guidelines. Finally, all 4 guidelines recommended prescribing a limited duration of opioids for the acute pain episode, with US-based guidelines recommending 1 to 2 weeks as the maximum duration of opioid use, including the period of hospitalization.

There are limitations to our evaluation. As previously noted, in order to avoid substantial heterogeneity in management recommendations, we excluded 2 guidelines intended for anesthesiologists that focused exclusively on perioperative management,^20,21 and one guideline focused on management in the intensive care unit.²² Accordingly, recommendations contained in this review may or may not be applicable to those settings, and readers interested in those settings specifically are directed to those guidelines. Additionally, we decided to exclude guidelines that focused on managing acute pain in specific conditions (eg, sickle cell disease and pancreatitis) because our goal was to identify generalizable principles of safe prescribing of opioids that apply regardless of clinical condition. Despite this goal, it is important to recognize that not all of the recommendations are generalizable to all types of pain; clinicians interested in management principles specific to certain disease states are encouraged to review disease-specific informational material. Finally, although we used rigorous, pre-defined search criteria and registered our protocol on PROSPERO, it is possible that our search strategy missed relevant guidelines.

In conclusion, we identified few guidelines on safe opioid prescribing practices for managing acute, noncancer pain, outside of the context of specific conditions or nonhospital settings, and no guidelines focused on acute pain management in general, nonintensive care areas of the hospital specifically. Nevertheless, the guidelines that we identified make consistent recommendations related to our prespecified topic areas of relevance to the hospital setting, although most recommendations are based exclusively on expert opinion. Our systematic review nonetheless provides guidance in an area where guidance has thus far been limited. Future research should investigate risk factors for opioid-related adverse events in hospitalized, nonsurgical patients, and the effectiveness of interventions designed to reduce their occurrence.

Dr. Herzig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from SHM for their facilitation of this project and dedication to this purpose.

Disclosures: Dr. Herzig received compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena received consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance and material support, but had no role in or influence on the scientific conduct of the study. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported, in part, by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, or reporting of the study

Pain is prevalent among hospitalized patients, occurring in 52%-71% of patients in cross-sectional surveys.^1-3 Opioid administration is also common, with more than half of nonsurgical patients in United States (US) hospitals receiving at least one dose of opioid during hospitalization.⁴ Studies have also begun to define the degree to which hospital prescribing contributes to long-term use. Among opioid-naïve patients admitted to the hospital, 15%-25% fill an opioid prescription in the week after hospital discharge,^5,6 43% of such patients fill another opioid prescription 90 days postdischarge,⁶ and 15% meet the criteria for long-term use at one year.⁷ With about 37 million discharges from US hospitals each year,⁸ these estimates suggest that hospitalization contributes to initiation of long-term opioid use in millions of adults each year.

Additionally, studies in the emergency department and hospital settings demonstrate large variations in prescribing of opioids between providers and hospitals.^4,9 Variation unrelated to patient characteristics highlights areas of clinical uncertainty and the corresponding need for prescribing standards and guidance. To our knowledge, there are no existing guidelines on safe prescribing of opioids in hospitalized patients, aside from guidelines specifically focused on the perioperative, palliative care, or end-of-life settings.

Thus, in the context of the current opioid epidemic, the Society of Hospital Medicine (SHM) sought to develop a consensus statement to assist clinicians practicing medicine in the inpatient setting in safe prescribing of opioids for acute, noncancer pain on the medical services. We define “safe” prescribing as proposed by Aronson: “a process that recommends a medicine appropriate to the patient’s condition and minimizes the risk of undue harm from it.”¹⁰ To inform development of the consensus statement, SHM convened a working group to systematically review existing guidelines on the more general management of acute pain. This article describes the methods and results of our systematic review of existing guidelines for managing acute pain. The Consensus Statement derived from these existing guidelines, applied to the hospital setting, appears in a companion article.

Steps in the systematic review process included: 1) searching for relevant guidelines, 2) applying exclusion criteria, 3) assessing the quality of the guidelines, and 4) synthesizing guideline recommendations to identify issues potentially relevant to medical inpatients with acute pain. Details of the protocol for this systematic review were registered on PROSPERO and can be accessed at https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=71846.

Data Sources and Search Terms

Guideline Inclusion/Exclusion Criteria

We defined guidelines as statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harm of alternative care options, consistent with the National Academies’ definition.¹¹ To be eligible, guidelines had to be published in English and include recommendations on prescribing opioids for acute, noncancer pain. We excluded guidelines focused on chronic pain or palliative care, guidelines derived entirely from another guideline, and guidelines published before 2010, since such guidelines may contain outdated information.¹² Because we were interested in general principles regarding safe use of opioids for managing acute pain, we excluded guidelines that focused exclusively on specific disease processes (eg, cancer, low-back pain, and sickle cell anemia). As we were specifically interested in the management of acute pain in the hospital setting, we also excluded guidelines that focused exclusively on specific nonhospital settings of care (eg, outpatient care clinics and nursing homes). We included guidelines related to care in the emergency department (ED) given the hospital-based location of care and the high degree of similarity in scope of practice and patient population, as most hospitalized adults are admitted through the ED. Finally, we excluded guidelines focusing on management in the intensive care setting (including the post-anesthesia care unit) given the inherent differences in patient population and management options between the intensive and nonintensive care areas of the hospital.

Guideline Quality Assessment

Guideline Synthesis and Analysis

We extracted recommendations from each guideline related to the following topics: 1) deciding when to use opioids, nonopioid medications, and nonmedication-based pain management modalities, 2) best practices in screening/monitoring/education prior to prescribing an opioid and/or during treatment, 3) opioid selection considerations, including selection of dose, duration, and route of administration, 4) strategies to minimize the risk of opioid-related adverse events, and 5) safe practices on discharge.

Role of the Funding Source

The Society of Hospital Medicine provided administrative and material support for the project, but had no role in the design or execution of the scientific evaluation.

Guideline Quality Assessment

See Table 1 for the AGREE II scaled domain scores, and Appendix Table 1 for the ratings on each individual item within a domain. The range of scaled scores for each of the AGREE II domains were as follows: Scope and purpose 52%-89%, stakeholder involvement 30%-81%, rigor of development 46%-81%, clarity of presentation 59%-72%, applicability 10%-57%, and editorial independence 42%-78%. Overall guideline assessment scores ranged from 4 to 5.33 on a scale from 1 to 7. Three of the guidelines (NICE, ACOEM, and WSAMDG)^16,17,19 were recommended for use without modification by 2 out of 3 guideline appraisers, and one of the guidelines (ACEP)¹⁸ was recommended for use with modification by all 3 appraisers. The guideline by NICE¹⁹ was rated the highest both overall (5.33), and on 4 of the 6 AGREE II domains.

Although the guidelines each included a systematic review of the literature, the NICE¹⁹ and WSAMDG¹⁷ guidelines did not include the strength of recommendations or provide clear links between each recommendation and the underlying evidence base. When citations were present, we reviewed them to determine the type of data upon which the recommendations were based and included this information in Table 2. The majority of the recommendations in Table 2 are based on expert opinion alone, or other guidelines.

Guideline Synthesis and Analysis

Table 2 contains a synthesis of the recommendations related to each of our 5 prespecified content areas. Despite the generally low quality of the evidence supporting the recommendations, there were many areas of concordance across guidelines.

Deciding When to Use Opioids, Nonopioid Medications, and Nonmedication-Based Pain Management Modalities

Three out of 4 guidelines recommended restricting opioid use to severe pain or pain that has not responded to nonopioid therapy,^16-18 2 guidelines recommended treating mild to moderate pain with nonopioid medications, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs),^16,17 and 2 guidelines recommended co-prescribing opioids with nonopioid analgesic medications to reduce total opioid requirements and improve pain control.^16,17 Each of these recommendations was supported by at least one randomized controlled trial.

Best Practices in Screening/Monitoring/Education to Occur Prior to Prescribing an Opioid and/or During Treatment

Three guidelines recommended checking prescription drug monitoring programs (PDMPs), all based on expert consensus.^16-18 Only the WSAMDG guideline offered guidance as to the optimal timing to check the PDMP in this setting, specifically recommending to check before prescribing opioids.¹⁷ Two guidelines also recommended helping patients set reasonable expectations about their recovery and educating patients about the risks/side effects of opioid therapy, all based on expert consensus or other guidelines.^17,19

Opioid Selection Considerations, Including Selection of Dose, Duration, and Route of Administration

Three guidelines recommended using the lowest effective dose, supported by expert consensus and observational data in the outpatient setting demonstrating that overdose risk increases with opioid dose.^16-18 Three guidelines recommended using short-acting opioids and/or avoiding use of long-acting/extended-release opioids for acute pain based on expert consensus.^16-18 Two guidelines recommended using as-needed rather than scheduled dosing of opioids based on expert recommendation.^{16, 17}

Strategies to Minimize the Risk of Opioid-Related Adverse Events

Several strategies to minimize the risk of opioid-related adverse events were identified, but most were only recommended by a single guideline. Strategies recommended by more than one guideline included using a recognized opioid dose conversion guide when prescribing, reviewing, or changing opioid prescriptions (based on expert consensus);^16,19 avoiding co-administration of parenteral and oral as-needed opioids, and if as-needed opioids from different routes are necessary, providing a clear indication for use of each (based on expert consensus and other guidelines);^17,19 and avoiding/using caution when co-prescribing opioids with other central nervous system depressant medications^16,17 (supported by observational studies demonstrating increased risk in the outpatient setting).

Safe Practices on Discharge

All 4 of the guidelines recommended prescribing a limited duration of opioids for the acute pain episode; however the maximum recommended duration varied widely from one week to 30 days.^16-19 It is important to note that because these guidelines were not focused on hospitalization specifically, these maximum recommended durations of use reflect the entire acute pain episode (ie, not prescribing on discharge specifically). The guideline with the longest maximum recommended duration was from NICE, based in the United Kingdom, while the US-based guideline development groups uniformly recommended 1 to 2 weeks as the maximum duration of opioid use, including the period of hospitalization.

This systematic review identified only 4 existing guidelines that included recommendations on safe opioid prescribing practices for managing acute, noncancer pain, outside of the context of specific conditions, specific nonhospital settings, or the intensive care setting. Although 2 of the identified guidelines offered sparse recommendations specific to the hospital setting, we found no guidelines that focused exclusively on the period of hospitalization specifically outside of the perioperative period. Furthermore, the guideline recommendations were largely based on expert opinion. Although these factors limit the confidence with which the recommendations can be applied to the hospital setting, they nonetheless represent the best guidance currently available to standardize and improve the safety of prescribing opioids in the hospital setting.

This paucity of guidance specific to patients hospitalized in general, nonintensive care areas of the hospital is important because pain management in this setting differs in a number of ways from pain management in the ambulatory or intensive care unit settings (including the post-anesthesia care unit). First, there are differences in the monitoring strategies that are available in each of these settings (eg, variability in nurse-to-patient ratios, frequency of measuring vital signs, and availability of continuous pulse oximetry/capnography). Second, there are differences in available/feasible routes of medication administration depending on the setting of care. Finally, there are differences in the patients themselves, including severity of illness, baseline and expected functional status, pain severity, and ability to communicate.

Accordingly, to avoid substantial heterogeneity in recommendations obtained from this review, we chose to focus on guidelines most relevant to clinicians practicing medicine in nonintensive care areas of the hospital. This resulted in the exclusion of 2 guidelines intended for anesthesiologists that focused exclusively on perioperative management and included use of advanced management procedures beyond the scope of practice for general internists,^20,21 and one guideline that focused on management in the intensive care unit.²² Within the set of guidelines included in this review, we did include recommendations designated for the postoperative period that we felt were relevant to the care of hospitalized patients more generally. In fact, the ACOEM guideline, which includes postoperative recommendations, specifically noted that these recommendations are mostly comparable to those for treating acute pain more generally.¹⁶

In addition to the lack of guidance specific to the setting in which most hospitalists practice, most of the recommendations in the existing guidelines are based on expert consensus. Guidelines based on expert opinion typically carry a lower strength of recommendation, and, accordingly, should be applied with some caution and accompanied by diligent tracking of outcome metrics, as these recommendations are applied to local health systems. Recommendations may have unintended consequences that are not necessarily apparent at the outset, and the specific circumstances of each patient must be considered when deciding how best to apply recommendations. Additional research will be necessary to track the impact of the recommended prescribing practices on patient outcomes, particularly given that many states have already begun instituting regulations on safe opioid prescribing despite the limited nature of the evidence. Furthermore, although several studies have identified patient- and prescribing-related risk factors for opioid-related adverse events in surgical patient populations, given the differences in patient characteristics and prescribing patterns in these settings, research to understand the risk factors in hospitalized medical patients specifically is important to inform evidence-based, safe prescribing recommendations in this setting.

Despite the largely expert consensus-based nature of the recommendations, we found substantial overlap in the recommendations between the guidelines, spanning our prespecified topics of interest related to safe prescribing. Most guidelines recommended restricting opioid use to severe pain or pain that has not responded to nonopioid therapy, checking PDMPs, using the lowest effective dose, and using short-acting opioids and/or avoiding use of long-acting/extended-release opioids for acute pain. There was less consensus on risk mitigation strategies, where the majority of recommendations were endorsed by only 1 or 2 guidelines. Finally, all 4 guidelines recommended prescribing a limited duration of opioids for the acute pain episode, with US-based guidelines recommending 1 to 2 weeks as the maximum duration of opioid use, including the period of hospitalization.

There are limitations to our evaluation. As previously noted, in order to avoid substantial heterogeneity in management recommendations, we excluded 2 guidelines intended for anesthesiologists that focused exclusively on perioperative management,^20,21 and one guideline focused on management in the intensive care unit.²² Accordingly, recommendations contained in this review may or may not be applicable to those settings, and readers interested in those settings specifically are directed to those guidelines. Additionally, we decided to exclude guidelines that focused on managing acute pain in specific conditions (eg, sickle cell disease and pancreatitis) because our goal was to identify generalizable principles of safe prescribing of opioids that apply regardless of clinical condition. Despite this goal, it is important to recognize that not all of the recommendations are generalizable to all types of pain; clinicians interested in management principles specific to certain disease states are encouraged to review disease-specific informational material. Finally, although we used rigorous, pre-defined search criteria and registered our protocol on PROSPERO, it is possible that our search strategy missed relevant guidelines.

In conclusion, we identified few guidelines on safe opioid prescribing practices for managing acute, noncancer pain, outside of the context of specific conditions or nonhospital settings, and no guidelines focused on acute pain management in general, nonintensive care areas of the hospital specifically. Nevertheless, the guidelines that we identified make consistent recommendations related to our prespecified topic areas of relevance to the hospital setting, although most recommendations are based exclusively on expert opinion. Our systematic review nonetheless provides guidance in an area where guidance has thus far been limited. Future research should investigate risk factors for opioid-related adverse events in hospitalized, nonsurgical patients, and the effectiveness of interventions designed to reduce their occurrence.

Dr. Herzig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from SHM for their facilitation of this project and dedication to this purpose.

Disclosures: Dr. Herzig received compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena received consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance and material support, but had no role in or influence on the scientific conduct of the study. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported, in part, by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, or reporting of the study

Pain is prevalent among hospitalized patients, occurring in 52%-71% of patients in cross-sectional surveys.^1-3 Opioid administration is also common, with more than half of nonsurgical patients in United States (US) hospitals receiving at least one dose of opioid during hospitalization.⁴ Studies have also begun to define the degree to which hospital prescribing contributes to long-term use. Among opioid-naïve patients admitted to the hospital, 15%-25% fill an opioid prescription in the week after hospital discharge,^5,6 43% of such patients fill another opioid prescription 90 days postdischarge,⁶ and 15% meet the criteria for long-term use at one year.⁷ With about 37 million discharges from US hospitals each year,⁸ these estimates suggest that hospitalization contributes to initiation of long-term opioid use in millions of adults each year.

Additionally, studies in the emergency department and hospital settings demonstrate large variations in prescribing of opioids between providers and hospitals.^4,9 Variation unrelated to patient characteristics highlights areas of clinical uncertainty and the corresponding need for prescribing standards and guidance. To our knowledge, there are no existing guidelines on safe prescribing of opioids in hospitalized patients, aside from guidelines specifically focused on the perioperative, palliative care, or end-of-life settings.

Thus, in the context of the current opioid epidemic, the Society of Hospital Medicine (SHM) sought to develop a consensus statement to assist clinicians practicing medicine in the inpatient setting in safe prescribing of opioids for acute, noncancer pain on the medical services. We define “safe” prescribing as proposed by Aronson: “a process that recommends a medicine appropriate to the patient’s condition and minimizes the risk of undue harm from it.”¹⁰ To inform development of the consensus statement, SHM convened a working group to systematically review existing guidelines on the more general management of acute pain. This article describes the methods and results of our systematic review of existing guidelines for managing acute pain. The Consensus Statement derived from these existing guidelines, applied to the hospital setting, appears in a companion article.

Steps in the systematic review process included: 1) searching for relevant guidelines, 2) applying exclusion criteria, 3) assessing the quality of the guidelines, and 4) synthesizing guideline recommendations to identify issues potentially relevant to medical inpatients with acute pain. Details of the protocol for this systematic review were registered on PROSPERO and can be accessed at https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=71846.

Data Sources and Search Terms

Guideline Inclusion/Exclusion Criteria

We defined guidelines as statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harm of alternative care options, consistent with the National Academies’ definition.¹¹ To be eligible, guidelines had to be published in English and include recommendations on prescribing opioids for acute, noncancer pain. We excluded guidelines focused on chronic pain or palliative care, guidelines derived entirely from another guideline, and guidelines published before 2010, since such guidelines may contain outdated information.¹² Because we were interested in general principles regarding safe use of opioids for managing acute pain, we excluded guidelines that focused exclusively on specific disease processes (eg, cancer, low-back pain, and sickle cell anemia). As we were specifically interested in the management of acute pain in the hospital setting, we also excluded guidelines that focused exclusively on specific nonhospital settings of care (eg, outpatient care clinics and nursing homes). We included guidelines related to care in the emergency department (ED) given the hospital-based location of care and the high degree of similarity in scope of practice and patient population, as most hospitalized adults are admitted through the ED. Finally, we excluded guidelines focusing on management in the intensive care setting (including the post-anesthesia care unit) given the inherent differences in patient population and management options between the intensive and nonintensive care areas of the hospital.

Guideline Quality Assessment

Guideline Synthesis and Analysis

We extracted recommendations from each guideline related to the following topics: 1) deciding when to use opioids, nonopioid medications, and nonmedication-based pain management modalities, 2) best practices in screening/monitoring/education prior to prescribing an opioid and/or during treatment, 3) opioid selection considerations, including selection of dose, duration, and route of administration, 4) strategies to minimize the risk of opioid-related adverse events, and 5) safe practices on discharge.

Role of the Funding Source

The Society of Hospital Medicine provided administrative and material support for the project, but had no role in the design or execution of the scientific evaluation.

Guideline Quality Assessment

See Table 1 for the AGREE II scaled domain scores, and Appendix Table 1 for the ratings on each individual item within a domain. The range of scaled scores for each of the AGREE II domains were as follows: Scope and purpose 52%-89%, stakeholder involvement 30%-81%, rigor of development 46%-81%, clarity of presentation 59%-72%, applicability 10%-57%, and editorial independence 42%-78%. Overall guideline assessment scores ranged from 4 to 5.33 on a scale from 1 to 7. Three of the guidelines (NICE, ACOEM, and WSAMDG)^16,17,19 were recommended for use without modification by 2 out of 3 guideline appraisers, and one of the guidelines (ACEP)¹⁸ was recommended for use with modification by all 3 appraisers. The guideline by NICE¹⁹ was rated the highest both overall (5.33), and on 4 of the 6 AGREE II domains.

Although the guidelines each included a systematic review of the literature, the NICE¹⁹ and WSAMDG¹⁷ guidelines did not include the strength of recommendations or provide clear links between each recommendation and the underlying evidence base. When citations were present, we reviewed them to determine the type of data upon which the recommendations were based and included this information in Table 2. The majority of the recommendations in Table 2 are based on expert opinion alone, or other guidelines.

Guideline Synthesis and Analysis

Table 2 contains a synthesis of the recommendations related to each of our 5 prespecified content areas. Despite the generally low quality of the evidence supporting the recommendations, there were many areas of concordance across guidelines.

Deciding When to Use Opioids, Nonopioid Medications, and Nonmedication-Based Pain Management Modalities

Three out of 4 guidelines recommended restricting opioid use to severe pain or pain that has not responded to nonopioid therapy,^16-18 2 guidelines recommended treating mild to moderate pain with nonopioid medications, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs),^16,17 and 2 guidelines recommended co-prescribing opioids with nonopioid analgesic medications to reduce total opioid requirements and improve pain control.^16,17 Each of these recommendations was supported by at least one randomized controlled trial.

Best Practices in Screening/Monitoring/Education to Occur Prior to Prescribing an Opioid and/or During Treatment

Three guidelines recommended checking prescription drug monitoring programs (PDMPs), all based on expert consensus.^16-18 Only the WSAMDG guideline offered guidance as to the optimal timing to check the PDMP in this setting, specifically recommending to check before prescribing opioids.¹⁷ Two guidelines also recommended helping patients set reasonable expectations about their recovery and educating patients about the risks/side effects of opioid therapy, all based on expert consensus or other guidelines.^17,19

Opioid Selection Considerations, Including Selection of Dose, Duration, and Route of Administration

Three guidelines recommended using the lowest effective dose, supported by expert consensus and observational data in the outpatient setting demonstrating that overdose risk increases with opioid dose.^16-18 Three guidelines recommended using short-acting opioids and/or avoiding use of long-acting/extended-release opioids for acute pain based on expert consensus.^16-18 Two guidelines recommended using as-needed rather than scheduled dosing of opioids based on expert recommendation.^{16, 17}

Strategies to Minimize the Risk of Opioid-Related Adverse Events

Several strategies to minimize the risk of opioid-related adverse events were identified, but most were only recommended by a single guideline. Strategies recommended by more than one guideline included using a recognized opioid dose conversion guide when prescribing, reviewing, or changing opioid prescriptions (based on expert consensus);^16,19 avoiding co-administration of parenteral and oral as-needed opioids, and if as-needed opioids from different routes are necessary, providing a clear indication for use of each (based on expert consensus and other guidelines);^17,19 and avoiding/using caution when co-prescribing opioids with other central nervous system depressant medications^16,17 (supported by observational studies demonstrating increased risk in the outpatient setting).

Safe Practices on Discharge

All 4 of the guidelines recommended prescribing a limited duration of opioids for the acute pain episode; however the maximum recommended duration varied widely from one week to 30 days.^16-19 It is important to note that because these guidelines were not focused on hospitalization specifically, these maximum recommended durations of use reflect the entire acute pain episode (ie, not prescribing on discharge specifically). The guideline with the longest maximum recommended duration was from NICE, based in the United Kingdom, while the US-based guideline development groups uniformly recommended 1 to 2 weeks as the maximum duration of opioid use, including the period of hospitalization.

This systematic review identified only 4 existing guidelines that included recommendations on safe opioid prescribing practices for managing acute, noncancer pain, outside of the context of specific conditions, specific nonhospital settings, or the intensive care setting. Although 2 of the identified guidelines offered sparse recommendations specific to the hospital setting, we found no guidelines that focused exclusively on the period of hospitalization specifically outside of the perioperative period. Furthermore, the guideline recommendations were largely based on expert opinion. Although these factors limit the confidence with which the recommendations can be applied to the hospital setting, they nonetheless represent the best guidance currently available to standardize and improve the safety of prescribing opioids in the hospital setting.

This paucity of guidance specific to patients hospitalized in general, nonintensive care areas of the hospital is important because pain management in this setting differs in a number of ways from pain management in the ambulatory or intensive care unit settings (including the post-anesthesia care unit). First, there are differences in the monitoring strategies that are available in each of these settings (eg, variability in nurse-to-patient ratios, frequency of measuring vital signs, and availability of continuous pulse oximetry/capnography). Second, there are differences in available/feasible routes of medication administration depending on the setting of care. Finally, there are differences in the patients themselves, including severity of illness, baseline and expected functional status, pain severity, and ability to communicate.

Accordingly, to avoid substantial heterogeneity in recommendations obtained from this review, we chose to focus on guidelines most relevant to clinicians practicing medicine in nonintensive care areas of the hospital. This resulted in the exclusion of 2 guidelines intended for anesthesiologists that focused exclusively on perioperative management and included use of advanced management procedures beyond the scope of practice for general internists,^20,21 and one guideline that focused on management in the intensive care unit.²² Within the set of guidelines included in this review, we did include recommendations designated for the postoperative period that we felt were relevant to the care of hospitalized patients more generally. In fact, the ACOEM guideline, which includes postoperative recommendations, specifically noted that these recommendations are mostly comparable to those for treating acute pain more generally.¹⁶

In addition to the lack of guidance specific to the setting in which most hospitalists practice, most of the recommendations in the existing guidelines are based on expert consensus. Guidelines based on expert opinion typically carry a lower strength of recommendation, and, accordingly, should be applied with some caution and accompanied by diligent tracking of outcome metrics, as these recommendations are applied to local health systems. Recommendations may have unintended consequences that are not necessarily apparent at the outset, and the specific circumstances of each patient must be considered when deciding how best to apply recommendations. Additional research will be necessary to track the impact of the recommended prescribing practices on patient outcomes, particularly given that many states have already begun instituting regulations on safe opioid prescribing despite the limited nature of the evidence. Furthermore, although several studies have identified patient- and prescribing-related risk factors for opioid-related adverse events in surgical patient populations, given the differences in patient characteristics and prescribing patterns in these settings, research to understand the risk factors in hospitalized medical patients specifically is important to inform evidence-based, safe prescribing recommendations in this setting.

Despite the largely expert consensus-based nature of the recommendations, we found substantial overlap in the recommendations between the guidelines, spanning our prespecified topics of interest related to safe prescribing. Most guidelines recommended restricting opioid use to severe pain or pain that has not responded to nonopioid therapy, checking PDMPs, using the lowest effective dose, and using short-acting opioids and/or avoiding use of long-acting/extended-release opioids for acute pain. There was less consensus on risk mitigation strategies, where the majority of recommendations were endorsed by only 1 or 2 guidelines. Finally, all 4 guidelines recommended prescribing a limited duration of opioids for the acute pain episode, with US-based guidelines recommending 1 to 2 weeks as the maximum duration of opioid use, including the period of hospitalization.

There are limitations to our evaluation. As previously noted, in order to avoid substantial heterogeneity in management recommendations, we excluded 2 guidelines intended for anesthesiologists that focused exclusively on perioperative management,^20,21 and one guideline focused on management in the intensive care unit.²² Accordingly, recommendations contained in this review may or may not be applicable to those settings, and readers interested in those settings specifically are directed to those guidelines. Additionally, we decided to exclude guidelines that focused on managing acute pain in specific conditions (eg, sickle cell disease and pancreatitis) because our goal was to identify generalizable principles of safe prescribing of opioids that apply regardless of clinical condition. Despite this goal, it is important to recognize that not all of the recommendations are generalizable to all types of pain; clinicians interested in management principles specific to certain disease states are encouraged to review disease-specific informational material. Finally, although we used rigorous, pre-defined search criteria and registered our protocol on PROSPERO, it is possible that our search strategy missed relevant guidelines.

In conclusion, we identified few guidelines on safe opioid prescribing practices for managing acute, noncancer pain, outside of the context of specific conditions or nonhospital settings, and no guidelines focused on acute pain management in general, nonintensive care areas of the hospital specifically. Nevertheless, the guidelines that we identified make consistent recommendations related to our prespecified topic areas of relevance to the hospital setting, although most recommendations are based exclusively on expert opinion. Our systematic review nonetheless provides guidance in an area where guidance has thus far been limited. Future research should investigate risk factors for opioid-related adverse events in hospitalized, nonsurgical patients, and the effectiveness of interventions designed to reduce their occurrence.

Dr. Herzig had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from SHM for their facilitation of this project and dedication to this purpose.

Disclosures: Dr. Herzig received compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena received consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance and material support, but had no role in or influence on the scientific conduct of the study. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported, in part, by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, or reporting of the study

Since the initial reports of an emerging opioid epidemic in the early 2000s, intense focus on improving opioid prescribing in outpatient settings has culminated in new guidelines for chronic pain.^1,2 Although opioid stewardship in the setting of chronic pain is of paramount importance in curbing the ongoing epidemic, long-term prescription opioid use often begins with treatment of acute pain.¹ In addition to differences in recommended management strategies for acute and chronic pain, there are unique aspects and challenges to pain management in the acute-care setting.

Opioids are commonly used for the treatment of acute pain in hospitalized patients, often at high doses.³ Recent reports highlight that hospital use of opioids impacts downstream use.^4-6 Additionally, opioid prescribing practices vary between hospital-based providers and hospitals,^3,7 highlighting the need for prescribing standards and guidance. To our knowledge, there are no existing guidelines for improving the safety of opioid use in hospitalized patients outside of the intensive care or immediate perioperative settings.

The Society of Hospital Medicine (SHM) convened a working group to systematically review existing guidelines and develop a consensus statement to assist clinicians in safe opioid use for acute, noncancer pain in hospitalized adults.

Consensus Statement Purpose and Scope

The purpose of this Consensus Statement is to present clinical recommendations on the safe use of opioids for the treatment of acute, noncancer pain in hospitalized adults. The guidance is intended for clinicians practicing medicine in the inpatient setting (eg, hospitalists, primary care physicians, family physicians, nurse practitioners, and physician assistants) and is intended to apply to hospitalized adults with acute, noncancer pain (ie, pain that typically lasts <3 months or during the period of normal tissue healing) outside of the palliative, end-of-life, and intensive care settings.

Consensus Statement Development

Our working group included experts in opioid use in the hospital setting, defined by 1) engagement in the clinical practice of hospital medicine and 2) involvement in clinical research related to usage patterns and clinical outcomes of opioid use in hospitalized patients (see Appendix Table 1). The SHM provided administrative assistance with the project and funded the in-person working group meeting, but it had no role in formulating the recommendations. The SHM Board of Directors provided approval of the Consensus Statement without modification.

An overview of the sequential steps in the Consensus Statement development process is described below; details of the methods and results can be found in the Appendix (eMethods).

Performing the Systematic Review

Drafting the Consensus Statement

After performing the systematic review, the working group drafted and iteratively revised a set of recommendations using a variation of the Delphi Method⁸ to identify consensus among group members.

External Review

Following agreement on a draft set of recommendations, we obtained feedback from external groups, including 1) individuals involved in the SHM’s Reducing Adverse Drug Events Related to Opioids (RADEO) initiative, including those involved in the development of the implementation guide and site leads for the Mentored Implementation program, 2) SHM members, SHM Patient-Family Advisory Council (PFAC) members, and leaders of other relevant professional societies, and 3) peer-reviewers at the Journal of Hospital Medicine.

Deciding Whether to Use Opioids During Hospitalization

1. SHM recommends that clinicians limit the use of opioids to patients with 1) severe pain or 2) moderate pain that has not responded to nonopioid therapy, or where nonopioid therapy is contraindicated or anticipated to be ineffective.

Opioids are associated with several well-recognized risks ranging from mild to severe, including nausea, constipation, urinary retention, falls, delirium, sedation, physical dependence, addiction, respiratory depression, and death. Given these risks, the risk-to-benefit ratio is generally not favorable at lower levels of pain severity. Furthermore, for most painful conditions, including those causing severe pain, nonopioid analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), have been demonstrated to be equally or more effective with less risk of harm than opioids.^9-13 Clinicians should consider drug–drug and drug–disease associations when deciding between these different therapies and make a determination in each patient regarding whether the benefits outweigh the risks. Often, drug–disease interactions do not represent absolute contraindications, and risks can be mitigated by adhering to dosage limits and, with respect to NSAIDs, 1) monitoring renal function, 2) monitoring volume status in patients with congestive heart failure, and 3) considering a selective cyclooxygenase-2 (COX-2) inhibitor rather than a nonselective NSAID or pairing the NSAID with an acid-suppressive medication in patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease. For these reasons, a trial of nonopioid therapy (including pharmacologic and nonpharmacologic modalities) should always be considered before using opioids for pain of any severity. This does not imply that a trial of nonopioid therapy must be performed in all patients, but rather, that the likelihood of benefit and associated risks of opioid and nonopioid therapy should be considered for all patients in determining the best initial management strategy.

2. SHM recommends that clinicians use extra caution when administering opioids to patients with risk factors for opioid-related adverse events.

Several factors have been consistently demonstrated to increase the risk of opioid-related adverse events–most importantly, respiratory depression and overdose–in varied patient populations and settings, including age 65 years and older,^1,14-17 renal insufficiency,^1,14,18 hepatic insufficiency,^1,14 chronic respiratory failure (including chronic obstructive pulmonary disease, sleep apnea, etc.), and receipt of other central nervous system (CNS) depressant medications (including, but not limited to, benzodiazepines).^1,18-20 History of any substance use disorder and psychiatric disorders have been associated with an increased risk for the development of opioid use disorder.^21-24 These factors should be weighed against the benefits when deciding on opioid appropriateness in a given patient. However, identification of these risks should not preclude opioids as part of pain management. When a decision is made to use opioids in patients with these risk factors, clinicians should 1) use a reduced starting dose (generally, at least a 50% reduction in the usual starting dose) and 2) consider closer monitoring for adverse effects (eg, more frequent nursing assessments, capnography, or more frequent outpatient visits).

3. SHM recommends that clinicians review the information contained in the prescription drug monitoring program (PDMP) database to inform decision-making around opioid therapy.

Although data on the impact of use of the state PDMP database on prescribing practices or patient outcomes are limited, PDMP use has been advocated by multiple guidelines on acute pain management.^25-27 The PDMP provides information that can be useful in several ways, including 1) confirmation of prior opioid exposure and dosage, which should be used to guide appropriate dosage selection in the hospital, 2) identification of existing controlled substance prescriptions, which should be considered in prescribing decisions in the hospital and on discharge, and 3) identification of signs of aberrant behavior. For example, the identification of controlled substance prescriptions written by multiple different clinicians can facilitate early identification of potential diversion or evolving or existing opioid use disorder and the opportunity for intervention,²⁸ which may include referral to support services, initiation of medication-assisted treatment, and/or pain specialist consultation when available. Concerns regarding evolving or existing opioid use disorder should prompt further discussion between the clinician and the patient, both to clarify their understanding of their recent prescription history and to discuss concerns for patient safety related to the increased risk of opioid-related adverse effects (including respiratory depression and overdose) among patients with controlled substance prescriptions written by multiple providers. Although such concerns should not automatically preclude the use of opioids for acute pain in the hospital setting, they should be considered in the assessment of whether the benefits of opioid therapy outweigh the risks for a given patient.

4. SHM recommends that clinicians educate patients and families or caregivers about the potential risks and side effects of opioid therapy as well as alternative pharmacologic and nonpharmacologic therapies for managing pain.

Patients are often unaware of the risks of opioid therapy (see Consensus Statement 1 for key risks),²⁹ or that there are often equally effective alternative therapies. As with any therapy associated with substantial risk, clinicians should discuss these risks with patients and/or caregivers at the outset of therapy, as well as the potential benefits of nonopioid pharmacologic and nonpharmacologic therapies for managing pain. Patients should be informed that they may request nonopioid therapy in lieu of opioids, even for severe pain.

Once a Decision Has Been Made to Use Opioids During Hospitalization

5. SHM recommends that clinicians use the lowest effective opioid dose for the shortest duration possible.

Higher opioid doses are associated with an increased incidence of opioid-related adverse events, particularly overdose, in studies of both inpatient and outpatient populations.^{1,17,19,30,31} Studies in the inpatient and outpatient settings consistently demonstrate that risk increases with dosage.^19,30,31 Clinicians should reduce the usual starting dose by at least 50% among patients with conditions that increase susceptibility to opioid-related adverse events (see Consensus Statement 2). The ongoing need for opioids should be re-assessed regularly-at least daily-during the hospitalization, with attempts at tapering as healing occurs and/or pain and function improve.

6. SHM recommends that clinicians use immediate-release opioid formulations and avoid initiation of long-acting or extended-release formulations (including transdermal fentanyl) for treatment of acute pain.

Studies in outpatient settings demonstrate that the use of long-acting opioids is associated with greater risk for overdose–especially in opioid-naïve patients–and long-term use.^32,33 Further, hospitalized patients frequently have fluctuating renal function and rapidly changing pain levels. We therefore recommend that initiation of long-acting opioids be avoided for the treatment of acute, noncancer pain in hospitalized medical patients. It is important to note that although we recommend avoiding initiation of long-acting opioids for the treatment of acute, noncancer pain, there are circumstances outside of the scope of this Consensus Statement for which initiation of long-acting opioids may be indicated, including the treatment of opioid withdrawal. We also do not recommend discontinuation of long-acting or extended-release opioids in patients who are taking these medications for chronic pain at the time of hospital admission (unless there are concerns regarding adverse effects or drug–disease interactions).

7. SHM recommends that clinicians use the oral route of administration whenever possible. Intravenous opioids should be reserved for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal malabsorption, or when immediate pain control and/or rapid dose titration is necessary.

Intravenous opioid administration is associated with an increased risk of side effects, adverse events, and medication errors.^34-36 Additionally, studies demonstrate that in general, the addiction potential of medications is greater the more rapid the onset of action (the onset of action is 5–10 min for intravenous and 15–30 minutes for oral administration).^37,38 Furthermore, the duration of action is greater for oral compared to that of intravenous administration, potentially allowing for more consistent pain relief and less frequent administrations. As such, intravenous administration should be reserved for situations when oral administration is not possible or likely to be ineffective, or when immediate pain control and/or rapid titration is necessary.

8. SHM recommends that clinicians use an opioid equivalency table or calculator to understand the relative potency of different opioids 1) when initiating opioid therapy, 2) when changing from one route of administration to another, and 3) when changing from one opioid to another. When changing from one opioid to another, clinicians should generally reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids as well as possible incomplete cross-tolerance.

Most errors causing preventable adverse drug events in hospitals occur at the ordering stage.^39,40 Clinicians are often unaware of the potency of different types of opioids relative to each other or to morphine (ie, morphine equivalent dose), which can lead to inadvertent overdose when initiating therapy with nonmorphine opioids and when converting from one opioid to another. To facilitate safe opioid use, we recommend that clinicians use one of several available opioid equivalency tables or calculators to better understand the relative potencies of opioids and to inform both starting dose calculations and conversions between opioids and routes of administration. When converting from one opioid to another, we caution clinicians to reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids and the potential for incomplete cross-tolerance, wherein tolerance to a currently administered opioid does not extend completely to other opioids. Clinicians should use extreme caution when performing conversions to and from methadone and consider consultation with a hospital pharmacist or a pain management specialist, when available, to assist with conversion decisions and calculations.

9. SHM recommends that clinicians pair opioids with scheduled nonopioid analgesic medications, unless contraindicated, and always consider pairing with nonpharmacologic pain management strategies (ie, multimodal analgesia).

Concurrent receipt of opioids and nonopioid analgesic medications (including acetaminophen, NSAIDs, and gabapentin or pregabalin, depending on the underlying pathophysiology of the pain) has been demonstrated to reduce total opioid requirements and improve pain management.^41,42 Clinicians should be familiar with contraindications and maximum dosage recommendations for each of these adjunctive nonopioid medications. We recommend separate orders for each, rather than using drug formulations that combine opioids and nonopioid analgesics in the same pill, due to the risk of inadvertently exceeding the maximum recommended doses of the nonopioid analgesic (particularly acetaminophen) with combination products. We recommend that nonopioid analgesics be ordered at a scheduled frequency, rather than as needed, to facilitate consistent administration that is not dependent on opioid administration. Topical agents, including lidocaine and capsaicin, should also be considered. Nonpharmacologic pain management strategies can include procedure-based (eg, regional and local anesthesia) and nonprocedure-based therapies depending on the underlying condition and institutional availability. Although few studies have assessed the benefit of nonpharmacologic, nonprocedure-based therapies for the treatment of acute pain in hospitalized patients, the lack of harm associated with their use argues for their adoption. Simple nonpharmacologic therapies that can usually be provided to patients in any hospital setting include music therapy, cold or hot packs, chaplain or social work visits (possibly including mindfulness training),⁴³ and physical therapy, among others.

10. SHM recommends that, unless contraindicated, clinicians order a bowel regimen to prevent opioid-induced constipation in patients receiving opioids.

Constipation is a common adverse effect of opioid therapy and results from the activation of mu opioid receptors in the colon, resulting in decreased peristalsis. Hospitalized patients are already prone to constipation due to their often-limited physical mobility. To mitigate this complication, we recommend the administration of a bowel regimen to all hospitalized medical patients receiving opioid therapy, provided the patient is not having diarrhea. Given the mechanism of opioid-induced constipation, stimulant laxatives (eg, senna, bisacodyl) have been recommended for this purpose.⁴⁴ Osmotic laxatives (eg, polyethylene glycol, lactulose) have demonstrated efficacy for the treatment of constipation more generally (ie, not necessarily opioid-induced constipation). Stool softeners, although frequently used in the inpatient setting, are not recommended due to limited and conflicting evidence for efficacy in prevention or treatment of constipation.⁴⁵ Bowel movements should be tracked during hospitalization, and the bowel regimen modified accordingly.

11. SHM recommends that clinicians limit co-administration of opioids with other central nervous system depressant medications to the extent possible.

This combination has been demonstrated to increase the risk of opioid-related adverse events in multiple settings of care, including during hospitalization.^1,18,19 Although benzodiazepines have received the most attention in this respect, other medications with CNS depressant properties may also increase the risk, including, but not limited to, nonbenzodiazepine sedative-hypnotics (eg, zolpidem, zaleplon, zopiclone), muscle relaxants, sedating antidepressants, antipsychotics, and antihistamines.^18,19,46 For some patients, the combination will be unavoidable, and we do not suggest routine discontinuation of longstanding medications that preexisted hospitalization, given the risks of withdrawal and/or worsening of the underlying condition for which these medications are prescribed. Rather, clinicians should carefully consider the necessity of each medication class with input from the patient’s outpatient providers, taper the frequency and/or the dose of CNS depressants when appropriate and feasible, and avoid new coprescriptions to the extent possible, both during hospitalization and on hospital discharge.

12. SHM recommends that clinicians work with patients and families or caregivers to establish realistic goals and expectations of opioid therapy and the expected course of recovery.

Discussing expectations at the start of therapy is important to facilitate a clear understanding of how meaningful improvement will be defined and measured during the hospitalization and how long the patient is anticipated to require opioid therapy. Meaningful improvement should be defined to include improvement in both pain and function. Clinicians should discuss with patients 1) that the goal of opioid therapy is tolerability of pain such that meaningful improvement in function can be achieved and 2) that a decrease in pain intensity in the absence of improved function is not considered meaningful improvement in most situations and should prompt reevaluation of the appropriateness of continued opioid therapy as well as close follow-up with a clinician following hospital discharge. Discussions regarding the expected course of recovery should include that acute pain is expected to resolve as the underlying medical condition improves and that although pain may persist beyond the hospitalization, pain that is severe enough to require opioids will often be resolved or almost resolved by the time of hospital discharge.

13. SHM recommends that clinicians monitor the response to opioid therapy, including assessment for functional improvement and development of adverse effects.

Pain severity and function should be assessed at least daily, and improvement in reported pain severity without improvement in function over several days should, in most circumstances, prompt reconsideration of ongoing opioid therapy and reconsideration of the underlying etiology of pain. Although hospital-specific functional measures in the setting of acute pain have not yet been validated, we suggest that such measures and goals should be individualized based on preexisting function and may include the ability to sit up or move in bed, move to a chair, work with physical therapy, or ambulate in the hallway. Protocols for the assessment for adverse effects are not well established. Because sedation typically precedes respiratory depression, it is generally recommended that patients are evaluated (eg, by nursing staff) for sedation after each opioid administration (10–20 minutes for intravenous and 30–60 minutes for oral administration based on the time-to-peak effect). Whether certain patients may benefit from more intensive respiratory monitoring, such as pulse oximetry or capnography, is an area of active investigation and not yet established.

Prescribing at the Time of Hospital Discharge

14. SHM recommends that clinicians ask patients about any existing opioid supply at home and account for any such supply when issuing an opioid prescription on discharge.

Even in the setting of acute pain, patients may have previously received an opioid prescription from an outpatient clinician prior to hospitalization. Unused prescription opioids create the possibility of both overdose (when patients take multiple opioids concurrently, intentionally or inadvertently) and diversion (many adults with prescription opioid misuse obtained their opioids from a friend or a relative who may or may not have known that this occurred⁴⁷). The PDMP database can provide information related to the potential existence of any prior opioid supplies, which should be confirmed with the patient and considered when providing a new prescription on hospital discharge. Information on proper disposal should be provided if use of the preexisting opioid is no longer intended.

15. SHM recommends that clinicians prescribe the minimum quantity of opioids anticipated to be necessary based on the expected course and duration of pain that is severe enough to require opioid therapy after hospital discharge.

For many patients, the condition causing their acute pain will be mostly or completely resolved by the time of hospital discharge. When pain is still present at the time of discharge, most pain can be completely managed with nonopioid therapies. For those with ongoing pain that is severe enough to require opioids after hospital discharge, decisions regarding the duration of therapy should be made on a case-by-case basis; generally, however, provision of a 3- to 5-day supply will be sufficient, and provision of more than a 7-day supply of opioids should generally be avoided for several reasons. These include 1) acute pain lasting longer than 7 days after appropriate treatment of any existing underlying conditions should prompt re-evaluation of the working diagnosis and/or reconsideration of the management approach, 2) receiving higher intensity opioid therapy (including longer courses) in the setting of acute pain has been associated with an increased risk of long-term disability and long-term opioid use,^33,48,49 and 3) unused opioids create the possibility of intentional or unintentional opioid diversion (see Consensus Statement 14).⁴⁷ Accordingly, clinicians should attempt to arrange an outpatient follow-up appointment for re-evaluation within 7 days, rather than providing an extended opioid prescription on hospital discharge. In situations where this is not feasible, and pain that is severe enough to require opioids is expected to persist longer than 7 days, an extended prescription may be indicated. However, some states have begun enacting legislation to limit the duration of first-time opioid prescriptions, typically using a 5-to-7 day supply as an upper limit; clinicians should be aware of and adhere to individual state laws governing their practice.

16. SHM recommends that clinicians ensure that patients and families or caregivers receive information regarding how to minimize the risks of opioid therapy for themselves, their families, and their communities. This includes but is not limited to 1) how to take their opioids correctly (the planned medications, doses, schedule); 2) that they should take the minimum quantity necessary to achieve tolerable levels of pain and meaningful functional improvement, reducing the dose and/or frequency as pain and function improve; 3) how to safeguard their supply and dispose of any unused supply; 4) that they should avoid agents that may potentiate the sedative effect of opioids, including sleeping medication and alcohol; 5) that they should avoid driving or operating heavy machinery while taking opioids; and 6) that they should seek help if they begin to experience any potential adverse effects, with inclusion of information on early warning signs.

Clear and concise patient instructions on home opioid dosing and administration will limit opioid-related adverse events and dosing errors upon hospital discharge. Each of these recommendations derive from one or more of the existing guidelines and reflect the transfer of responsibility for safe opioid use practices that occurs as patients transition from a closely monitored inpatient setting to the more self-regulated home environment.

This Consensus Statement reflects a synthesis of the key recommendations from a systematic review of existing guidelines on acute pain management, adapted for a hospital-specific scope of practice. Despite a paucity of data on the comparative effectiveness of different management strategies for acute pain, several areas of expert consensus emerged across existing guidelines, which were felt to be relevant and applicable to the hospital setting. The objective of these recommendations is to provide information that can be used to inform and support opioid-related management decisions for acute pain by clinicians practicing medicine in the inpatient setting.

Although these recommendations are not intended to apply to the immediate perioperative setting (ie, care in the postanesthesia care unit), many of the recommendations in the existing guidelines upon which this Consensus Statement was based were intended for the postoperative setting, and, as others have noted, recommendations in this setting are mostly comparable to those for treating acute pain more generally.²⁷ Those interested in pain management in the postoperative setting specifically may wish to review the recent guidelines released by the American Pain Society,⁵⁰ the content of which is in close alignment with our Consensus Statement.

Several important issues were raised during the extensive external feedback process undertaken as part of the development of this Consensus Statement. Although many issues were incorporated into the recommendations, there were several suggestions for which we felt the evidence base was not sufficient to allow a clear or valid recommendation to be made. For example, several reviewers requested endorsement of specific patient education tools and opioid equivalency calculators. In the absence of tools specifically validated for this purpose, we felt that the evidence was insufficient to make specific recommendations. Validating such tools for use in the inpatient setting should be an area of future investigation. In the meantime, we note that there are several existing and widely available resources for both patient education (ie, opioid information sheets, including opioid risks, safe containment and disposal, and safe use practices) and opioid equivalency calculations that clinicians and hospitals can adapt for their purposes.

Several individuals suggested recommendations on communication with outpatient continuity providers around opioid management decisions during hospitalization and on discharge. Although we believe that it is of paramount importance for outpatient providers to be aware of and have input into these decisions, the optimal timing and the method for such communication are unclear and likely to be institution-specific depending on the availability and integration of electronic records across care settings. We recommend that clinicians use their judgment as to the best format and timing for assuring that outpatient physicians are aware of and have input into these important management decisions with downstream consequences.

Concerns were also raised about the time required to complete the recommended practices and the importance of emphasizing the need for a team-based approach in this realm. We agree wholeheartedly with this sentiment and believe that many of the recommended practices can and should be automated and/or shared across the care team. For example, PDMPs allow prescribers to appoint delegates to check the PDMP on their behalf. Additionally, we suggest that hospitals work to develop systems to assist care teams with performance of these tasks in a standardized and streamlined manner (eg, integrating access to the PDMP and opioid equivalency tables within the electronic health record and developing standard patient educational handouts). Provision of written materials on opioid risks, side effects, and safety practices may be helpful in facilitating consistent messaging and efficient workflow for members of the care team.

Finally, the working group carefully considered whether to include a recommendation regarding naloxone prescribing at the time of hospital discharge. The provision of naloxone kits to laypersons through Overdose Education and Naloxone Distribution Programs has been shown to reduce opioid overdose deaths^51,52 and hospitalizations^53,54 and is both safe and cost-effective.⁵⁵ The Centers for Disease Control and Preventionrecommend that clinicians “consider offering naloxone to patients with a history of overdose, a current or past substance use disorder, receipt of ≥50 mg of morphine equivalents per day or concurrent benzodiazepine use.”¹ However, these recommendations are intended for patients on chronic opioid therapy; presently, no clear evidence exists to guide decisions about the benefits and costs associated with prescribing naloxone in the setting of short-term opioid therapy for acute pain. Further research in this area is warranted.

The greatest limitation of this Consensus Statement is the lack of high-quality studies informing most of the recommendations in the guidelines upon which our Consensus Statement was based. The majority of recommendations in the existing guidelines were based on expert opinion alone. Additional research is necessary before evidence-based recommendations can be formulated.

Accordingly, the working group identified several key areas for future research, in addition to those noted above. First, ongoing efforts to develop and evaluate the effectiveness of nonopioid and nonpharmacologic management strategies for acute pain in hospitalized patients are necessary. Second, studies identifying the risk factors for opioid-related adverse events in hospitalized patients would help inform management decisions and allow deployment of resources and specialized monitoring strategies to patients at heightened risk. The working group also noted the need for research investigating the impact of PDMP use on management decisions and downstream outcomes among hospitalized patients. Finally, conversations around pain management and concerns related to aberrant behaviors are often challenging in the hospital setting owing to the brief, high-intensity nature of the care and the lack of a longstanding therapeutic alliance. There is a great need to develop strategies and language to facilitate these conversations.

In conclusion, until more high-quality evidence becomes available, clinicians can use the recommendations contained in this Consensus Statement along with their clinical judgment and consultation with pharmacists, interventional pain specialists, and other staff (eg, social work, nursing) to help facilitate consistent, high-quality care across providers and hospitals. We believe that doing so will help increase the appropriateness of opioid therapy, minimize adverse events, facilitate shared decision-making, and foster stronger therapeutic alliances at the outset of the hospitalization for patients suffering from acute pain.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from the SHM for their facilitation of this project and dedication to this purpose.

The authors would also like to thank the many individuals who provided comments on the draft recommendations, including the participants in the SHM RADEO program; the SHM members; the representatives of specialty societies, including the American Academy of Family Physicians, the American College of Physicians, the American Hospital Association, the American Society of Addiction Medicine, the American Society of Anesthesiologists, the American Society of Health-System Pharmacists, the Society of Critical Care Medicine, and the Society of General Internal Medicine; and the representatives of patient advocacy groups, including SHM PFAC, Regions Hospital Patient and Family Advisory Committee, Patient and Family Centered Care Council of St. Louis Children’s Hospital, Missouri Family Partnership, and Parent and Family Care.

Disclosures: Dr. Herzig reports receiving compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena reports receiving consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics, a consultancy to the life sciences industry (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance with the project and funded the in-person working group meeting but had no role in or influence on developing the content of the recommendations themselves. The SHM Board of Directors provided approval to submit the manuscript for publication without modification. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported in part by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, and reporting of the study

Since the initial reports of an emerging opioid epidemic in the early 2000s, intense focus on improving opioid prescribing in outpatient settings has culminated in new guidelines for chronic pain.^1,2 Although opioid stewardship in the setting of chronic pain is of paramount importance in curbing the ongoing epidemic, long-term prescription opioid use often begins with treatment of acute pain.¹ In addition to differences in recommended management strategies for acute and chronic pain, there are unique aspects and challenges to pain management in the acute-care setting.

Opioids are commonly used for the treatment of acute pain in hospitalized patients, often at high doses.³ Recent reports highlight that hospital use of opioids impacts downstream use.^4-6 Additionally, opioid prescribing practices vary between hospital-based providers and hospitals,^3,7 highlighting the need for prescribing standards and guidance. To our knowledge, there are no existing guidelines for improving the safety of opioid use in hospitalized patients outside of the intensive care or immediate perioperative settings.

The Society of Hospital Medicine (SHM) convened a working group to systematically review existing guidelines and develop a consensus statement to assist clinicians in safe opioid use for acute, noncancer pain in hospitalized adults.

Consensus Statement Purpose and Scope

The purpose of this Consensus Statement is to present clinical recommendations on the safe use of opioids for the treatment of acute, noncancer pain in hospitalized adults. The guidance is intended for clinicians practicing medicine in the inpatient setting (eg, hospitalists, primary care physicians, family physicians, nurse practitioners, and physician assistants) and is intended to apply to hospitalized adults with acute, noncancer pain (ie, pain that typically lasts <3 months or during the period of normal tissue healing) outside of the palliative, end-of-life, and intensive care settings.

Consensus Statement Development

Our working group included experts in opioid use in the hospital setting, defined by 1) engagement in the clinical practice of hospital medicine and 2) involvement in clinical research related to usage patterns and clinical outcomes of opioid use in hospitalized patients (see Appendix Table 1). The SHM provided administrative assistance with the project and funded the in-person working group meeting, but it had no role in formulating the recommendations. The SHM Board of Directors provided approval of the Consensus Statement without modification.

An overview of the sequential steps in the Consensus Statement development process is described below; details of the methods and results can be found in the Appendix (eMethods).

Performing the Systematic Review

Drafting the Consensus Statement

After performing the systematic review, the working group drafted and iteratively revised a set of recommendations using a variation of the Delphi Method⁸ to identify consensus among group members.

External Review

Following agreement on a draft set of recommendations, we obtained feedback from external groups, including 1) individuals involved in the SHM’s Reducing Adverse Drug Events Related to Opioids (RADEO) initiative, including those involved in the development of the implementation guide and site leads for the Mentored Implementation program, 2) SHM members, SHM Patient-Family Advisory Council (PFAC) members, and leaders of other relevant professional societies, and 3) peer-reviewers at the Journal of Hospital Medicine.

Deciding Whether to Use Opioids During Hospitalization

1. SHM recommends that clinicians limit the use of opioids to patients with 1) severe pain or 2) moderate pain that has not responded to nonopioid therapy, or where nonopioid therapy is contraindicated or anticipated to be ineffective.

Opioids are associated with several well-recognized risks ranging from mild to severe, including nausea, constipation, urinary retention, falls, delirium, sedation, physical dependence, addiction, respiratory depression, and death. Given these risks, the risk-to-benefit ratio is generally not favorable at lower levels of pain severity. Furthermore, for most painful conditions, including those causing severe pain, nonopioid analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), have been demonstrated to be equally or more effective with less risk of harm than opioids.^9-13 Clinicians should consider drug–drug and drug–disease associations when deciding between these different therapies and make a determination in each patient regarding whether the benefits outweigh the risks. Often, drug–disease interactions do not represent absolute contraindications, and risks can be mitigated by adhering to dosage limits and, with respect to NSAIDs, 1) monitoring renal function, 2) monitoring volume status in patients with congestive heart failure, and 3) considering a selective cyclooxygenase-2 (COX-2) inhibitor rather than a nonselective NSAID or pairing the NSAID with an acid-suppressive medication in patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease. For these reasons, a trial of nonopioid therapy (including pharmacologic and nonpharmacologic modalities) should always be considered before using opioids for pain of any severity. This does not imply that a trial of nonopioid therapy must be performed in all patients, but rather, that the likelihood of benefit and associated risks of opioid and nonopioid therapy should be considered for all patients in determining the best initial management strategy.

2. SHM recommends that clinicians use extra caution when administering opioids to patients with risk factors for opioid-related adverse events.

Several factors have been consistently demonstrated to increase the risk of opioid-related adverse events–most importantly, respiratory depression and overdose–in varied patient populations and settings, including age 65 years and older,^1,14-17 renal insufficiency,^1,14,18 hepatic insufficiency,^1,14 chronic respiratory failure (including chronic obstructive pulmonary disease, sleep apnea, etc.), and receipt of other central nervous system (CNS) depressant medications (including, but not limited to, benzodiazepines).^1,18-20 History of any substance use disorder and psychiatric disorders have been associated with an increased risk for the development of opioid use disorder.^21-24 These factors should be weighed against the benefits when deciding on opioid appropriateness in a given patient. However, identification of these risks should not preclude opioids as part of pain management. When a decision is made to use opioids in patients with these risk factors, clinicians should 1) use a reduced starting dose (generally, at least a 50% reduction in the usual starting dose) and 2) consider closer monitoring for adverse effects (eg, more frequent nursing assessments, capnography, or more frequent outpatient visits).

3. SHM recommends that clinicians review the information contained in the prescription drug monitoring program (PDMP) database to inform decision-making around opioid therapy.

Although data on the impact of use of the state PDMP database on prescribing practices or patient outcomes are limited, PDMP use has been advocated by multiple guidelines on acute pain management.^25-27 The PDMP provides information that can be useful in several ways, including 1) confirmation of prior opioid exposure and dosage, which should be used to guide appropriate dosage selection in the hospital, 2) identification of existing controlled substance prescriptions, which should be considered in prescribing decisions in the hospital and on discharge, and 3) identification of signs of aberrant behavior. For example, the identification of controlled substance prescriptions written by multiple different clinicians can facilitate early identification of potential diversion or evolving or existing opioid use disorder and the opportunity for intervention,²⁸ which may include referral to support services, initiation of medication-assisted treatment, and/or pain specialist consultation when available. Concerns regarding evolving or existing opioid use disorder should prompt further discussion between the clinician and the patient, both to clarify their understanding of their recent prescription history and to discuss concerns for patient safety related to the increased risk of opioid-related adverse effects (including respiratory depression and overdose) among patients with controlled substance prescriptions written by multiple providers. Although such concerns should not automatically preclude the use of opioids for acute pain in the hospital setting, they should be considered in the assessment of whether the benefits of opioid therapy outweigh the risks for a given patient.

4. SHM recommends that clinicians educate patients and families or caregivers about the potential risks and side effects of opioid therapy as well as alternative pharmacologic and nonpharmacologic therapies for managing pain.

Patients are often unaware of the risks of opioid therapy (see Consensus Statement 1 for key risks),²⁹ or that there are often equally effective alternative therapies. As with any therapy associated with substantial risk, clinicians should discuss these risks with patients and/or caregivers at the outset of therapy, as well as the potential benefits of nonopioid pharmacologic and nonpharmacologic therapies for managing pain. Patients should be informed that they may request nonopioid therapy in lieu of opioids, even for severe pain.

Once a Decision Has Been Made to Use Opioids During Hospitalization

5. SHM recommends that clinicians use the lowest effective opioid dose for the shortest duration possible.

Higher opioid doses are associated with an increased incidence of opioid-related adverse events, particularly overdose, in studies of both inpatient and outpatient populations.^{1,17,19,30,31} Studies in the inpatient and outpatient settings consistently demonstrate that risk increases with dosage.^19,30,31 Clinicians should reduce the usual starting dose by at least 50% among patients with conditions that increase susceptibility to opioid-related adverse events (see Consensus Statement 2). The ongoing need for opioids should be re-assessed regularly-at least daily-during the hospitalization, with attempts at tapering as healing occurs and/or pain and function improve.

6. SHM recommends that clinicians use immediate-release opioid formulations and avoid initiation of long-acting or extended-release formulations (including transdermal fentanyl) for treatment of acute pain.

Studies in outpatient settings demonstrate that the use of long-acting opioids is associated with greater risk for overdose–especially in opioid-naïve patients–and long-term use.^32,33 Further, hospitalized patients frequently have fluctuating renal function and rapidly changing pain levels. We therefore recommend that initiation of long-acting opioids be avoided for the treatment of acute, noncancer pain in hospitalized medical patients. It is important to note that although we recommend avoiding initiation of long-acting opioids for the treatment of acute, noncancer pain, there are circumstances outside of the scope of this Consensus Statement for which initiation of long-acting opioids may be indicated, including the treatment of opioid withdrawal. We also do not recommend discontinuation of long-acting or extended-release opioids in patients who are taking these medications for chronic pain at the time of hospital admission (unless there are concerns regarding adverse effects or drug–disease interactions).

7. SHM recommends that clinicians use the oral route of administration whenever possible. Intravenous opioids should be reserved for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal malabsorption, or when immediate pain control and/or rapid dose titration is necessary.

Intravenous opioid administration is associated with an increased risk of side effects, adverse events, and medication errors.^34-36 Additionally, studies demonstrate that in general, the addiction potential of medications is greater the more rapid the onset of action (the onset of action is 5–10 min for intravenous and 15–30 minutes for oral administration).^37,38 Furthermore, the duration of action is greater for oral compared to that of intravenous administration, potentially allowing for more consistent pain relief and less frequent administrations. As such, intravenous administration should be reserved for situations when oral administration is not possible or likely to be ineffective, or when immediate pain control and/or rapid titration is necessary.

8. SHM recommends that clinicians use an opioid equivalency table or calculator to understand the relative potency of different opioids 1) when initiating opioid therapy, 2) when changing from one route of administration to another, and 3) when changing from one opioid to another. When changing from one opioid to another, clinicians should generally reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids as well as possible incomplete cross-tolerance.

Most errors causing preventable adverse drug events in hospitals occur at the ordering stage.^39,40 Clinicians are often unaware of the potency of different types of opioids relative to each other or to morphine (ie, morphine equivalent dose), which can lead to inadvertent overdose when initiating therapy with nonmorphine opioids and when converting from one opioid to another. To facilitate safe opioid use, we recommend that clinicians use one of several available opioid equivalency tables or calculators to better understand the relative potencies of opioids and to inform both starting dose calculations and conversions between opioids and routes of administration. When converting from one opioid to another, we caution clinicians to reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids and the potential for incomplete cross-tolerance, wherein tolerance to a currently administered opioid does not extend completely to other opioids. Clinicians should use extreme caution when performing conversions to and from methadone and consider consultation with a hospital pharmacist or a pain management specialist, when available, to assist with conversion decisions and calculations.

9. SHM recommends that clinicians pair opioids with scheduled nonopioid analgesic medications, unless contraindicated, and always consider pairing with nonpharmacologic pain management strategies (ie, multimodal analgesia).

Concurrent receipt of opioids and nonopioid analgesic medications (including acetaminophen, NSAIDs, and gabapentin or pregabalin, depending on the underlying pathophysiology of the pain) has been demonstrated to reduce total opioid requirements and improve pain management.^41,42 Clinicians should be familiar with contraindications and maximum dosage recommendations for each of these adjunctive nonopioid medications. We recommend separate orders for each, rather than using drug formulations that combine opioids and nonopioid analgesics in the same pill, due to the risk of inadvertently exceeding the maximum recommended doses of the nonopioid analgesic (particularly acetaminophen) with combination products. We recommend that nonopioid analgesics be ordered at a scheduled frequency, rather than as needed, to facilitate consistent administration that is not dependent on opioid administration. Topical agents, including lidocaine and capsaicin, should also be considered. Nonpharmacologic pain management strategies can include procedure-based (eg, regional and local anesthesia) and nonprocedure-based therapies depending on the underlying condition and institutional availability. Although few studies have assessed the benefit of nonpharmacologic, nonprocedure-based therapies for the treatment of acute pain in hospitalized patients, the lack of harm associated with their use argues for their adoption. Simple nonpharmacologic therapies that can usually be provided to patients in any hospital setting include music therapy, cold or hot packs, chaplain or social work visits (possibly including mindfulness training),⁴³ and physical therapy, among others.

10. SHM recommends that, unless contraindicated, clinicians order a bowel regimen to prevent opioid-induced constipation in patients receiving opioids.

Constipation is a common adverse effect of opioid therapy and results from the activation of mu opioid receptors in the colon, resulting in decreased peristalsis. Hospitalized patients are already prone to constipation due to their often-limited physical mobility. To mitigate this complication, we recommend the administration of a bowel regimen to all hospitalized medical patients receiving opioid therapy, provided the patient is not having diarrhea. Given the mechanism of opioid-induced constipation, stimulant laxatives (eg, senna, bisacodyl) have been recommended for this purpose.⁴⁴ Osmotic laxatives (eg, polyethylene glycol, lactulose) have demonstrated efficacy for the treatment of constipation more generally (ie, not necessarily opioid-induced constipation). Stool softeners, although frequently used in the inpatient setting, are not recommended due to limited and conflicting evidence for efficacy in prevention or treatment of constipation.⁴⁵ Bowel movements should be tracked during hospitalization, and the bowel regimen modified accordingly.

11. SHM recommends that clinicians limit co-administration of opioids with other central nervous system depressant medications to the extent possible.

This combination has been demonstrated to increase the risk of opioid-related adverse events in multiple settings of care, including during hospitalization.^1,18,19 Although benzodiazepines have received the most attention in this respect, other medications with CNS depressant properties may also increase the risk, including, but not limited to, nonbenzodiazepine sedative-hypnotics (eg, zolpidem, zaleplon, zopiclone), muscle relaxants, sedating antidepressants, antipsychotics, and antihistamines.^18,19,46 For some patients, the combination will be unavoidable, and we do not suggest routine discontinuation of longstanding medications that preexisted hospitalization, given the risks of withdrawal and/or worsening of the underlying condition for which these medications are prescribed. Rather, clinicians should carefully consider the necessity of each medication class with input from the patient’s outpatient providers, taper the frequency and/or the dose of CNS depressants when appropriate and feasible, and avoid new coprescriptions to the extent possible, both during hospitalization and on hospital discharge.

12. SHM recommends that clinicians work with patients and families or caregivers to establish realistic goals and expectations of opioid therapy and the expected course of recovery.

Discussing expectations at the start of therapy is important to facilitate a clear understanding of how meaningful improvement will be defined and measured during the hospitalization and how long the patient is anticipated to require opioid therapy. Meaningful improvement should be defined to include improvement in both pain and function. Clinicians should discuss with patients 1) that the goal of opioid therapy is tolerability of pain such that meaningful improvement in function can be achieved and 2) that a decrease in pain intensity in the absence of improved function is not considered meaningful improvement in most situations and should prompt reevaluation of the appropriateness of continued opioid therapy as well as close follow-up with a clinician following hospital discharge. Discussions regarding the expected course of recovery should include that acute pain is expected to resolve as the underlying medical condition improves and that although pain may persist beyond the hospitalization, pain that is severe enough to require opioids will often be resolved or almost resolved by the time of hospital discharge.

13. SHM recommends that clinicians monitor the response to opioid therapy, including assessment for functional improvement and development of adverse effects.

Pain severity and function should be assessed at least daily, and improvement in reported pain severity without improvement in function over several days should, in most circumstances, prompt reconsideration of ongoing opioid therapy and reconsideration of the underlying etiology of pain. Although hospital-specific functional measures in the setting of acute pain have not yet been validated, we suggest that such measures and goals should be individualized based on preexisting function and may include the ability to sit up or move in bed, move to a chair, work with physical therapy, or ambulate in the hallway. Protocols for the assessment for adverse effects are not well established. Because sedation typically precedes respiratory depression, it is generally recommended that patients are evaluated (eg, by nursing staff) for sedation after each opioid administration (10–20 minutes for intravenous and 30–60 minutes for oral administration based on the time-to-peak effect). Whether certain patients may benefit from more intensive respiratory monitoring, such as pulse oximetry or capnography, is an area of active investigation and not yet established.

Prescribing at the Time of Hospital Discharge

14. SHM recommends that clinicians ask patients about any existing opioid supply at home and account for any such supply when issuing an opioid prescription on discharge.

Even in the setting of acute pain, patients may have previously received an opioid prescription from an outpatient clinician prior to hospitalization. Unused prescription opioids create the possibility of both overdose (when patients take multiple opioids concurrently, intentionally or inadvertently) and diversion (many adults with prescription opioid misuse obtained their opioids from a friend or a relative who may or may not have known that this occurred⁴⁷). The PDMP database can provide information related to the potential existence of any prior opioid supplies, which should be confirmed with the patient and considered when providing a new prescription on hospital discharge. Information on proper disposal should be provided if use of the preexisting opioid is no longer intended.

15. SHM recommends that clinicians prescribe the minimum quantity of opioids anticipated to be necessary based on the expected course and duration of pain that is severe enough to require opioid therapy after hospital discharge.

For many patients, the condition causing their acute pain will be mostly or completely resolved by the time of hospital discharge. When pain is still present at the time of discharge, most pain can be completely managed with nonopioid therapies. For those with ongoing pain that is severe enough to require opioids after hospital discharge, decisions regarding the duration of therapy should be made on a case-by-case basis; generally, however, provision of a 3- to 5-day supply will be sufficient, and provision of more than a 7-day supply of opioids should generally be avoided for several reasons. These include 1) acute pain lasting longer than 7 days after appropriate treatment of any existing underlying conditions should prompt re-evaluation of the working diagnosis and/or reconsideration of the management approach, 2) receiving higher intensity opioid therapy (including longer courses) in the setting of acute pain has been associated with an increased risk of long-term disability and long-term opioid use,^33,48,49 and 3) unused opioids create the possibility of intentional or unintentional opioid diversion (see Consensus Statement 14).⁴⁷ Accordingly, clinicians should attempt to arrange an outpatient follow-up appointment for re-evaluation within 7 days, rather than providing an extended opioid prescription on hospital discharge. In situations where this is not feasible, and pain that is severe enough to require opioids is expected to persist longer than 7 days, an extended prescription may be indicated. However, some states have begun enacting legislation to limit the duration of first-time opioid prescriptions, typically using a 5-to-7 day supply as an upper limit; clinicians should be aware of and adhere to individual state laws governing their practice.

16. SHM recommends that clinicians ensure that patients and families or caregivers receive information regarding how to minimize the risks of opioid therapy for themselves, their families, and their communities. This includes but is not limited to 1) how to take their opioids correctly (the planned medications, doses, schedule); 2) that they should take the minimum quantity necessary to achieve tolerable levels of pain and meaningful functional improvement, reducing the dose and/or frequency as pain and function improve; 3) how to safeguard their supply and dispose of any unused supply; 4) that they should avoid agents that may potentiate the sedative effect of opioids, including sleeping medication and alcohol; 5) that they should avoid driving or operating heavy machinery while taking opioids; and 6) that they should seek help if they begin to experience any potential adverse effects, with inclusion of information on early warning signs.

Clear and concise patient instructions on home opioid dosing and administration will limit opioid-related adverse events and dosing errors upon hospital discharge. Each of these recommendations derive from one or more of the existing guidelines and reflect the transfer of responsibility for safe opioid use practices that occurs as patients transition from a closely monitored inpatient setting to the more self-regulated home environment.

This Consensus Statement reflects a synthesis of the key recommendations from a systematic review of existing guidelines on acute pain management, adapted for a hospital-specific scope of practice. Despite a paucity of data on the comparative effectiveness of different management strategies for acute pain, several areas of expert consensus emerged across existing guidelines, which were felt to be relevant and applicable to the hospital setting. The objective of these recommendations is to provide information that can be used to inform and support opioid-related management decisions for acute pain by clinicians practicing medicine in the inpatient setting.

Although these recommendations are not intended to apply to the immediate perioperative setting (ie, care in the postanesthesia care unit), many of the recommendations in the existing guidelines upon which this Consensus Statement was based were intended for the postoperative setting, and, as others have noted, recommendations in this setting are mostly comparable to those for treating acute pain more generally.²⁷ Those interested in pain management in the postoperative setting specifically may wish to review the recent guidelines released by the American Pain Society,⁵⁰ the content of which is in close alignment with our Consensus Statement.

Several important issues were raised during the extensive external feedback process undertaken as part of the development of this Consensus Statement. Although many issues were incorporated into the recommendations, there were several suggestions for which we felt the evidence base was not sufficient to allow a clear or valid recommendation to be made. For example, several reviewers requested endorsement of specific patient education tools and opioid equivalency calculators. In the absence of tools specifically validated for this purpose, we felt that the evidence was insufficient to make specific recommendations. Validating such tools for use in the inpatient setting should be an area of future investigation. In the meantime, we note that there are several existing and widely available resources for both patient education (ie, opioid information sheets, including opioid risks, safe containment and disposal, and safe use practices) and opioid equivalency calculations that clinicians and hospitals can adapt for their purposes.

Several individuals suggested recommendations on communication with outpatient continuity providers around opioid management decisions during hospitalization and on discharge. Although we believe that it is of paramount importance for outpatient providers to be aware of and have input into these decisions, the optimal timing and the method for such communication are unclear and likely to be institution-specific depending on the availability and integration of electronic records across care settings. We recommend that clinicians use their judgment as to the best format and timing for assuring that outpatient physicians are aware of and have input into these important management decisions with downstream consequences.

Concerns were also raised about the time required to complete the recommended practices and the importance of emphasizing the need for a team-based approach in this realm. We agree wholeheartedly with this sentiment and believe that many of the recommended practices can and should be automated and/or shared across the care team. For example, PDMPs allow prescribers to appoint delegates to check the PDMP on their behalf. Additionally, we suggest that hospitals work to develop systems to assist care teams with performance of these tasks in a standardized and streamlined manner (eg, integrating access to the PDMP and opioid equivalency tables within the electronic health record and developing standard patient educational handouts). Provision of written materials on opioid risks, side effects, and safety practices may be helpful in facilitating consistent messaging and efficient workflow for members of the care team.

Finally, the working group carefully considered whether to include a recommendation regarding naloxone prescribing at the time of hospital discharge. The provision of naloxone kits to laypersons through Overdose Education and Naloxone Distribution Programs has been shown to reduce opioid overdose deaths^51,52 and hospitalizations^53,54 and is both safe and cost-effective.⁵⁵ The Centers for Disease Control and Preventionrecommend that clinicians “consider offering naloxone to patients with a history of overdose, a current or past substance use disorder, receipt of ≥50 mg of morphine equivalents per day or concurrent benzodiazepine use.”¹ However, these recommendations are intended for patients on chronic opioid therapy; presently, no clear evidence exists to guide decisions about the benefits and costs associated with prescribing naloxone in the setting of short-term opioid therapy for acute pain. Further research in this area is warranted.

The greatest limitation of this Consensus Statement is the lack of high-quality studies informing most of the recommendations in the guidelines upon which our Consensus Statement was based. The majority of recommendations in the existing guidelines were based on expert opinion alone. Additional research is necessary before evidence-based recommendations can be formulated.

Accordingly, the working group identified several key areas for future research, in addition to those noted above. First, ongoing efforts to develop and evaluate the effectiveness of nonopioid and nonpharmacologic management strategies for acute pain in hospitalized patients are necessary. Second, studies identifying the risk factors for opioid-related adverse events in hospitalized patients would help inform management decisions and allow deployment of resources and specialized monitoring strategies to patients at heightened risk. The working group also noted the need for research investigating the impact of PDMP use on management decisions and downstream outcomes among hospitalized patients. Finally, conversations around pain management and concerns related to aberrant behaviors are often challenging in the hospital setting owing to the brief, high-intensity nature of the care and the lack of a longstanding therapeutic alliance. There is a great need to develop strategies and language to facilitate these conversations.

In conclusion, until more high-quality evidence becomes available, clinicians can use the recommendations contained in this Consensus Statement along with their clinical judgment and consultation with pharmacists, interventional pain specialists, and other staff (eg, social work, nursing) to help facilitate consistent, high-quality care across providers and hospitals. We believe that doing so will help increase the appropriateness of opioid therapy, minimize adverse events, facilitate shared decision-making, and foster stronger therapeutic alliances at the outset of the hospitalization for patients suffering from acute pain.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from the SHM for their facilitation of this project and dedication to this purpose.

The authors would also like to thank the many individuals who provided comments on the draft recommendations, including the participants in the SHM RADEO program; the SHM members; the representatives of specialty societies, including the American Academy of Family Physicians, the American College of Physicians, the American Hospital Association, the American Society of Addiction Medicine, the American Society of Anesthesiologists, the American Society of Health-System Pharmacists, the Society of Critical Care Medicine, and the Society of General Internal Medicine; and the representatives of patient advocacy groups, including SHM PFAC, Regions Hospital Patient and Family Advisory Committee, Patient and Family Centered Care Council of St. Louis Children’s Hospital, Missouri Family Partnership, and Parent and Family Care.

Disclosures: Dr. Herzig reports receiving compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena reports receiving consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics, a consultancy to the life sciences industry (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance with the project and funded the in-person working group meeting but had no role in or influence on developing the content of the recommendations themselves. The SHM Board of Directors provided approval to submit the manuscript for publication without modification. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported in part by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, and reporting of the study

Since the initial reports of an emerging opioid epidemic in the early 2000s, intense focus on improving opioid prescribing in outpatient settings has culminated in new guidelines for chronic pain.^1,2 Although opioid stewardship in the setting of chronic pain is of paramount importance in curbing the ongoing epidemic, long-term prescription opioid use often begins with treatment of acute pain.¹ In addition to differences in recommended management strategies for acute and chronic pain, there are unique aspects and challenges to pain management in the acute-care setting.

Opioids are commonly used for the treatment of acute pain in hospitalized patients, often at high doses.³ Recent reports highlight that hospital use of opioids impacts downstream use.^4-6 Additionally, opioid prescribing practices vary between hospital-based providers and hospitals,^3,7 highlighting the need for prescribing standards and guidance. To our knowledge, there are no existing guidelines for improving the safety of opioid use in hospitalized patients outside of the intensive care or immediate perioperative settings.

The Society of Hospital Medicine (SHM) convened a working group to systematically review existing guidelines and develop a consensus statement to assist clinicians in safe opioid use for acute, noncancer pain in hospitalized adults.

Consensus Statement Purpose and Scope

The purpose of this Consensus Statement is to present clinical recommendations on the safe use of opioids for the treatment of acute, noncancer pain in hospitalized adults. The guidance is intended for clinicians practicing medicine in the inpatient setting (eg, hospitalists, primary care physicians, family physicians, nurse practitioners, and physician assistants) and is intended to apply to hospitalized adults with acute, noncancer pain (ie, pain that typically lasts <3 months or during the period of normal tissue healing) outside of the palliative, end-of-life, and intensive care settings.

Consensus Statement Development

Our working group included experts in opioid use in the hospital setting, defined by 1) engagement in the clinical practice of hospital medicine and 2) involvement in clinical research related to usage patterns and clinical outcomes of opioid use in hospitalized patients (see Appendix Table 1). The SHM provided administrative assistance with the project and funded the in-person working group meeting, but it had no role in formulating the recommendations. The SHM Board of Directors provided approval of the Consensus Statement without modification.

An overview of the sequential steps in the Consensus Statement development process is described below; details of the methods and results can be found in the Appendix (eMethods).

Performing the Systematic Review

Drafting the Consensus Statement

After performing the systematic review, the working group drafted and iteratively revised a set of recommendations using a variation of the Delphi Method⁸ to identify consensus among group members.

External Review

Following agreement on a draft set of recommendations, we obtained feedback from external groups, including 1) individuals involved in the SHM’s Reducing Adverse Drug Events Related to Opioids (RADEO) initiative, including those involved in the development of the implementation guide and site leads for the Mentored Implementation program, 2) SHM members, SHM Patient-Family Advisory Council (PFAC) members, and leaders of other relevant professional societies, and 3) peer-reviewers at the Journal of Hospital Medicine.

Deciding Whether to Use Opioids During Hospitalization

1. SHM recommends that clinicians limit the use of opioids to patients with 1) severe pain or 2) moderate pain that has not responded to nonopioid therapy, or where nonopioid therapy is contraindicated or anticipated to be ineffective.

Opioids are associated with several well-recognized risks ranging from mild to severe, including nausea, constipation, urinary retention, falls, delirium, sedation, physical dependence, addiction, respiratory depression, and death. Given these risks, the risk-to-benefit ratio is generally not favorable at lower levels of pain severity. Furthermore, for most painful conditions, including those causing severe pain, nonopioid analgesics, including acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), have been demonstrated to be equally or more effective with less risk of harm than opioids.^9-13 Clinicians should consider drug–drug and drug–disease associations when deciding between these different therapies and make a determination in each patient regarding whether the benefits outweigh the risks. Often, drug–disease interactions do not represent absolute contraindications, and risks can be mitigated by adhering to dosage limits and, with respect to NSAIDs, 1) monitoring renal function, 2) monitoring volume status in patients with congestive heart failure, and 3) considering a selective cyclooxygenase-2 (COX-2) inhibitor rather than a nonselective NSAID or pairing the NSAID with an acid-suppressive medication in patients with a history of peptic ulcer disease or at elevated risk for gastroduodenal disease. For these reasons, a trial of nonopioid therapy (including pharmacologic and nonpharmacologic modalities) should always be considered before using opioids for pain of any severity. This does not imply that a trial of nonopioid therapy must be performed in all patients, but rather, that the likelihood of benefit and associated risks of opioid and nonopioid therapy should be considered for all patients in determining the best initial management strategy.

2. SHM recommends that clinicians use extra caution when administering opioids to patients with risk factors for opioid-related adverse events.

Several factors have been consistently demonstrated to increase the risk of opioid-related adverse events–most importantly, respiratory depression and overdose–in varied patient populations and settings, including age 65 years and older,^1,14-17 renal insufficiency,^1,14,18 hepatic insufficiency,^1,14 chronic respiratory failure (including chronic obstructive pulmonary disease, sleep apnea, etc.), and receipt of other central nervous system (CNS) depressant medications (including, but not limited to, benzodiazepines).^1,18-20 History of any substance use disorder and psychiatric disorders have been associated with an increased risk for the development of opioid use disorder.^21-24 These factors should be weighed against the benefits when deciding on opioid appropriateness in a given patient. However, identification of these risks should not preclude opioids as part of pain management. When a decision is made to use opioids in patients with these risk factors, clinicians should 1) use a reduced starting dose (generally, at least a 50% reduction in the usual starting dose) and 2) consider closer monitoring for adverse effects (eg, more frequent nursing assessments, capnography, or more frequent outpatient visits).

3. SHM recommends that clinicians review the information contained in the prescription drug monitoring program (PDMP) database to inform decision-making around opioid therapy.

Although data on the impact of use of the state PDMP database on prescribing practices or patient outcomes are limited, PDMP use has been advocated by multiple guidelines on acute pain management.^25-27 The PDMP provides information that can be useful in several ways, including 1) confirmation of prior opioid exposure and dosage, which should be used to guide appropriate dosage selection in the hospital, 2) identification of existing controlled substance prescriptions, which should be considered in prescribing decisions in the hospital and on discharge, and 3) identification of signs of aberrant behavior. For example, the identification of controlled substance prescriptions written by multiple different clinicians can facilitate early identification of potential diversion or evolving or existing opioid use disorder and the opportunity for intervention,²⁸ which may include referral to support services, initiation of medication-assisted treatment, and/or pain specialist consultation when available. Concerns regarding evolving or existing opioid use disorder should prompt further discussion between the clinician and the patient, both to clarify their understanding of their recent prescription history and to discuss concerns for patient safety related to the increased risk of opioid-related adverse effects (including respiratory depression and overdose) among patients with controlled substance prescriptions written by multiple providers. Although such concerns should not automatically preclude the use of opioids for acute pain in the hospital setting, they should be considered in the assessment of whether the benefits of opioid therapy outweigh the risks for a given patient.

4. SHM recommends that clinicians educate patients and families or caregivers about the potential risks and side effects of opioid therapy as well as alternative pharmacologic and nonpharmacologic therapies for managing pain.

Patients are often unaware of the risks of opioid therapy (see Consensus Statement 1 for key risks),²⁹ or that there are often equally effective alternative therapies. As with any therapy associated with substantial risk, clinicians should discuss these risks with patients and/or caregivers at the outset of therapy, as well as the potential benefits of nonopioid pharmacologic and nonpharmacologic therapies for managing pain. Patients should be informed that they may request nonopioid therapy in lieu of opioids, even for severe pain.

Once a Decision Has Been Made to Use Opioids During Hospitalization

5. SHM recommends that clinicians use the lowest effective opioid dose for the shortest duration possible.

Higher opioid doses are associated with an increased incidence of opioid-related adverse events, particularly overdose, in studies of both inpatient and outpatient populations.^{1,17,19,30,31} Studies in the inpatient and outpatient settings consistently demonstrate that risk increases with dosage.^19,30,31 Clinicians should reduce the usual starting dose by at least 50% among patients with conditions that increase susceptibility to opioid-related adverse events (see Consensus Statement 2). The ongoing need for opioids should be re-assessed regularly-at least daily-during the hospitalization, with attempts at tapering as healing occurs and/or pain and function improve.

6. SHM recommends that clinicians use immediate-release opioid formulations and avoid initiation of long-acting or extended-release formulations (including transdermal fentanyl) for treatment of acute pain.

Studies in outpatient settings demonstrate that the use of long-acting opioids is associated with greater risk for overdose–especially in opioid-naïve patients–and long-term use.^32,33 Further, hospitalized patients frequently have fluctuating renal function and rapidly changing pain levels. We therefore recommend that initiation of long-acting opioids be avoided for the treatment of acute, noncancer pain in hospitalized medical patients. It is important to note that although we recommend avoiding initiation of long-acting opioids for the treatment of acute, noncancer pain, there are circumstances outside of the scope of this Consensus Statement for which initiation of long-acting opioids may be indicated, including the treatment of opioid withdrawal. We also do not recommend discontinuation of long-acting or extended-release opioids in patients who are taking these medications for chronic pain at the time of hospital admission (unless there are concerns regarding adverse effects or drug–disease interactions).

7. SHM recommends that clinicians use the oral route of administration whenever possible. Intravenous opioids should be reserved for patients who cannot take food or medications by mouth, patients suspected of gastrointestinal malabsorption, or when immediate pain control and/or rapid dose titration is necessary.

Intravenous opioid administration is associated with an increased risk of side effects, adverse events, and medication errors.^34-36 Additionally, studies demonstrate that in general, the addiction potential of medications is greater the more rapid the onset of action (the onset of action is 5–10 min for intravenous and 15–30 minutes for oral administration).^37,38 Furthermore, the duration of action is greater for oral compared to that of intravenous administration, potentially allowing for more consistent pain relief and less frequent administrations. As such, intravenous administration should be reserved for situations when oral administration is not possible or likely to be ineffective, or when immediate pain control and/or rapid titration is necessary.

8. SHM recommends that clinicians use an opioid equivalency table or calculator to understand the relative potency of different opioids 1) when initiating opioid therapy, 2) when changing from one route of administration to another, and 3) when changing from one opioid to another. When changing from one opioid to another, clinicians should generally reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids as well as possible incomplete cross-tolerance.

Most errors causing preventable adverse drug events in hospitals occur at the ordering stage.^39,40 Clinicians are often unaware of the potency of different types of opioids relative to each other or to morphine (ie, morphine equivalent dose), which can lead to inadvertent overdose when initiating therapy with nonmorphine opioids and when converting from one opioid to another. To facilitate safe opioid use, we recommend that clinicians use one of several available opioid equivalency tables or calculators to better understand the relative potencies of opioids and to inform both starting dose calculations and conversions between opioids and routes of administration. When converting from one opioid to another, we caution clinicians to reduce the dose of the new opioid by at least 25%–50% of the calculated equianalgesic dose to account for interindividual variability in the response to opioids and the potential for incomplete cross-tolerance, wherein tolerance to a currently administered opioid does not extend completely to other opioids. Clinicians should use extreme caution when performing conversions to and from methadone and consider consultation with a hospital pharmacist or a pain management specialist, when available, to assist with conversion decisions and calculations.

9. SHM recommends that clinicians pair opioids with scheduled nonopioid analgesic medications, unless contraindicated, and always consider pairing with nonpharmacologic pain management strategies (ie, multimodal analgesia).

Concurrent receipt of opioids and nonopioid analgesic medications (including acetaminophen, NSAIDs, and gabapentin or pregabalin, depending on the underlying pathophysiology of the pain) has been demonstrated to reduce total opioid requirements and improve pain management.^41,42 Clinicians should be familiar with contraindications and maximum dosage recommendations for each of these adjunctive nonopioid medications. We recommend separate orders for each, rather than using drug formulations that combine opioids and nonopioid analgesics in the same pill, due to the risk of inadvertently exceeding the maximum recommended doses of the nonopioid analgesic (particularly acetaminophen) with combination products. We recommend that nonopioid analgesics be ordered at a scheduled frequency, rather than as needed, to facilitate consistent administration that is not dependent on opioid administration. Topical agents, including lidocaine and capsaicin, should also be considered. Nonpharmacologic pain management strategies can include procedure-based (eg, regional and local anesthesia) and nonprocedure-based therapies depending on the underlying condition and institutional availability. Although few studies have assessed the benefit of nonpharmacologic, nonprocedure-based therapies for the treatment of acute pain in hospitalized patients, the lack of harm associated with their use argues for their adoption. Simple nonpharmacologic therapies that can usually be provided to patients in any hospital setting include music therapy, cold or hot packs, chaplain or social work visits (possibly including mindfulness training),⁴³ and physical therapy, among others.

10. SHM recommends that, unless contraindicated, clinicians order a bowel regimen to prevent opioid-induced constipation in patients receiving opioids.

Constipation is a common adverse effect of opioid therapy and results from the activation of mu opioid receptors in the colon, resulting in decreased peristalsis. Hospitalized patients are already prone to constipation due to their often-limited physical mobility. To mitigate this complication, we recommend the administration of a bowel regimen to all hospitalized medical patients receiving opioid therapy, provided the patient is not having diarrhea. Given the mechanism of opioid-induced constipation, stimulant laxatives (eg, senna, bisacodyl) have been recommended for this purpose.⁴⁴ Osmotic laxatives (eg, polyethylene glycol, lactulose) have demonstrated efficacy for the treatment of constipation more generally (ie, not necessarily opioid-induced constipation). Stool softeners, although frequently used in the inpatient setting, are not recommended due to limited and conflicting evidence for efficacy in prevention or treatment of constipation.⁴⁵ Bowel movements should be tracked during hospitalization, and the bowel regimen modified accordingly.

11. SHM recommends that clinicians limit co-administration of opioids with other central nervous system depressant medications to the extent possible.

This combination has been demonstrated to increase the risk of opioid-related adverse events in multiple settings of care, including during hospitalization.^1,18,19 Although benzodiazepines have received the most attention in this respect, other medications with CNS depressant properties may also increase the risk, including, but not limited to, nonbenzodiazepine sedative-hypnotics (eg, zolpidem, zaleplon, zopiclone), muscle relaxants, sedating antidepressants, antipsychotics, and antihistamines.^18,19,46 For some patients, the combination will be unavoidable, and we do not suggest routine discontinuation of longstanding medications that preexisted hospitalization, given the risks of withdrawal and/or worsening of the underlying condition for which these medications are prescribed. Rather, clinicians should carefully consider the necessity of each medication class with input from the patient’s outpatient providers, taper the frequency and/or the dose of CNS depressants when appropriate and feasible, and avoid new coprescriptions to the extent possible, both during hospitalization and on hospital discharge.

12. SHM recommends that clinicians work with patients and families or caregivers to establish realistic goals and expectations of opioid therapy and the expected course of recovery.

Discussing expectations at the start of therapy is important to facilitate a clear understanding of how meaningful improvement will be defined and measured during the hospitalization and how long the patient is anticipated to require opioid therapy. Meaningful improvement should be defined to include improvement in both pain and function. Clinicians should discuss with patients 1) that the goal of opioid therapy is tolerability of pain such that meaningful improvement in function can be achieved and 2) that a decrease in pain intensity in the absence of improved function is not considered meaningful improvement in most situations and should prompt reevaluation of the appropriateness of continued opioid therapy as well as close follow-up with a clinician following hospital discharge. Discussions regarding the expected course of recovery should include that acute pain is expected to resolve as the underlying medical condition improves and that although pain may persist beyond the hospitalization, pain that is severe enough to require opioids will often be resolved or almost resolved by the time of hospital discharge.

13. SHM recommends that clinicians monitor the response to opioid therapy, including assessment for functional improvement and development of adverse effects.

Pain severity and function should be assessed at least daily, and improvement in reported pain severity without improvement in function over several days should, in most circumstances, prompt reconsideration of ongoing opioid therapy and reconsideration of the underlying etiology of pain. Although hospital-specific functional measures in the setting of acute pain have not yet been validated, we suggest that such measures and goals should be individualized based on preexisting function and may include the ability to sit up or move in bed, move to a chair, work with physical therapy, or ambulate in the hallway. Protocols for the assessment for adverse effects are not well established. Because sedation typically precedes respiratory depression, it is generally recommended that patients are evaluated (eg, by nursing staff) for sedation after each opioid administration (10–20 minutes for intravenous and 30–60 minutes for oral administration based on the time-to-peak effect). Whether certain patients may benefit from more intensive respiratory monitoring, such as pulse oximetry or capnography, is an area of active investigation and not yet established.

Prescribing at the Time of Hospital Discharge

14. SHM recommends that clinicians ask patients about any existing opioid supply at home and account for any such supply when issuing an opioid prescription on discharge.

Even in the setting of acute pain, patients may have previously received an opioid prescription from an outpatient clinician prior to hospitalization. Unused prescription opioids create the possibility of both overdose (when patients take multiple opioids concurrently, intentionally or inadvertently) and diversion (many adults with prescription opioid misuse obtained their opioids from a friend or a relative who may or may not have known that this occurred⁴⁷). The PDMP database can provide information related to the potential existence of any prior opioid supplies, which should be confirmed with the patient and considered when providing a new prescription on hospital discharge. Information on proper disposal should be provided if use of the preexisting opioid is no longer intended.

15. SHM recommends that clinicians prescribe the minimum quantity of opioids anticipated to be necessary based on the expected course and duration of pain that is severe enough to require opioid therapy after hospital discharge.

For many patients, the condition causing their acute pain will be mostly or completely resolved by the time of hospital discharge. When pain is still present at the time of discharge, most pain can be completely managed with nonopioid therapies. For those with ongoing pain that is severe enough to require opioids after hospital discharge, decisions regarding the duration of therapy should be made on a case-by-case basis; generally, however, provision of a 3- to 5-day supply will be sufficient, and provision of more than a 7-day supply of opioids should generally be avoided for several reasons. These include 1) acute pain lasting longer than 7 days after appropriate treatment of any existing underlying conditions should prompt re-evaluation of the working diagnosis and/or reconsideration of the management approach, 2) receiving higher intensity opioid therapy (including longer courses) in the setting of acute pain has been associated with an increased risk of long-term disability and long-term opioid use,^33,48,49 and 3) unused opioids create the possibility of intentional or unintentional opioid diversion (see Consensus Statement 14).⁴⁷ Accordingly, clinicians should attempt to arrange an outpatient follow-up appointment for re-evaluation within 7 days, rather than providing an extended opioid prescription on hospital discharge. In situations where this is not feasible, and pain that is severe enough to require opioids is expected to persist longer than 7 days, an extended prescription may be indicated. However, some states have begun enacting legislation to limit the duration of first-time opioid prescriptions, typically using a 5-to-7 day supply as an upper limit; clinicians should be aware of and adhere to individual state laws governing their practice.

16. SHM recommends that clinicians ensure that patients and families or caregivers receive information regarding how to minimize the risks of opioid therapy for themselves, their families, and their communities. This includes but is not limited to 1) how to take their opioids correctly (the planned medications, doses, schedule); 2) that they should take the minimum quantity necessary to achieve tolerable levels of pain and meaningful functional improvement, reducing the dose and/or frequency as pain and function improve; 3) how to safeguard their supply and dispose of any unused supply; 4) that they should avoid agents that may potentiate the sedative effect of opioids, including sleeping medication and alcohol; 5) that they should avoid driving or operating heavy machinery while taking opioids; and 6) that they should seek help if they begin to experience any potential adverse effects, with inclusion of information on early warning signs.

Clear and concise patient instructions on home opioid dosing and administration will limit opioid-related adverse events and dosing errors upon hospital discharge. Each of these recommendations derive from one or more of the existing guidelines and reflect the transfer of responsibility for safe opioid use practices that occurs as patients transition from a closely monitored inpatient setting to the more self-regulated home environment.

This Consensus Statement reflects a synthesis of the key recommendations from a systematic review of existing guidelines on acute pain management, adapted for a hospital-specific scope of practice. Despite a paucity of data on the comparative effectiveness of different management strategies for acute pain, several areas of expert consensus emerged across existing guidelines, which were felt to be relevant and applicable to the hospital setting. The objective of these recommendations is to provide information that can be used to inform and support opioid-related management decisions for acute pain by clinicians practicing medicine in the inpatient setting.

Although these recommendations are not intended to apply to the immediate perioperative setting (ie, care in the postanesthesia care unit), many of the recommendations in the existing guidelines upon which this Consensus Statement was based were intended for the postoperative setting, and, as others have noted, recommendations in this setting are mostly comparable to those for treating acute pain more generally.²⁷ Those interested in pain management in the postoperative setting specifically may wish to review the recent guidelines released by the American Pain Society,⁵⁰ the content of which is in close alignment with our Consensus Statement.

Several important issues were raised during the extensive external feedback process undertaken as part of the development of this Consensus Statement. Although many issues were incorporated into the recommendations, there were several suggestions for which we felt the evidence base was not sufficient to allow a clear or valid recommendation to be made. For example, several reviewers requested endorsement of specific patient education tools and opioid equivalency calculators. In the absence of tools specifically validated for this purpose, we felt that the evidence was insufficient to make specific recommendations. Validating such tools for use in the inpatient setting should be an area of future investigation. In the meantime, we note that there are several existing and widely available resources for both patient education (ie, opioid information sheets, including opioid risks, safe containment and disposal, and safe use practices) and opioid equivalency calculations that clinicians and hospitals can adapt for their purposes.

Several individuals suggested recommendations on communication with outpatient continuity providers around opioid management decisions during hospitalization and on discharge. Although we believe that it is of paramount importance for outpatient providers to be aware of and have input into these decisions, the optimal timing and the method for such communication are unclear and likely to be institution-specific depending on the availability and integration of electronic records across care settings. We recommend that clinicians use their judgment as to the best format and timing for assuring that outpatient physicians are aware of and have input into these important management decisions with downstream consequences.

Concerns were also raised about the time required to complete the recommended practices and the importance of emphasizing the need for a team-based approach in this realm. We agree wholeheartedly with this sentiment and believe that many of the recommended practices can and should be automated and/or shared across the care team. For example, PDMPs allow prescribers to appoint delegates to check the PDMP on their behalf. Additionally, we suggest that hospitals work to develop systems to assist care teams with performance of these tasks in a standardized and streamlined manner (eg, integrating access to the PDMP and opioid equivalency tables within the electronic health record and developing standard patient educational handouts). Provision of written materials on opioid risks, side effects, and safety practices may be helpful in facilitating consistent messaging and efficient workflow for members of the care team.

Finally, the working group carefully considered whether to include a recommendation regarding naloxone prescribing at the time of hospital discharge. The provision of naloxone kits to laypersons through Overdose Education and Naloxone Distribution Programs has been shown to reduce opioid overdose deaths^51,52 and hospitalizations^53,54 and is both safe and cost-effective.⁵⁵ The Centers for Disease Control and Preventionrecommend that clinicians “consider offering naloxone to patients with a history of overdose, a current or past substance use disorder, receipt of ≥50 mg of morphine equivalents per day or concurrent benzodiazepine use.”¹ However, these recommendations are intended for patients on chronic opioid therapy; presently, no clear evidence exists to guide decisions about the benefits and costs associated with prescribing naloxone in the setting of short-term opioid therapy for acute pain. Further research in this area is warranted.

The greatest limitation of this Consensus Statement is the lack of high-quality studies informing most of the recommendations in the guidelines upon which our Consensus Statement was based. The majority of recommendations in the existing guidelines were based on expert opinion alone. Additional research is necessary before evidence-based recommendations can be formulated.

Accordingly, the working group identified several key areas for future research, in addition to those noted above. First, ongoing efforts to develop and evaluate the effectiveness of nonopioid and nonpharmacologic management strategies for acute pain in hospitalized patients are necessary. Second, studies identifying the risk factors for opioid-related adverse events in hospitalized patients would help inform management decisions and allow deployment of resources and specialized monitoring strategies to patients at heightened risk. The working group also noted the need for research investigating the impact of PDMP use on management decisions and downstream outcomes among hospitalized patients. Finally, conversations around pain management and concerns related to aberrant behaviors are often challenging in the hospital setting owing to the brief, high-intensity nature of the care and the lack of a longstanding therapeutic alliance. There is a great need to develop strategies and language to facilitate these conversations.

In conclusion, until more high-quality evidence becomes available, clinicians can use the recommendations contained in this Consensus Statement along with their clinical judgment and consultation with pharmacists, interventional pain specialists, and other staff (eg, social work, nursing) to help facilitate consistent, high-quality care across providers and hospitals. We believe that doing so will help increase the appropriateness of opioid therapy, minimize adverse events, facilitate shared decision-making, and foster stronger therapeutic alliances at the outset of the hospitalization for patients suffering from acute pain.

The authors would like to acknowledge and thank Kevin Vuernick, Jenna Goldstein, Meghan Mallouk, and Chris Frost, MD, from the SHM for their facilitation of this project and dedication to this purpose.

The authors would also like to thank the many individuals who provided comments on the draft recommendations, including the participants in the SHM RADEO program; the SHM members; the representatives of specialty societies, including the American Academy of Family Physicians, the American College of Physicians, the American Hospital Association, the American Society of Addiction Medicine, the American Society of Anesthesiologists, the American Society of Health-System Pharmacists, the Society of Critical Care Medicine, and the Society of General Internal Medicine; and the representatives of patient advocacy groups, including SHM PFAC, Regions Hospital Patient and Family Advisory Committee, Patient and Family Centered Care Council of St. Louis Children’s Hospital, Missouri Family Partnership, and Parent and Family Care.

Disclosures: Dr. Herzig reports receiving compensation from the Society of Hospital Medicine for her editorial role at the Journal of Hospital Medicine (unrelated to the present work). Dr. Jena reports receiving consulting fees from Pfizer, Inc., Hill Rom Services, Inc., Bristol Myers Squibb, Novartis Pharmaceuticals, Vertex Pharmaceuticals, and Precision Health Economics, a consultancy to the life sciences industry (all unrelated to the present work). None of the other authors have any conflicts of interest to disclose.

Funding: The Society of Hospital Medicine (SHM) provided administrative assistance with the project and funded the in-person working group meeting but had no role in or influence on developing the content of the recommendations themselves. The SHM Board of Directors provided approval to submit the manuscript for publication without modification. Dr. Herzig was funded by grant number K23AG042459 from the National Institute on Aging. Dr. Mosher was supported in part by the Department of Veterans Affairs Office of Academic Affiliations and Office of Research and Development and Health Services Research and Development Service (HSR&D) through the Comprehensive Access and Delivery Research and Evaluation Center (CIN 13-412). None of the funding agencies had involvement in any aspect of the study, including design, conduct, and reporting of the study

A 71-year-old woman is brought to the emergency department by her neighbor after complaining of fatigue and light-headedness for the last 8 hours. The patient lives alone and was feeling well when she woke up this morning, but then began to feel nauseated and vomited twice.

The patient appears drowsy and confused and cannot provide any further history. Her medical records show that she was seen in the cardiology clinic 6 months ago but has not kept her appointments since then.

Her medical history includes atrial fibrillation, hypertension, type 2 diabetes mellitus, and osteoarthritis. Her medications are daily warfarin, atenolol, aspirin, candesartan, and metformin, and she takes acetaminophen as needed. She is neither a smoker nor a drug user, but she drinks alcohol occasionally. Her family history is significant for her mother’s death from breast cancer at age 55.

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Her neck veins are flat, and her chest is clear to auscultation with normal heart sounds. Abdominal palpation elicits discomfort in the middle segments, voluntary withdrawal, and abdominal wall rigidity. Her skin feels dry and cool, with decreased turgor.

Initial treatment

The patient is given 1 L of 0.9% saline intravenously over the first hour and then is transferred to the intensive care unit, where a norepinephrine drip is started to treat her ongoing hypotension. Normal saline is continued at a rate of 500 mL per hour for the next 4 hours.

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her blood pH is 7.34 (reference range 7.35–7.45), and her bicarbonate level is 18 mmol/L (22–26); a low pH and low bicarbonate together indicate metabolic acidosis. Her sodium level is 128 mmol/L (135–145), her chloride level is 100 mmol/L (97–107), and, as mentioned, her bicarbonate level is 18 mmol/L; therefore, her anion gap is 128 – (100 + 18) = 10 mmol/L, which is normal (≤ 10).¹

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

• Adrenal crisis
• Cardiogenic shock due to decreased cardiac contractility
• Intracranial hemorrhage
• Acute abdomen due to small bowel obstruction
• Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

The sudden onset and laboratory results that include hyperkalemia, hyponatremia, and normal anion gap metabolic acidosis raise suspicion of adrenal crisis resulting in acute mineralocorticoid and glucocorticoid insufficiency.¹

The patient’s elevated serum creatinine and high blood urea nitrogen-to-creatinine ratio of 26.9 (reference range 10–20) also suggest intravascular volume contraction. Her low hemoglobin level and supratherapeutic INR, possibly due to an interaction between warfarin and acetaminophen combined with poor medical follow-up, raise suspicion of acute bilateral adrenal necrosis due to hemorrhage.

Bilateral adrenal hemorrhage is one cause of adrenal crisis resulting in bilateral adrenal necrosis. Risk factors for adrenal hemorrhage include anticoagulation therapy, underlying coagulopathy, postoperative states, and certain infections such as meningococcemia and Haemophilus influenzae infection.^2–5 Nevertheless, in most cases the INR is in the therapeutic range and the patient has no bleeding elsewhere.⁴ Other causes of adrenal necrosis include emboli, sepsis, and blunt trauma.^6,7

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Intracranial hemorrhage can present with a decreased level of consciousness, but it is less likely to cause hypotension, as the cranial space is limited. If massive intracranial hemorrhage would occur, the increase in intracranial pressure would more likely cause hypertension by the Cushing reflex than hypotension.

Acute abdomen

Abdominal pain and rigidity along with fever can be presenting symptoms of both adrenal insufficiency and an acute abdomen due to intestinal obstruction.⁴ However, intestinal obstruction typically causes a high anion gap metabolic acidosis due to lactic acidosis, instead of the normal anion gap metabolic acidosis present in this patient.⁸ Moreover, her deranged electrolytes, supratherapeutic INR, and absence of previous gastroenterologic conditions make adrenal crisis a more likely diagnosis.

Septic shock

Septic shock would also cause fever and hypotension as bacterial toxins induce a pyrexic response and vasodilation. However, at such an early stage of sepsis, the patient would be expected to be warm and hyperemic, whereas this patient’s skin is cool and dry due to volume depletion secondary to adrenal insufficiency.⁹ Sepsis would also cause a high anion gap metabolic acidosis due to lactic acidosis, as opposed to this patient’s normal anion gap metabolic acidosis. These findings, along with the metabolic derangements and the absence of a focus of infection, make sepsis a less likely possibility.

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Blood is drawn for cultures and measurement of troponins and lactic acid, and urine samples are taken for culture and biochemical analysis. Chest radiography shows mild cardiomegaly. The patient is started empirically on vancomycin and cefepime, and her warfarin is discontinued.

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

• Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
• Perform abdominal computed tomography (CT) without contrast
• Perform transthoracic echocardiography
• Increase the norepinephrine infusion
• Immediately give fludrocortisone

First give fluids

The first step in managing a patient with suspected adrenal crisis is liberal intravenous fluid administration to replenish the depleted intravascular space. The amount and choice of fluid is empiric, but a recommendation is 1 L of normal saline or dextrose 5% in normal saline, infused quickly over the first hour and then titrated according to the patient’s fluid status.¹⁰

Measure cortisol and ACTH; start corticosteroids immediately

Immediate therapy with an appropriate stress dose of intravenous corticosteroids (eg, hydrocortisone 100 mg) is essential. However, this should be done after drawing blood for cortisol and ACTH measurements.¹⁰

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

In addition, in the early phase of evolving primary adrenal insufficiency, measurement of plasma renin and aldosterone levels may be beneficial, as mineralocorticoid deficiency may predominate.^10,12,13

One of the most important aims of early corticosteroid supplementation is to prevent further hyponatremia by reducing a reactive increase in antidiuretic hormone secretion caused by cortisol deficiency. Corticosteroids also help to restore normal blood pressure by increasing vascular tone, as glucocorticoid receptor activation potentiates the vasoconstrictor actions of norepinephrine, angiotensin II, and other vasoconstrictors.^14,15

Which corticosteroid to use?

Which corticosteroid to use in previously undiagnosed adrenal insufficiency is controversial. The Endocrine Society¹⁰ and Japan Endocrine Society¹⁶ clinical practice guidelines recommend hydrocortisone in a 100-mg intravenous bolus followed by 200 mg over 24 hours.

The choice of hydrocortisone is justified by its superior mineralocorticoid activity.^10,16 Further, hydrocortisone is preferred over dexamethasone if the patient is known to have primary adrenal insufficiency, or if the serum potassium level is higher than 6.0 mmol/L.

Some clinicians, on the other hand, recommend dexamethasone, given as a 4-mg intravenous bolus followed by 4-mg boluses every 12 hours. Their rationale is that dexamethasone, unlike hydrocortisone, does not interfere with subsequent serum cortisol assays if the patient later undergoes ACTH stimulation testing.¹⁷ Dexamethasone may also be preferred to minimize unwanted mineralocorticoid effects, such as in neurosurgical patients at risk of brain edema.

If hydrocortisone is used, ACTH stimulation testing can be done after withholding hydrocortisone for 24 hours once the patient is stable. (It should be restarted after the test if the results are abnormal.)

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

Echocardiography. Our patient is likely to have an element of cardiac failure, given her hypertension and cardiomegaly. However, decompensated heart failure is probably not the cause of her presentation. Thus, the first priority is to treat her adrenal crisis, and echocardiography should be deferred.

Increasing the norepinephrine infusion is unlikely to improve her blood pressure very much, as she is significantly volume-depleted. Further, low cortisol decreases the vascular response to norepinephrine.¹⁵

Mineralocorticoids such as fludrocortisone are used to treat primary adrenal insufficiency. However, they are not required during acute management of adrenal crisis, as 40 mg of hydrocortisone offers mineralocorticoid activity equivalent to 100 µg of fludrocortisone. Thus, the high doses of hydrocortisone used to treat adrenal crisis provide adequate mineralocorticoid therapy.^10,18

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

The patient’s blood is drawn for serum cortisol and plasma ACTH measurements. A 100-mg intravenous bolus of hydrocortisone is given, followed by a 50-mg bolus every 6 hours until the patient stabilizes.

Twenty-four hours later, the patient states that she has more energy, and her appetite has improved. The norepinephrine infusion is stopped 48 hours after presentation, at which time her blood pressure is 120/70 mm Hg, heart rate 85 beats per minute and irregular, and temperature 36.7°C (98.1°F). Her current laboratory values include the following:

• Serum sodium 137 mmolL
• Serum potassium 4.3 mmol/L
• Hemoglobin 9.3 g/dL
• Serum cortisol (random) 7.2 μg/dL
• Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

• 7 am total serum cortisol measurement
• Random serum cortisol measurement
• 7 am salivary cortisol measurement
• 24-hour urinary free cortisol measurement
• ACTH stimulation test for cortisol
• Insulin tolerance test for cortisol

These tests also help determine the type of adrenal insufficiency (primary, secondary, or tertiary) and guide further management. Secondary adrenal insufficiency is caused by inadequate pituitary ACTH secretion and subsequent inadequate cortisol production, whereas tertiary adrenal insufficiency is caused by inadequate hypothalamic corticotropin-releasing hormone secretion and subsequent inadequate ACTH and cortisol production. The diagnosis of adrenal insufficiency relies first on demonstrating inappropriately low total serum cortisol production. Subsequently, serum ACTH helps to differentiate between primary (high ACTH) and secondary or tertiary (low or inappropriately normal ACTH) adrenal insufficiency.

Each test listed above may demonstrate a low cortisol level. However, in a nonacute setting, safety concerns (especially regarding insulin tolerance testing), poor diagnostic value, feasibility (ie, the difficulty of 24-hour tests), and poor sensitivity of 7 am cortisol make the ACTH stimulation test the most appropriate test in clinical practice to establish the diagnosis of adrenal insufficiency.

7 am serum cortisol measurement

Measuring the serum cortisol level early in the morning in the nonacute setting could be of diagnostic value, as an extremely low value (< 3–5 μg/dL) is almost 100% specific for adrenal insufficiency in the absence of concurrent exogenous steroid intake. However, the very low cutoff for this test causes poor sensitivity (about 33%), as many patients have partial adrenal insufficiency and hence have higher serum cortisol levels that may even be in the normal physiologic range.^19–22

Random serum cortisol measurements

Random serum cortisol measurements are not very useful in a nonacute setting, since cortisol levels are affected by factors such as stress and hydration status. Moreover, they fluctuate during the day in a circadian rhythm.

On the other hand, random serum cortisol is a very good test to evaluate for adrenal insufficiency in the acute setting. A random value higher than 15 to 18 μg/dL is almost always associated with adequate adrenal function and generally rules out adrenal insufficiency.^11,23,24

The same principle applies to early morning salivary cortisol. Only extremely low values (< 2.65 ng/mL) may distinguish patients with adrenal insufficiency from healthy individuals, with 97.1% sensitivity and 93.3% specificity.²⁵

Of note, early morning salivary cortisol is not routinely measured in most clinical practices for evaluation of adrenal function. Hence, morning serum and morning salivary cortisol are useful screening tools and have meaningful results when their values are in the extremes of the spectrum, but they are not reliable as a single test, as they may overlook patients with partial adrenal insufficiency.

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test involves an intramuscular or intravenous injection of cosyntropin (a synthetic analogue of ACTH fragment 1–24 that has the full activity of native ACTH) and measuring total serum cortisol at baseline, 30 minutes, and 60 minutes to assess the response of the adrenal glands.

The test can be done using a high or low dose of cosyntropin. The Endocrine Society’s 2016 guidelines recommend the high dose (250 μg) for most patients.¹⁰ The standard high-dose stimulation test can be done at any time during the day.²⁶ If the cosyntropin is injected intravenously, any value higher than 18 to 20 μg/dL indicates normal adrenal function and excludes adrenal insufficiency.^27,28 If intramuscular injection is used, any value higher than 16 to 18 μg/dL at 30 minutes post-consyntropin excludes adrenal insufficiency.²⁹

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

Insulin tolerance testing remains the gold standard for diagnosing adrenal insufficiency and assessing the integrity of the pituitary-adrenal axis. However, given its difficulty to perform, safety concerns, and the availability of other reliable tests, its use in clinical practice is limited. It is nonetheless useful in assessing patients with recent onset of ACTH deficiency.^30,31

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

She is started on oral hydrocortisone and fludrocortisone after intravenous hydrocortisone is discontinued. She is counseled about adhering to medications, wearing a medical alert bracelet, giving herself emergency cortisol injections, taking higher doses of hydrocortisone if she is ill, and monitoring her INR. She is discharged home after her symptoms resolve.

The patient does not keep her scheduled appointment and is lost to follow-up. She returns 2 years later complaining of fatigue and feeling unwell. She admits that she stopped taking hydrocortisone 1 year ago after reading an online article about corticosteroid side effects. She has continued to take fludrocortisone.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

4. Which of the following is least likely to be present in this patient at this time?

• Intravascular volume depletion
• Hyponatremia
• Skin hyperpigmentation
• Normokalemia
• Elevated serum ACTH level

Intravascular volume depletion

Intravascular volume depletion is the least likely to be present. This is because intravascular volume depletion is mainly secondary to mineralocorticoid deficiency rather than corticosteroid deficiency, which is not present in this patient, as she is compliant with her mineralocorticoid replacement therapy.^32,33 However, even with sufficient mineralocorticoid replacement, mild hypotension may be present in this patient due to corticosteroid deficiency-induced loss of vascular tone.

Hyponatremia

Hyponatremia in adrenal insufficiency is not due only to mineralocorticoid deficiency. Patients with secondary or tertiary adrenal insufficiency may also exhibit hyponatremia.³⁴ ACTH deficiency in such patients is not expected to cause mineralocorticoid deficiency, as ACTH has only a minor role in aldosterone production.

It has been proposed that hyponatremia in secondary adrenal insufficiency is due to cortisol deficiency resulting in an increase of antidiuretic hormone secretion.^35,36 The mechanisms for increased antidiuretic hormone include cortisol deficiency resulting in an increased corticotropin-releasing hormone level, which acts as an antidiuretic hormone secretagogue,^37,38 and cortisol directly suppressing antidiuretic hormone secretion.³⁹

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation of the skin is present only in long-standing primary adrenal insufficiency. This is due to chronic cortisol deficiency causing an increased secretion of pro-opiomelanocortin, a prohormone that is cleaved into ACTH, melanocyte-stimulating hormone, and other hormones. Melanocyte-stimulating hormone causes skin hyperpigmentation due to increased melanin synthesis.⁴⁰ The hyperpigmentation is seen in sun-exposed areas, pressure areas, palmar creases, nipples, and mucous membranes.

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

Mineralocorticoid deficiency results in hyperkalemia and metabolic acidosis by impairing renal excretion of potassium and acid.⁴¹ This patient is compliant with her mineralocorticoid replacement regimen; thus, potassium levels and pH are expected to be normal.

TAKE-HOME POINTS

• Suspect adrenal crisis in any patient who presents with shock.
• Acute abdomen or unexplained fever could be among the manifestations.
• Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
• Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
• In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
• Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

A 71-year-old woman is brought to the emergency department by her neighbor after complaining of fatigue and light-headedness for the last 8 hours. The patient lives alone and was feeling well when she woke up this morning, but then began to feel nauseated and vomited twice.

The patient appears drowsy and confused and cannot provide any further history. Her medical records show that she was seen in the cardiology clinic 6 months ago but has not kept her appointments since then.

Her medical history includes atrial fibrillation, hypertension, type 2 diabetes mellitus, and osteoarthritis. Her medications are daily warfarin, atenolol, aspirin, candesartan, and metformin, and she takes acetaminophen as needed. She is neither a smoker nor a drug user, but she drinks alcohol occasionally. Her family history is significant for her mother’s death from breast cancer at age 55.

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Her neck veins are flat, and her chest is clear to auscultation with normal heart sounds. Abdominal palpation elicits discomfort in the middle segments, voluntary withdrawal, and abdominal wall rigidity. Her skin feels dry and cool, with decreased turgor.

Initial treatment

The patient is given 1 L of 0.9% saline intravenously over the first hour and then is transferred to the intensive care unit, where a norepinephrine drip is started to treat her ongoing hypotension. Normal saline is continued at a rate of 500 mL per hour for the next 4 hours.

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her blood pH is 7.34 (reference range 7.35–7.45), and her bicarbonate level is 18 mmol/L (22–26); a low pH and low bicarbonate together indicate metabolic acidosis. Her sodium level is 128 mmol/L (135–145), her chloride level is 100 mmol/L (97–107), and, as mentioned, her bicarbonate level is 18 mmol/L; therefore, her anion gap is 128 – (100 + 18) = 10 mmol/L, which is normal (≤ 10).¹

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

• Adrenal crisis
• Cardiogenic shock due to decreased cardiac contractility
• Intracranial hemorrhage
• Acute abdomen due to small bowel obstruction
• Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

The sudden onset and laboratory results that include hyperkalemia, hyponatremia, and normal anion gap metabolic acidosis raise suspicion of adrenal crisis resulting in acute mineralocorticoid and glucocorticoid insufficiency.¹

The patient’s elevated serum creatinine and high blood urea nitrogen-to-creatinine ratio of 26.9 (reference range 10–20) also suggest intravascular volume contraction. Her low hemoglobin level and supratherapeutic INR, possibly due to an interaction between warfarin and acetaminophen combined with poor medical follow-up, raise suspicion of acute bilateral adrenal necrosis due to hemorrhage.

Bilateral adrenal hemorrhage is one cause of adrenal crisis resulting in bilateral adrenal necrosis. Risk factors for adrenal hemorrhage include anticoagulation therapy, underlying coagulopathy, postoperative states, and certain infections such as meningococcemia and Haemophilus influenzae infection.^2–5 Nevertheless, in most cases the INR is in the therapeutic range and the patient has no bleeding elsewhere.⁴ Other causes of adrenal necrosis include emboli, sepsis, and blunt trauma.^6,7

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Intracranial hemorrhage can present with a decreased level of consciousness, but it is less likely to cause hypotension, as the cranial space is limited. If massive intracranial hemorrhage would occur, the increase in intracranial pressure would more likely cause hypertension by the Cushing reflex than hypotension.

Acute abdomen

Abdominal pain and rigidity along with fever can be presenting symptoms of both adrenal insufficiency and an acute abdomen due to intestinal obstruction.⁴ However, intestinal obstruction typically causes a high anion gap metabolic acidosis due to lactic acidosis, instead of the normal anion gap metabolic acidosis present in this patient.⁸ Moreover, her deranged electrolytes, supratherapeutic INR, and absence of previous gastroenterologic conditions make adrenal crisis a more likely diagnosis.

Septic shock

Septic shock would also cause fever and hypotension as bacterial toxins induce a pyrexic response and vasodilation. However, at such an early stage of sepsis, the patient would be expected to be warm and hyperemic, whereas this patient’s skin is cool and dry due to volume depletion secondary to adrenal insufficiency.⁹ Sepsis would also cause a high anion gap metabolic acidosis due to lactic acidosis, as opposed to this patient’s normal anion gap metabolic acidosis. These findings, along with the metabolic derangements and the absence of a focus of infection, make sepsis a less likely possibility.

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Blood is drawn for cultures and measurement of troponins and lactic acid, and urine samples are taken for culture and biochemical analysis. Chest radiography shows mild cardiomegaly. The patient is started empirically on vancomycin and cefepime, and her warfarin is discontinued.

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

• Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
• Perform abdominal computed tomography (CT) without contrast
• Perform transthoracic echocardiography
• Increase the norepinephrine infusion
• Immediately give fludrocortisone

First give fluids

The first step in managing a patient with suspected adrenal crisis is liberal intravenous fluid administration to replenish the depleted intravascular space. The amount and choice of fluid is empiric, but a recommendation is 1 L of normal saline or dextrose 5% in normal saline, infused quickly over the first hour and then titrated according to the patient’s fluid status.¹⁰

Measure cortisol and ACTH; start corticosteroids immediately

Immediate therapy with an appropriate stress dose of intravenous corticosteroids (eg, hydrocortisone 100 mg) is essential. However, this should be done after drawing blood for cortisol and ACTH measurements.¹⁰

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

In addition, in the early phase of evolving primary adrenal insufficiency, measurement of plasma renin and aldosterone levels may be beneficial, as mineralocorticoid deficiency may predominate.^10,12,13

One of the most important aims of early corticosteroid supplementation is to prevent further hyponatremia by reducing a reactive increase in antidiuretic hormone secretion caused by cortisol deficiency. Corticosteroids also help to restore normal blood pressure by increasing vascular tone, as glucocorticoid receptor activation potentiates the vasoconstrictor actions of norepinephrine, angiotensin II, and other vasoconstrictors.^14,15

Which corticosteroid to use?

Which corticosteroid to use in previously undiagnosed adrenal insufficiency is controversial. The Endocrine Society¹⁰ and Japan Endocrine Society¹⁶ clinical practice guidelines recommend hydrocortisone in a 100-mg intravenous bolus followed by 200 mg over 24 hours.

The choice of hydrocortisone is justified by its superior mineralocorticoid activity.^10,16 Further, hydrocortisone is preferred over dexamethasone if the patient is known to have primary adrenal insufficiency, or if the serum potassium level is higher than 6.0 mmol/L.

Some clinicians, on the other hand, recommend dexamethasone, given as a 4-mg intravenous bolus followed by 4-mg boluses every 12 hours. Their rationale is that dexamethasone, unlike hydrocortisone, does not interfere with subsequent serum cortisol assays if the patient later undergoes ACTH stimulation testing.¹⁷ Dexamethasone may also be preferred to minimize unwanted mineralocorticoid effects, such as in neurosurgical patients at risk of brain edema.

If hydrocortisone is used, ACTH stimulation testing can be done after withholding hydrocortisone for 24 hours once the patient is stable. (It should be restarted after the test if the results are abnormal.)

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

Echocardiography. Our patient is likely to have an element of cardiac failure, given her hypertension and cardiomegaly. However, decompensated heart failure is probably not the cause of her presentation. Thus, the first priority is to treat her adrenal crisis, and echocardiography should be deferred.

Increasing the norepinephrine infusion is unlikely to improve her blood pressure very much, as she is significantly volume-depleted. Further, low cortisol decreases the vascular response to norepinephrine.¹⁵

Mineralocorticoids such as fludrocortisone are used to treat primary adrenal insufficiency. However, they are not required during acute management of adrenal crisis, as 40 mg of hydrocortisone offers mineralocorticoid activity equivalent to 100 µg of fludrocortisone. Thus, the high doses of hydrocortisone used to treat adrenal crisis provide adequate mineralocorticoid therapy.^10,18

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

The patient’s blood is drawn for serum cortisol and plasma ACTH measurements. A 100-mg intravenous bolus of hydrocortisone is given, followed by a 50-mg bolus every 6 hours until the patient stabilizes.

Twenty-four hours later, the patient states that she has more energy, and her appetite has improved. The norepinephrine infusion is stopped 48 hours after presentation, at which time her blood pressure is 120/70 mm Hg, heart rate 85 beats per minute and irregular, and temperature 36.7°C (98.1°F). Her current laboratory values include the following:

• Serum sodium 137 mmolL
• Serum potassium 4.3 mmol/L
• Hemoglobin 9.3 g/dL
• Serum cortisol (random) 7.2 μg/dL
• Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

• 7 am total serum cortisol measurement
• Random serum cortisol measurement
• 7 am salivary cortisol measurement
• 24-hour urinary free cortisol measurement
• ACTH stimulation test for cortisol
• Insulin tolerance test for cortisol

These tests also help determine the type of adrenal insufficiency (primary, secondary, or tertiary) and guide further management. Secondary adrenal insufficiency is caused by inadequate pituitary ACTH secretion and subsequent inadequate cortisol production, whereas tertiary adrenal insufficiency is caused by inadequate hypothalamic corticotropin-releasing hormone secretion and subsequent inadequate ACTH and cortisol production. The diagnosis of adrenal insufficiency relies first on demonstrating inappropriately low total serum cortisol production. Subsequently, serum ACTH helps to differentiate between primary (high ACTH) and secondary or tertiary (low or inappropriately normal ACTH) adrenal insufficiency.

Each test listed above may demonstrate a low cortisol level. However, in a nonacute setting, safety concerns (especially regarding insulin tolerance testing), poor diagnostic value, feasibility (ie, the difficulty of 24-hour tests), and poor sensitivity of 7 am cortisol make the ACTH stimulation test the most appropriate test in clinical practice to establish the diagnosis of adrenal insufficiency.

7 am serum cortisol measurement

Measuring the serum cortisol level early in the morning in the nonacute setting could be of diagnostic value, as an extremely low value (< 3–5 μg/dL) is almost 100% specific for adrenal insufficiency in the absence of concurrent exogenous steroid intake. However, the very low cutoff for this test causes poor sensitivity (about 33%), as many patients have partial adrenal insufficiency and hence have higher serum cortisol levels that may even be in the normal physiologic range.^19–22

Random serum cortisol measurements

Random serum cortisol measurements are not very useful in a nonacute setting, since cortisol levels are affected by factors such as stress and hydration status. Moreover, they fluctuate during the day in a circadian rhythm.

On the other hand, random serum cortisol is a very good test to evaluate for adrenal insufficiency in the acute setting. A random value higher than 15 to 18 μg/dL is almost always associated with adequate adrenal function and generally rules out adrenal insufficiency.^11,23,24

The same principle applies to early morning salivary cortisol. Only extremely low values (< 2.65 ng/mL) may distinguish patients with adrenal insufficiency from healthy individuals, with 97.1% sensitivity and 93.3% specificity.²⁵

Of note, early morning salivary cortisol is not routinely measured in most clinical practices for evaluation of adrenal function. Hence, morning serum and morning salivary cortisol are useful screening tools and have meaningful results when their values are in the extremes of the spectrum, but they are not reliable as a single test, as they may overlook patients with partial adrenal insufficiency.

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test involves an intramuscular or intravenous injection of cosyntropin (a synthetic analogue of ACTH fragment 1–24 that has the full activity of native ACTH) and measuring total serum cortisol at baseline, 30 minutes, and 60 minutes to assess the response of the adrenal glands.

The test can be done using a high or low dose of cosyntropin. The Endocrine Society’s 2016 guidelines recommend the high dose (250 μg) for most patients.¹⁰ The standard high-dose stimulation test can be done at any time during the day.²⁶ If the cosyntropin is injected intravenously, any value higher than 18 to 20 μg/dL indicates normal adrenal function and excludes adrenal insufficiency.^27,28 If intramuscular injection is used, any value higher than 16 to 18 μg/dL at 30 minutes post-consyntropin excludes adrenal insufficiency.²⁹

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

Insulin tolerance testing remains the gold standard for diagnosing adrenal insufficiency and assessing the integrity of the pituitary-adrenal axis. However, given its difficulty to perform, safety concerns, and the availability of other reliable tests, its use in clinical practice is limited. It is nonetheless useful in assessing patients with recent onset of ACTH deficiency.^30,31

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

She is started on oral hydrocortisone and fludrocortisone after intravenous hydrocortisone is discontinued. She is counseled about adhering to medications, wearing a medical alert bracelet, giving herself emergency cortisol injections, taking higher doses of hydrocortisone if she is ill, and monitoring her INR. She is discharged home after her symptoms resolve.

The patient does not keep her scheduled appointment and is lost to follow-up. She returns 2 years later complaining of fatigue and feeling unwell. She admits that she stopped taking hydrocortisone 1 year ago after reading an online article about corticosteroid side effects. She has continued to take fludrocortisone.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

4. Which of the following is least likely to be present in this patient at this time?

• Intravascular volume depletion
• Hyponatremia
• Skin hyperpigmentation
• Normokalemia
• Elevated serum ACTH level

Intravascular volume depletion

Intravascular volume depletion is the least likely to be present. This is because intravascular volume depletion is mainly secondary to mineralocorticoid deficiency rather than corticosteroid deficiency, which is not present in this patient, as she is compliant with her mineralocorticoid replacement therapy.^32,33 However, even with sufficient mineralocorticoid replacement, mild hypotension may be present in this patient due to corticosteroid deficiency-induced loss of vascular tone.

Hyponatremia

Hyponatremia in adrenal insufficiency is not due only to mineralocorticoid deficiency. Patients with secondary or tertiary adrenal insufficiency may also exhibit hyponatremia.³⁴ ACTH deficiency in such patients is not expected to cause mineralocorticoid deficiency, as ACTH has only a minor role in aldosterone production.

It has been proposed that hyponatremia in secondary adrenal insufficiency is due to cortisol deficiency resulting in an increase of antidiuretic hormone secretion.^35,36 The mechanisms for increased antidiuretic hormone include cortisol deficiency resulting in an increased corticotropin-releasing hormone level, which acts as an antidiuretic hormone secretagogue,^37,38 and cortisol directly suppressing antidiuretic hormone secretion.³⁹

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation of the skin is present only in long-standing primary adrenal insufficiency. This is due to chronic cortisol deficiency causing an increased secretion of pro-opiomelanocortin, a prohormone that is cleaved into ACTH, melanocyte-stimulating hormone, and other hormones. Melanocyte-stimulating hormone causes skin hyperpigmentation due to increased melanin synthesis.⁴⁰ The hyperpigmentation is seen in sun-exposed areas, pressure areas, palmar creases, nipples, and mucous membranes.

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

Mineralocorticoid deficiency results in hyperkalemia and metabolic acidosis by impairing renal excretion of potassium and acid.⁴¹ This patient is compliant with her mineralocorticoid replacement regimen; thus, potassium levels and pH are expected to be normal.

TAKE-HOME POINTS

• Suspect adrenal crisis in any patient who presents with shock.
• Acute abdomen or unexplained fever could be among the manifestations.
• Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
• Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
• In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
• Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

A 71-year-old woman is brought to the emergency department by her neighbor after complaining of fatigue and light-headedness for the last 8 hours. The patient lives alone and was feeling well when she woke up this morning, but then began to feel nauseated and vomited twice.

The patient appears drowsy and confused and cannot provide any further history. Her medical records show that she was seen in the cardiology clinic 6 months ago but has not kept her appointments since then.

Her medical history includes atrial fibrillation, hypertension, type 2 diabetes mellitus, and osteoarthritis. Her medications are daily warfarin, atenolol, aspirin, candesartan, and metformin, and she takes acetaminophen as needed. She is neither a smoker nor a drug user, but she drinks alcohol occasionally. Her family history is significant for her mother’s death from breast cancer at age 55.

The neighbor confirms that the patient appeared well this morning and has not had any recent illnesses except for a minor cold last week that improved over 5 days with acetaminophen only.

INITIAL EVALUATION AND MANAGEMENT

Physical examination

On physical examination, her blood pressure is 80/40 mm Hg, respiratory rate 25 breaths per minute, oral temperature 38.3°C (100.9°F), and heart rate 130 beats per minute and irregular.

Her neck veins are flat, and her chest is clear to auscultation with normal heart sounds. Abdominal palpation elicits discomfort in the middle segments, voluntary withdrawal, and abdominal wall rigidity. Her skin feels dry and cool, with decreased turgor.

Initial treatment

The patient is given 1 L of 0.9% saline intravenously over the first hour and then is transferred to the intensive care unit, where a norepinephrine drip is started to treat her ongoing hypotension. Normal saline is continued at a rate of 500 mL per hour for the next 4 hours.

Cardiac monitoring and 12-lead electrocardiography show atrial fibrillation with a rapid ventricular response of 138 beats per minute, but electrical cardioversion is not done.

Initial laboratory tests

Of note, her international normalized ratio (INR) is 6.13, while the therapeutic range for a patient taking warfarin because of atrial fibrillation is 2.0 to 3.0.

Her blood pH is 7.34 (reference range 7.35–7.45), and her bicarbonate level is 18 mmol/L (22–26); a low pH and low bicarbonate together indicate metabolic acidosis. Her sodium level is 128 mmol/L (135–145), her chloride level is 100 mmol/L (97–107), and, as mentioned, her bicarbonate level is 18 mmol/L; therefore, her anion gap is 128 – (100 + 18) = 10 mmol/L, which is normal (≤ 10).¹

Her serum creatinine level is 1.3 mg/dL (0.5–1.1), and her blood urea nitrogen level is 35 mg/dL (7–20).

Her potassium level is 5.8 mmol/L, which is consistent with hyperkalemia (reference range 3.5–5.2).

DIFFERENTIAL DIAGNOSIS

1. Which of the following is the most likely cause of this patient’s symptoms?

• Adrenal crisis
• Cardiogenic shock due to decreased cardiac contractility
• Intracranial hemorrhage
• Acute abdomen due to small bowel obstruction
• Septic shock due to bacterial toxin-induced loss of vascular tone

Our patient is presenting with shock. Given our inability to obtain a meaningful history, the differential diagnosis is broad and includes all of the above.

Adrenal crisis

The sudden onset and laboratory results that include hyperkalemia, hyponatremia, and normal anion gap metabolic acidosis raise suspicion of adrenal crisis resulting in acute mineralocorticoid and glucocorticoid insufficiency.¹

The patient’s elevated serum creatinine and high blood urea nitrogen-to-creatinine ratio of 26.9 (reference range 10–20) also suggest intravascular volume contraction. Her low hemoglobin level and supratherapeutic INR, possibly due to an interaction between warfarin and acetaminophen combined with poor medical follow-up, raise suspicion of acute bilateral adrenal necrosis due to hemorrhage.

Bilateral adrenal hemorrhage is one cause of adrenal crisis resulting in bilateral adrenal necrosis. Risk factors for adrenal hemorrhage include anticoagulation therapy, underlying coagulopathy, postoperative states, and certain infections such as meningococcemia and Haemophilus influenzae infection.^2–5 Nevertheless, in most cases the INR is in the therapeutic range and the patient has no bleeding elsewhere.⁴ Other causes of adrenal necrosis include emboli, sepsis, and blunt trauma.^6,7

Other causes of adrenal crisis are listed in Table 3.

Cardiogenic shock

Intracranial hemorrhage can present with a decreased level of consciousness, but it is less likely to cause hypotension, as the cranial space is limited. If massive intracranial hemorrhage would occur, the increase in intracranial pressure would more likely cause hypertension by the Cushing reflex than hypotension.

Acute abdomen

Abdominal pain and rigidity along with fever can be presenting symptoms of both adrenal insufficiency and an acute abdomen due to intestinal obstruction.⁴ However, intestinal obstruction typically causes a high anion gap metabolic acidosis due to lactic acidosis, instead of the normal anion gap metabolic acidosis present in this patient.⁸ Moreover, her deranged electrolytes, supratherapeutic INR, and absence of previous gastroenterologic conditions make adrenal crisis a more likely diagnosis.

Septic shock

Septic shock would also cause fever and hypotension as bacterial toxins induce a pyrexic response and vasodilation. However, at such an early stage of sepsis, the patient would be expected to be warm and hyperemic, whereas this patient’s skin is cool and dry due to volume depletion secondary to adrenal insufficiency.⁹ Sepsis would also cause a high anion gap metabolic acidosis due to lactic acidosis, as opposed to this patient’s normal anion gap metabolic acidosis. These findings, along with the metabolic derangements and the absence of a focus of infection, make sepsis a less likely possibility.

CASE CONTINUED: CARDIOMEGALY, PERSISTENT HYPOTENSION

Blood is drawn for cultures and measurement of troponins and lactic acid, and urine samples are taken for culture and biochemical analysis. Chest radiography shows mild cardiomegaly. The patient is started empirically on vancomycin and cefepime, and her warfarin is discontinued.

Five hours after presenting to the emergency department, her blood pressure remains at 80/40 mm Hg even after receiving 3 L of normal saline intravenously.

PROMPT MANAGEMENT OF ADRENAL CRISIS

2. Which of the following is the most appropriate next step in managing this patient?

• Draw samples for serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels, then give hydrocortisone 100 mg intravenously
• Perform abdominal computed tomography (CT) without contrast
• Perform transthoracic echocardiography
• Increase the norepinephrine infusion
• Immediately give fludrocortisone

First give fluids

The first step in managing a patient with suspected adrenal crisis is liberal intravenous fluid administration to replenish the depleted intravascular space. The amount and choice of fluid is empiric, but a recommendation is 1 L of normal saline or dextrose 5% in normal saline, infused quickly over the first hour and then titrated according to the patient’s fluid status.¹⁰

Measure cortisol and ACTH; start corticosteroids immediately

Immediate therapy with an appropriate stress dose of intravenous corticosteroids (eg, hydrocortisone 100 mg) is essential. However, this should be done after drawing blood for cortisol and ACTH measurements.¹⁰

Do not delay corticosteroid therapy while awaiting the results of the diagnostic tests.

In addition, in the early phase of evolving primary adrenal insufficiency, measurement of plasma renin and aldosterone levels may be beneficial, as mineralocorticoid deficiency may predominate.^10,12,13

One of the most important aims of early corticosteroid supplementation is to prevent further hyponatremia by reducing a reactive increase in antidiuretic hormone secretion caused by cortisol deficiency. Corticosteroids also help to restore normal blood pressure by increasing vascular tone, as glucocorticoid receptor activation potentiates the vasoconstrictor actions of norepinephrine, angiotensin II, and other vasoconstrictors.^14,15

Which corticosteroid to use?

Which corticosteroid to use in previously undiagnosed adrenal insufficiency is controversial. The Endocrine Society¹⁰ and Japan Endocrine Society¹⁶ clinical practice guidelines recommend hydrocortisone in a 100-mg intravenous bolus followed by 200 mg over 24 hours.

The choice of hydrocortisone is justified by its superior mineralocorticoid activity.^10,16 Further, hydrocortisone is preferred over dexamethasone if the patient is known to have primary adrenal insufficiency, or if the serum potassium level is higher than 6.0 mmol/L.

Some clinicians, on the other hand, recommend dexamethasone, given as a 4-mg intravenous bolus followed by 4-mg boluses every 12 hours. Their rationale is that dexamethasone, unlike hydrocortisone, does not interfere with subsequent serum cortisol assays if the patient later undergoes ACTH stimulation testing.¹⁷ Dexamethasone may also be preferred to minimize unwanted mineralocorticoid effects, such as in neurosurgical patients at risk of brain edema.

If hydrocortisone is used, ACTH stimulation testing can be done after withholding hydrocortisone for 24 hours once the patient is stable. (It should be restarted after the test if the results are abnormal.)

Abdominal CT should be done in our patient to address the possibility of bilateral adrenal hemorrhage. However, it is preferable to wait until the patient is stabilized.

Echocardiography. Our patient is likely to have an element of cardiac failure, given her hypertension and cardiomegaly. However, decompensated heart failure is probably not the cause of her presentation. Thus, the first priority is to treat her adrenal crisis, and echocardiography should be deferred.

Increasing the norepinephrine infusion is unlikely to improve her blood pressure very much, as she is significantly volume-depleted. Further, low cortisol decreases the vascular response to norepinephrine.¹⁵

Mineralocorticoids such as fludrocortisone are used to treat primary adrenal insufficiency. However, they are not required during acute management of adrenal crisis, as 40 mg of hydrocortisone offers mineralocorticoid activity equivalent to 100 µg of fludrocortisone. Thus, the high doses of hydrocortisone used to treat adrenal crisis provide adequate mineralocorticoid therapy.^10,18

If dexamethasone is used, its effect along with normal saline supplementation would be sufficient to replete the intravenous space and bring the sodium level back up to normal in the acute setting.

CASE RESUMED: IMPROVEMENT WITH HYDROCORTISONE

The patient’s blood is drawn for serum cortisol and plasma ACTH measurements. A 100-mg intravenous bolus of hydrocortisone is given, followed by a 50-mg bolus every 6 hours until the patient stabilizes.

Twenty-four hours later, the patient states that she has more energy, and her appetite has improved. The norepinephrine infusion is stopped 48 hours after presentation, at which time her blood pressure is 120/70 mm Hg, heart rate 85 beats per minute and irregular, and temperature 36.7°C (98.1°F). Her current laboratory values include the following:

• Serum sodium 137 mmolL
• Serum potassium 4.3 mmol/L
• Hemoglobin 9.3 g/dL
• Serum cortisol (random) 7.2 μg/dL
• Plasma ACTH 752 pg/mL (10–60 pg/mL).

ESTABLISHING THE DIAGNOSIS OF ADRENAL INSUFFICIENCY

3. Which of the following is the most appropriate test to establish the diagnosis of adrenal insufficiency?

• 7 am total serum cortisol measurement
• Random serum cortisol measurement
• 7 am salivary cortisol measurement
• 24-hour urinary free cortisol measurement
• ACTH stimulation test for cortisol
• Insulin tolerance test for cortisol

These tests also help determine the type of adrenal insufficiency (primary, secondary, or tertiary) and guide further management. Secondary adrenal insufficiency is caused by inadequate pituitary ACTH secretion and subsequent inadequate cortisol production, whereas tertiary adrenal insufficiency is caused by inadequate hypothalamic corticotropin-releasing hormone secretion and subsequent inadequate ACTH and cortisol production. The diagnosis of adrenal insufficiency relies first on demonstrating inappropriately low total serum cortisol production. Subsequently, serum ACTH helps to differentiate between primary (high ACTH) and secondary or tertiary (low or inappropriately normal ACTH) adrenal insufficiency.

Each test listed above may demonstrate a low cortisol level. However, in a nonacute setting, safety concerns (especially regarding insulin tolerance testing), poor diagnostic value, feasibility (ie, the difficulty of 24-hour tests), and poor sensitivity of 7 am cortisol make the ACTH stimulation test the most appropriate test in clinical practice to establish the diagnosis of adrenal insufficiency.

7 am serum cortisol measurement

Measuring the serum cortisol level early in the morning in the nonacute setting could be of diagnostic value, as an extremely low value (< 3–5 μg/dL) is almost 100% specific for adrenal insufficiency in the absence of concurrent exogenous steroid intake. However, the very low cutoff for this test causes poor sensitivity (about 33%), as many patients have partial adrenal insufficiency and hence have higher serum cortisol levels that may even be in the normal physiologic range.^19–22

Random serum cortisol measurements

Random serum cortisol measurements are not very useful in a nonacute setting, since cortisol levels are affected by factors such as stress and hydration status. Moreover, they fluctuate during the day in a circadian rhythm.

On the other hand, random serum cortisol is a very good test to evaluate for adrenal insufficiency in the acute setting. A random value higher than 15 to 18 μg/dL is almost always associated with adequate adrenal function and generally rules out adrenal insufficiency.^11,23,24

The same principle applies to early morning salivary cortisol. Only extremely low values (< 2.65 ng/mL) may distinguish patients with adrenal insufficiency from healthy individuals, with 97.1% sensitivity and 93.3% specificity.²⁵

Of note, early morning salivary cortisol is not routinely measured in most clinical practices for evaluation of adrenal function. Hence, morning serum and morning salivary cortisol are useful screening tools and have meaningful results when their values are in the extremes of the spectrum, but they are not reliable as a single test, as they may overlook patients with partial adrenal insufficiency.

Urinary cortisol measurement

Urinary cortisol measurement is not used to diagnose adrenal insufficiency, as values can be normal in patients with partial adrenal insufficiency.

The ACTH stimulation test

The ACTH stimulation test involves an intramuscular or intravenous injection of cosyntropin (a synthetic analogue of ACTH fragment 1–24 that has the full activity of native ACTH) and measuring total serum cortisol at baseline, 30 minutes, and 60 minutes to assess the response of the adrenal glands.

The test can be done using a high or low dose of cosyntropin. The Endocrine Society’s 2016 guidelines recommend the high dose (250 μg) for most patients.¹⁰ The standard high-dose stimulation test can be done at any time during the day.²⁶ If the cosyntropin is injected intravenously, any value higher than 18 to 20 μg/dL indicates normal adrenal function and excludes adrenal insufficiency.^27,28 If intramuscular injection is used, any value higher than 16 to 18 μg/dL at 30 minutes post-consyntropin excludes adrenal insufficiency.²⁹

The ACTH stimulation test may not exclude acute secondary or tertiary adrenal insufficiency.

Insulin tolerance testing

Insulin tolerance testing remains the gold standard for diagnosing adrenal insufficiency and assessing the integrity of the pituitary-adrenal axis. However, given its difficulty to perform, safety concerns, and the availability of other reliable tests, its use in clinical practice is limited. It is nonetheless useful in assessing patients with recent onset of ACTH deficiency.^30,31

CASE RESUMED: PATIENT DISCHARGED, LOST TO FOLLOW-UP

Abdominal CT without contrast is done and demonstrates bilateral adrenal hemorrhage. Thus, the patient is diagnosed with primary acute adrenal insufficiency due to adrenal necrosis.

She is started on oral hydrocortisone and fludrocortisone after intravenous hydrocortisone is discontinued. She is counseled about adhering to medications, wearing a medical alert bracelet, giving herself emergency cortisol injections, taking higher doses of hydrocortisone if she is ill, and monitoring her INR. She is discharged home after her symptoms resolve.

The patient does not keep her scheduled appointment and is lost to follow-up. She returns 2 years later complaining of fatigue and feeling unwell. She admits that she stopped taking hydrocortisone 1 year ago after reading an online article about corticosteroid side effects. She has continued to take fludrocortisone.

MINERALOCORTICOID VS CORTICOSTEROID DEFICIENCY

4. Which of the following is least likely to be present in this patient at this time?

• Intravascular volume depletion
• Hyponatremia
• Skin hyperpigmentation
• Normokalemia
• Elevated serum ACTH level

Intravascular volume depletion

Intravascular volume depletion is the least likely to be present. This is because intravascular volume depletion is mainly secondary to mineralocorticoid deficiency rather than corticosteroid deficiency, which is not present in this patient, as she is compliant with her mineralocorticoid replacement therapy.^32,33 However, even with sufficient mineralocorticoid replacement, mild hypotension may be present in this patient due to corticosteroid deficiency-induced loss of vascular tone.

Hyponatremia

Hyponatremia in adrenal insufficiency is not due only to mineralocorticoid deficiency. Patients with secondary or tertiary adrenal insufficiency may also exhibit hyponatremia.³⁴ ACTH deficiency in such patients is not expected to cause mineralocorticoid deficiency, as ACTH has only a minor role in aldosterone production.

It has been proposed that hyponatremia in secondary adrenal insufficiency is due to cortisol deficiency resulting in an increase of antidiuretic hormone secretion.^35,36 The mechanisms for increased antidiuretic hormone include cortisol deficiency resulting in an increased corticotropin-releasing hormone level, which acts as an antidiuretic hormone secretagogue,^37,38 and cortisol directly suppressing antidiuretic hormone secretion.³⁹

In our patient, volume expansion and hyponatremia are expected due to increased antidiuretic hormone secretion as a result of corticosteroid insufficiency.

Hyperpigmentation of the skin is present only in long-standing primary adrenal insufficiency. This is due to chronic cortisol deficiency causing an increased secretion of pro-opiomelanocortin, a prohormone that is cleaved into ACTH, melanocyte-stimulating hormone, and other hormones. Melanocyte-stimulating hormone causes skin hyperpigmentation due to increased melanin synthesis.⁴⁰ The hyperpigmentation is seen in sun-exposed areas, pressure areas, palmar creases, nipples, and mucous membranes.

This patient has long-standing corticosteroid deficiency due to noncompliance and primary adrenal insufficiency, and as a result she is expected to have elevated serum ACTH and hyperpigmentation.

Normokalemia

Mineralocorticoid deficiency results in hyperkalemia and metabolic acidosis by impairing renal excretion of potassium and acid.⁴¹ This patient is compliant with her mineralocorticoid replacement regimen; thus, potassium levels and pH are expected to be normal.

TAKE-HOME POINTS

• Suspect adrenal crisis in any patient who presents with shock.
• Acute abdomen or unexplained fever could be among the manifestations.
• Initial management requires liberal normal saline intravenous fluid administration to replete the intravascular space.
• Draw blood samples for serum chemistry, cortisol, and ACTH, followed immediately by intravenous hydrocortisone supplementation.
• In critically ill patients, evaluate adrenal function with random serum cortisol; in a nonacute setting use the ACTH stimulation test.
• Chronic management of primary adrenal insufficiency requires corticosteroid and mineralocorticoid therapy.

To the Editor: We read with great interest the article by Munyon et al¹ addressing recent developments in perioperative medicine. We would like to comment on the perioperative interruption of dual antiplatelet therapy, a common clinical problem.

Several registry analyses have shown that, with second-generation drug-eluting stents, interruption of 1 antiplatelet agent after the first month is safe.^2,3 These registries included a substantial proportion of patients whose index stenting procedure was performed for acute coronary syndrome (up to 60%).² On average, antiplatelet therapy interruption was brief (about 6 to 7 days).

Additional registry analyses have shown that surgery may be safely performed beyond the first month after drug-eluting stent placement.^4,5 Specifically, a large Danish analysis of patients with a drug-eluting stent who underwent noncardiac surgery, matched to control patients without ischemic heart disease, showed that the risk of perioperative myocardial infarction and death was not increased beyond the first month after drug-eluting stent implantation. Specifically, the risk was not increased at the 1- to 2-month and 2- to 12-month postimplantation intervals. Acute coronary syndrome was the indication for stenting in 56% of the patients.

Therefore, while surgery is preferably delayed 6 months after drug-eluting stent implantation (class I recommendation in the European Society of Cardiology guidelines), surgery may be selectively performed 1 to 6 months after drug-eluting stent implantation with an acceptable risk. This is particularly so if the index stenting was performed in the setting of stable coronary arterial disease (class IIa recommendation if stenting was performed in the setting of stable coronary arterial disease without complex procedural features; class IIb recommendation if stenting was performed in the setting of acute coronary syndrome or complex procedural features).⁶ After drug-eluting stent implantation, the earliest cutpoint for considering surgery is 1 month rather than 3 months.

When surgery is performed within this 1- to 6-month interval, thienopyridine interruption should be kept brief and dual antiplatelet therapy reinitiated as soon as possible postoperatively. In fact, when thienopyridine therapy is interrupted 1 to 6 months after drug-eluting stent implantation, stent thrombosis typically occurs more than 6 or 7 days after interruption.⁷

To the Editor: We read with great interest the article by Munyon et al¹ addressing recent developments in perioperative medicine. We would like to comment on the perioperative interruption of dual antiplatelet therapy, a common clinical problem.

Several registry analyses have shown that, with second-generation drug-eluting stents, interruption of 1 antiplatelet agent after the first month is safe.^2,3 These registries included a substantial proportion of patients whose index stenting procedure was performed for acute coronary syndrome (up to 60%).² On average, antiplatelet therapy interruption was brief (about 6 to 7 days).

Additional registry analyses have shown that surgery may be safely performed beyond the first month after drug-eluting stent placement.^4,5 Specifically, a large Danish analysis of patients with a drug-eluting stent who underwent noncardiac surgery, matched to control patients without ischemic heart disease, showed that the risk of perioperative myocardial infarction and death was not increased beyond the first month after drug-eluting stent implantation. Specifically, the risk was not increased at the 1- to 2-month and 2- to 12-month postimplantation intervals. Acute coronary syndrome was the indication for stenting in 56% of the patients.

Therefore, while surgery is preferably delayed 6 months after drug-eluting stent implantation (class I recommendation in the European Society of Cardiology guidelines), surgery may be selectively performed 1 to 6 months after drug-eluting stent implantation with an acceptable risk. This is particularly so if the index stenting was performed in the setting of stable coronary arterial disease (class IIa recommendation if stenting was performed in the setting of stable coronary arterial disease without complex procedural features; class IIb recommendation if stenting was performed in the setting of acute coronary syndrome or complex procedural features).⁶ After drug-eluting stent implantation, the earliest cutpoint for considering surgery is 1 month rather than 3 months.

When surgery is performed within this 1- to 6-month interval, thienopyridine interruption should be kept brief and dual antiplatelet therapy reinitiated as soon as possible postoperatively. In fact, when thienopyridine therapy is interrupted 1 to 6 months after drug-eluting stent implantation, stent thrombosis typically occurs more than 6 or 7 days after interruption.⁷

To the Editor: We read with great interest the article by Munyon et al¹ addressing recent developments in perioperative medicine. We would like to comment on the perioperative interruption of dual antiplatelet therapy, a common clinical problem.

Several registry analyses have shown that, with second-generation drug-eluting stents, interruption of 1 antiplatelet agent after the first month is safe.^2,3 These registries included a substantial proportion of patients whose index stenting procedure was performed for acute coronary syndrome (up to 60%).² On average, antiplatelet therapy interruption was brief (about 6 to 7 days).

Additional registry analyses have shown that surgery may be safely performed beyond the first month after drug-eluting stent placement.^4,5 Specifically, a large Danish analysis of patients with a drug-eluting stent who underwent noncardiac surgery, matched to control patients without ischemic heart disease, showed that the risk of perioperative myocardial infarction and death was not increased beyond the first month after drug-eluting stent implantation. Specifically, the risk was not increased at the 1- to 2-month and 2- to 12-month postimplantation intervals. Acute coronary syndrome was the indication for stenting in 56% of the patients.

Therefore, while surgery is preferably delayed 6 months after drug-eluting stent implantation (class I recommendation in the European Society of Cardiology guidelines), surgery may be selectively performed 1 to 6 months after drug-eluting stent implantation with an acceptable risk. This is particularly so if the index stenting was performed in the setting of stable coronary arterial disease (class IIa recommendation if stenting was performed in the setting of stable coronary arterial disease without complex procedural features; class IIb recommendation if stenting was performed in the setting of acute coronary syndrome or complex procedural features).⁶ After drug-eluting stent implantation, the earliest cutpoint for considering surgery is 1 month rather than 3 months.

When surgery is performed within this 1- to 6-month interval, thienopyridine interruption should be kept brief and dual antiplatelet therapy reinitiated as soon as possible postoperatively. In fact, when thienopyridine therapy is interrupted 1 to 6 months after drug-eluting stent implantation, stent thrombosis typically occurs more than 6 or 7 days after interruption.⁷

In Reply: We reported on publications from 2016–2017 and, unfortunately, at the time we were writing our paper, the European Society of Cardiology (ESC) update on dual antiplatelet therapy¹ had not yet been published. We presented the recommendations from the American College of Cardiology (ACC) and American Heart Association (AHA),² which differ from the recently published ESC guidelines. The ESC suggests that the minimum waiting period after drug-eluting stent placement before noncardiac surgery should be 1 month rather than 3 months but acknowledges that in the setting of complex stenting or recent acute coronary syndrome, 6 months is preferred. The recommendation in this latter scenario is a class IIb C recommendation—essentially expert consensus opinion.

Further, in the study by Egholm et al,³ the event rates in patients undergoing noncardiac surgery in the 1- to 2-month period were numerically higher than in the control group, and no adjusted odds ratios were given. The numbers of events were very low, and a change of only 1 or 2 events in the other direction in the groups would likely make it statistically significant.

All of these recommendations are based on observational studies and registry data, as there are no randomized controlled trials to address this issue. There are many complexities to be accounted for including the type of stent, timing, circumstances surrounding stenting, anatomy, number of stents, patient comorbidities (particularly age, diabetes mellitus, cardiac disease), type of surgery and anesthesia, and perioperative management of antiplatelet therapy. While we acknowledge the ESC recommendation, we would urge caution in the recommendation to wait only 1 month, and in the United States most would prefer to wait 3 months if possible.

In Reply: We reported on publications from 2016–2017 and, unfortunately, at the time we were writing our paper, the European Society of Cardiology (ESC) update on dual antiplatelet therapy¹ had not yet been published. We presented the recommendations from the American College of Cardiology (ACC) and American Heart Association (AHA),² which differ from the recently published ESC guidelines. The ESC suggests that the minimum waiting period after drug-eluting stent placement before noncardiac surgery should be 1 month rather than 3 months but acknowledges that in the setting of complex stenting or recent acute coronary syndrome, 6 months is preferred. The recommendation in this latter scenario is a class IIb C recommendation—essentially expert consensus opinion.

Further, in the study by Egholm et al,³ the event rates in patients undergoing noncardiac surgery in the 1- to 2-month period were numerically higher than in the control group, and no adjusted odds ratios were given. The numbers of events were very low, and a change of only 1 or 2 events in the other direction in the groups would likely make it statistically significant.

All of these recommendations are based on observational studies and registry data, as there are no randomized controlled trials to address this issue. There are many complexities to be accounted for including the type of stent, timing, circumstances surrounding stenting, anatomy, number of stents, patient comorbidities (particularly age, diabetes mellitus, cardiac disease), type of surgery and anesthesia, and perioperative management of antiplatelet therapy. While we acknowledge the ESC recommendation, we would urge caution in the recommendation to wait only 1 month, and in the United States most would prefer to wait 3 months if possible.

In Reply: We reported on publications from 2016–2017 and, unfortunately, at the time we were writing our paper, the European Society of Cardiology (ESC) update on dual antiplatelet therapy¹ had not yet been published. We presented the recommendations from the American College of Cardiology (ACC) and American Heart Association (AHA),² which differ from the recently published ESC guidelines. The ESC suggests that the minimum waiting period after drug-eluting stent placement before noncardiac surgery should be 1 month rather than 3 months but acknowledges that in the setting of complex stenting or recent acute coronary syndrome, 6 months is preferred. The recommendation in this latter scenario is a class IIb C recommendation—essentially expert consensus opinion.

Further, in the study by Egholm et al,³ the event rates in patients undergoing noncardiac surgery in the 1- to 2-month period were numerically higher than in the control group, and no adjusted odds ratios were given. The numbers of events were very low, and a change of only 1 or 2 events in the other direction in the groups would likely make it statistically significant.

All of these recommendations are based on observational studies and registry data, as there are no randomized controlled trials to address this issue. There are many complexities to be accounted for including the type of stent, timing, circumstances surrounding stenting, anatomy, number of stents, patient comorbidities (particularly age, diabetes mellitus, cardiac disease), type of surgery and anesthesia, and perioperative management of antiplatelet therapy. While we acknowledge the ESC recommendation, we would urge caution in the recommendation to wait only 1 month, and in the United States most would prefer to wait 3 months if possible.

As many as one-third of workers in some sectors of health care and social service may have hearing loss, according to the researchers at the National Institute for Occupational Safety and Health (NIOSH) who studied audiograms from hundreds of US companies. Theirs is the first known study to estimate and compare the prevalence of noise-exposed worker hearing loss by subsector within the Health Care and Social Assistance (HSA) sector.

Some subsectors had higher than expected prevalence of hearing loss for an industry that has had assumed “low exposure” to noise, NIOSH says. Most of the HSA subsector prevalence estimates ranged from 14% to 18%, but the Medical and Diagnostic Laboratories subsector had 31% prevalence, the Offices of All Other Miscellaneous Health Practitioners had 24% prevalence, and Child Day Care Services had a 52% higher risk compared with that of the reference industry.

NIOSH says successful noise reduction measures have been documented in hospital settings. Exposure to chemotherapy drugs can be better prevented and laboratories can be modified to reduce the level of noise. When noise can’t be removed or reduced to safe levels, NIOSH recommends implementing an effective hearing conservation program.

Hearing loss is the third most common chronic physical condition in the US, NIOSH says. But Elizabeth Masterson, PhD, epidemiologist and lead author of the study, says, “Occupational hearing loss is entirely preventable.”

As many as one-third of workers in some sectors of health care and social service may have hearing loss, according to the researchers at the National Institute for Occupational Safety and Health (NIOSH) who studied audiograms from hundreds of US companies. Theirs is the first known study to estimate and compare the prevalence of noise-exposed worker hearing loss by subsector within the Health Care and Social Assistance (HSA) sector.

Some subsectors had higher than expected prevalence of hearing loss for an industry that has had assumed “low exposure” to noise, NIOSH says. Most of the HSA subsector prevalence estimates ranged from 14% to 18%, but the Medical and Diagnostic Laboratories subsector had 31% prevalence, the Offices of All Other Miscellaneous Health Practitioners had 24% prevalence, and Child Day Care Services had a 52% higher risk compared with that of the reference industry.

NIOSH says successful noise reduction measures have been documented in hospital settings. Exposure to chemotherapy drugs can be better prevented and laboratories can be modified to reduce the level of noise. When noise can’t be removed or reduced to safe levels, NIOSH recommends implementing an effective hearing conservation program.

Hearing loss is the third most common chronic physical condition in the US, NIOSH says. But Elizabeth Masterson, PhD, epidemiologist and lead author of the study, says, “Occupational hearing loss is entirely preventable.”

As many as one-third of workers in some sectors of health care and social service may have hearing loss, according to the researchers at the National Institute for Occupational Safety and Health (NIOSH) who studied audiograms from hundreds of US companies. Theirs is the first known study to estimate and compare the prevalence of noise-exposed worker hearing loss by subsector within the Health Care and Social Assistance (HSA) sector.

Some subsectors had higher than expected prevalence of hearing loss for an industry that has had assumed “low exposure” to noise, NIOSH says. Most of the HSA subsector prevalence estimates ranged from 14% to 18%, but the Medical and Diagnostic Laboratories subsector had 31% prevalence, the Offices of All Other Miscellaneous Health Practitioners had 24% prevalence, and Child Day Care Services had a 52% higher risk compared with that of the reference industry.

NIOSH says successful noise reduction measures have been documented in hospital settings. Exposure to chemotherapy drugs can be better prevented and laboratories can be modified to reduce the level of noise. When noise can’t be removed or reduced to safe levels, NIOSH recommends implementing an effective hearing conservation program.

Hearing loss is the third most common chronic physical condition in the US, NIOSH says. But Elizabeth Masterson, PhD, epidemiologist and lead author of the study, says, “Occupational hearing loss is entirely preventable.”

SHM Research, Innovation, and Clinical Vignettes Abstracts, Hospital Medicine 2018, April 8-11

SHM Research, Innovation, and Clinical Vignettes Abstracts, Hospital Medicine 2018, April 8-11

SHM Research, Innovation, and Clinical Vignettes Abstracts, Hospital Medicine 2018, April 8-11