The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

The term “dual diagnosis” describes the clinically challenging comorbidity of a substance use disorder (SUD) along with another major mental illness. Based on data from the Epidemiologic Catchment Area study, the lifetime prevalence of SUDs among patients with mental illness is approximately 30%, and is higher among patients with certain mental disorders, such as schizophrenia (47%), bipolar disorder (61%), and antisocial personality disorder (84%).¹ These statistics highlight that addiction is often the rule rather than the exception among those with severe mental illness.¹ Not surprisingly, the combined effects of having an SUD along with another mental illness are uniformly negative (Table 1^2-4).

Based on outcomes research, the core tenets of evidence-based dual-diagnosis treatment include the importance of integrated (rather than parallel) and simultaneous (rather than sequential) care, which means an ideal treatment program includes a unified, multidisciplinary team whose coordinated efforts focus on treating both disorders concurrently.² Evidence-based psychotherapies for addiction, including motivational interviewing, cognitive-behavioral therapy, relapse prevention, contingency management, skills training, and/or case management, are a necessity,^3,5 and must be balanced with rational and appropriate pharmacotherapy targeting both the SUD as well as the other disorder (Table 2^2,3,5-9).

3 ‘Real-world’ clinical challenges

Ideal vs real-world treatment

Treating patients with co-occurring disorders (CODs) within integrated dual-disorder treatment (IDDT) programs sounds straightforward. However, implementing evidence-based “best practice” treatment is a significant challenge in the real world for several reasons. First, individuals with CODs often struggle with poor insight, low motivation to change, and lack of access to health care. According to the Substance Abuse and Mental Health Services Administration (SAMHSA), 52% of individuals with CODs in the U.S. received no treatment at all in 2016.¹⁰ For patients with dual disorders who do seek care, most are not given access to specialty SUD treatment¹⁰ and may instead find themselves treated by psychiatrists with limited SUD training who fail to provide evidence-based psychotherapies and underutilize pharmacotherapies for SUDs.¹¹ In the setting of CODs, the “harm reduction model” can be conflated with therapeutic nihilism, resulting in the neglect of SUD issues, with clinicians expecting patients to seek SUD treatment on their own, through self-help groups such as Alcoholics Anonymous or in other community treatment programs staffed by nonprofessionals that often are not tailored to the unique needs of patients with dual disorders. Psychiatrists working with other mental health professionals who provide psychotherapy for SUDs often do so in parallel rather than in an evidence-based, integrated fashion.

IDDT programs are not widely available. One study found that fewer than 20% of addiction treatment programs and fewer than 10% of mental health programs in the U.S. met criteria for dual diagnosis–capable services.¹² Getting treatment programs to become dual diagnosis–capable is possible, but it is a time-consuming and costly endeavor that, once achieved, requires continuous staff training and programmatic adaptations to interruptions in funding.^13-16 With myriad barriers to the establishment and maintenance of IDDTs, many patients with dual disorders are left without access to the most effective and comprehensive care; as few as 4% of individuals with CODs are treated within integrated programs.¹⁷

Diagnostic dilemmas

Establishing whether or not a patient with an active SUD has another serious mental illness (SMI) is a crucial first step for optimizing treatment, but diagnostic reliability can prove challenging and requires careful clinical assessment (Table 3). As always in psychiatry, accurate diagnosis is limited to careful clinical assessment¹⁸ and, in the case of possible dual disorders, is complicated by the fact that both SUDs as well as non-SUDs can result in the same psychiatric symptoms (eg, insomnia, anxiety, depression, manic behaviors, and psychosis). Clinicians must therefore distinguish between:

• Symptoms of substance intoxication or withdrawal vs independent symptoms of an underlying psychiatric disorder (that persist beyond a month after cessation of intoxication or withdrawal)
• Subclinical symptoms vs threshold mental illness, keeping in mind that some mood and anxiety states can be normal given social situations and stressors (eg, turmoil in relationships, employment difficulties, homelessness, etc.)
• Any mental illness (AMI) vs SMI. The latter is defined by SAMHSA as AMI that substantially interferes with or limits ≥1 major life activities.¹⁰

With these distinctions in mind, data from the 2016 National Survey on Drug Use and Health indicate that dual-diagnosis comorbidity was higher when the thres­hold for mental illness was lower—among the 19 million adults in the U.S. with SUDs, the past-year prevalence was 43% for AMI and 14% for SMI.¹⁰ Looking at substance-induced disorders vs “independent” disorders, the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions found that for individuals with SUDs, the past-year prevalence of an independent mood or anxiety disorder was 35% and 26%, respectively.¹⁹ Taken together, these findings illustrate the substantial rate of dual-diagnosis comorbidity, the diagnostic heterogeneity and range of severity of CODs,²⁰ and the potential for both false negatives (eg, diagnosing a substance-induced syndrome when in fact a patient has an underlying disorder) and false positives (diagnosing a full-blown mental illness when symptoms are subclinical or substance-induced) when performing diagnostic assessments in the setting of known SUDs.

Continue to: False positives are more likely...

False positives are more likely when patients seeking treatment for non-SUDs don’t disclose active drug use, even when asked. Both patients and their treating clinicians may also be prone to underestimating the significant potential for morbidity associated with SUDs, such that substance-induced symptoms may be misattributed to a dual disorder. Diagnostic questioning and thorough chart review that includes careful assessment of whether psychiatric symptoms preceded the onset of substance use, and whether they persisted in the setting of extended sobriety, is therefore paramount for minimizing false positives when assessing for dual diagnoses.^18,21 Likewise, random urine toxicology testing can be invaluable in verifying claims regarding sobriety.

Another factor that can complicate diagnosis is that there are often considerable secondary gains (eg, disability income, hospitalization, housing, access to prescription medications, and mitigation of the blame and stigma associated with addiction) associated with having a dual disorder as opposed to having “just” a SUD. As a result, for some patients, obtaining a non-SUD diagnosis can be highly incentivized.^22,23 Clinicians must therefore be savvy about the high potential for malingering, embellishment, and mislabeling of symptoms when conducting diagnostic interviews. For example, in assessing for psychosis, the frequent endorsement of “hearing voices” in patients with SUDs often results in a diagnosis of schizophrenia or unspecified psychotic disorder,²² despite the fact that this symptom can occur during substance intoxication and withdrawal, is well documented among people without mental illness as well as those with non-psychotic disorders,²⁴ and can resolve without medications or with non-antipsychotic pharmacotherapy.²⁵

When assessing for dual disorders, diagnostic false positives and false negatives can both contribute to inappropriate treatment and unrealistic expectations for recovery, and therefore underscore the importance of careful diagnostic assessment. Even with diligent assessment, however, diagnostic clarity can prove elusive due to inadequate sobriety, inconsistent reporting, and poor memory.²⁶ Therefore, for patients with known SUDs but diagnostic uncertainty about a dual disorder, the work-up should include a trial of prospective observation, with completion of appropriate detoxification, throughout a 1-month period of sobriety and in the absence of psychiatric medications, to determine if there are persistent symptoms that would justify a dual diagnosis. In research settings, such observations have revealed that most of depressive symptoms among alcoholics who present for substance abuse treatment resolve after a month of abstinence.²⁷ A similar time course for resolution has been noted for anxiety, distress, fatigue, and depressive symptoms among individuals with cocaine dependence.²⁸ These findings support the guideline established in DSM-IV that symptoms persisting beyond a month of sobriety “should be considered to be manifestations of an independent, non-substance-induced mental disorder,”²⁹ while symptoms occurring within that month may well be substance-induced. Unfortunately, in real-world clinical practice, and particularly in outpatient settings, it can be quite difficult to achieve the requisite period of sobriety for reliable diagnosis, and patients are often prematurely prescribed medications (eg, an antidepressant, antipsychotic, or mood stabilizer) that can confound the cause of symptomatic resolution. Such prescriptions are driven by compelling pressures from patients to relieve their acute suffering, as well as the predilection of some clinicians to give patients “the benefit of doubt” in assessing for dual diagnoses. However, whether an inappropriate diagnosis or a prescription for an unnecessary medication represents a benefit is debatable at best.

Pharmacotherapy

A third real-world challenge in managing patients with dual disorders involves optimizing pharmacotherapy. Unfortunately, because patients with SUDs often are excluded from clinical trials, evidence-based guidance for patients with dual disorders is lacking. In addition, medications for both CODs often remain inaccessible to patients with dual disorders for 3 reasons:

• SUDs negatively impact medication adherence among patients with dual disorders, who sometimes point out that “it says right here on the bottle not to take this medication with drugs or alcohol!”
• Some self-help groups still espouse blanket opposition of any “psychotropic” medications, even when clearly indicated for patients with COD. Groups that recognize the importance of pharmacotherapy, such as Dual Diagnosis Anonymous (DDA), have emerged, but are not yet widely available.³⁰
• Although there are increasing options for FDA-approved medications for SUDs, they are limited to the treatment of alcohol, opioid, and nicotine use disorders³¹; are often restricted due to hospital and health insurance formularies³²; and remain underprescribed for patients with dual disorders.¹¹

Continue to: Although underutilization of pharmacotherapy is...

Although underutilization of pharmacotherapy is a pitfall to be avoided in the treatment of patients with dual disorders, medication overutilization can be just as problematic. Patients with dual disorders are sometimes singularly focused on resolving acute anxiety, depression, or psychosis at the expense of working towards sobriety.³³ Although the “self-medication hypothesis” is frequently invoked by patients and clinicians alike to suggest that substance use occurs in the service of “treating” underlying disorders,³⁴ this theory has not been well supported in studies.^35-37 Some patients may pledge dedication to abstinence, but still pressure physicians for a pharmacologic solution to their suffering. With expanding legalization of cannabis for both recreational and medical purposes, patients are increasingly seeking doctors’ recommendations for “medical marijuana” for a wide range of complaints, despite the fact that data supporting a therapeutic role for cannabis in the treatment of mental illness is sparse,³⁸ whereas the potential harm in terms of either causing or worsening psychosis is well established.^39,40 Clinicians must be knowledgeable about the abuse potential of prescribed medications, ranging from sleep aids, analgesics, and muscle relaxants to antidepressants and antipsychotics, while also being mindful of the psychological meaningfulness of seeking, prescribing, and not prescribing medications.⁴¹

Although the simultaneous treatment of patients with dual disorders that includes pharmacotherapy for both SUDs and CODs is vital for optimizing clinical outcomes, clinicians should strive for diagnostic accuracy and use medications judiciously. In addition, although pharmacotherapy often is necessary to deliver evidence-based treatment for patients with dual disorders, it is inadequate as standalone treatment and should be administered along with psychosocial interventions within an integrated, multidisciplinary treatment setting.

The keys to optimal outcomes

The treatment of patients with dual disorders can be challenging, to say the least. Ideal, evidence-based therapy in the form of an IDDT program can be difficult for clinicians to implement and for patients to access. Best efforts to perform meticulous clinical assessment to clarify diagnoses, use pharmacotherapy judiciously, work collaboratively in a multidisciplinary setting, and optimize treatment given available resources are keys to clinical success.

Bottom Line

Ideal treatment of patients with dual disorders consists of simultaneous, integrated interventions delivered by a multidisciplinary team. However, in the real world, limited resources, diagnostic challenges, and both over- and underutilization of pharmacotherapy often hamper optimal treatment.

Related Resources

• Substance Abuse and Mental Health Services Administration. Co-occurring disorders. https://www.samhsa.gov/disorders/co-occurring.
• National Alliance on Mental Illness. Dual diagnosis. https://www.nami.org/Learn-More/Mental-Health-Conditions/Related-Conditions/Dual-Diagnosis.
• Foundations Recovery Network. Dual diagnosis support groups. http://www.dualdiagnosis.org/resource/ddrn/self-helpsupport-groups/support-groups.
• Substance Abuse and Mental Health Services Administration. Integrated treatment for co-occurring disorders evidence-based practices (EBP) KIT. https://store.samhsa.gov/product/Integrated-Treatment-for-Co-Occurring-Disorders-Evidence-Based-Practices-EBP-KIT/SMA08-4367.
• Substance Abuse and Mental Health Services Administration. Substance abuse treatment for persons with co-occurring disorders. https://store.samhsa.gov/shin/content/SMA13-3992/SMA13-3992.pdf.

For patients with suspected opioid-induced constipation, start by taking a careful history of defecation and dietary patterns, stool consistency, incomplete evacuation, and “alarm symptoms,” such as bloody stools or weight loss, state new guidelines from the American Gastroenterological Association in Gastroenterology.

Hemera/thinkstock

Clinicians also should rule out other causes of constipation, such as pelvic outlet dysfunction, mechanical obstruction, metabolic abnormalities, and comorbidities or concurrent medications, wrote Seth D. Crockett, MD, MPH, of the University of North Carolina at Chapel Hill, together with his associates. The guideline was published online Sept. 1.

Opioid therapy can lead to a range of gastrointestinal symptoms, such as constipation, gastroesophageal reflux, nausea and vomiting, bloating, and abdominal pain. Among these, constipation is by far the most common and debilitating, the guideline notes. In past studies, 40%-80% of patients who received opioids developed opioid-induced constipation (OIC), a more severe presentation that involves a combination of reduced stool frequency in addition to other symptoms, such as harder stools, new or worsening straining during defecation, and a sense of incomplete rectal evacuation.

Treating OIC should start with lifestyle interventions, such as drinking more fluids, toileting as soon as possible when feeling the urge to defecate, and adding regular moderate exercise whenever tolerable, the guideline advises. For patients on oral or parenteral therapy, consider switching to an equianalgesic dose of a less-constipating opioid, such as transdermal fentanyl or oxycodone-naloxone combination therapy.

Many patients with OIC require interventions beyond lifestyle changes or opioid switching. For these patients, the guideline advises starting with conventional laxative therapies based on their safety, low cost, and “established efficacy” in the OIC setting. Options include stool softeners (docusate sodium), osmotic laxatives (polyethylene glycol, magnesium hydroxide, magnesium citrate, and lactulose), lubricants (mineral oil), and stimulant laxatives (bisacodyl, sodium picosulfate, and senna). “Of note, there is little evidence that routine use of stimulant laxatives is harmful to the colon, despite widespread concern to the contrary,” the guideline states. Although randomized, controlled trials have not evaluated particular laxative combinations or titrations for OIC, the best evidence supports stimulant and osmotic laxative therapy, the authors note.

Before deeming any case of OIC laxative refractory, ensure that a patient receives an adequate trial of at least two classes of laxatives administered on a regular schedule, not just “as needed,” the guideline specifies. For example, a patient might receive a 2-week trial of a daily osmotic laxative plus a stimulant laxative two to three times weekly. The guideline authors suggest restricting the use of enemas to rescue therapy. They also note that consuming more fiber tends not to help patients with OIC because fiber does not affect colonic motility.

For truly laxative-refractory OIC, the guidelines recommend escalating treatment to peripherally acting mu-opioid receptor antagonists (PAMORAs). These drugs restore the function of the enteric nervous system by blocking mu-opioid receptors in the gut. Among the PAMORAs, the guideline strongly recommends the use of naldemedine or naloxegol over no treatment, based on robust data from randomized, double-blind, placebo-controlled trials. In the phase 3 COMPOSE 1, 2, and 3 trials, about 52% of patients who received naldemedine achieved at least three spontaneous bowel movements per week, compared with 35% of patients who received placebo. Additionally, in a 52-week safety and efficacy study (COMPOSE 3), naldemedine was associated with one more spontaneous bowel movement per week versus placebo and with a low absolute increase in adverse events.

The guideline bases its strong recommendation for naloxegol on moderate-quality data from three studies, including two phase 3, double-blind, randomized, placebo-controlled trials. Although at least five randomized, controlled trials have evaluated methylnaltrexone, the evidence was low quality and therefore the guideline only conditionally recommends prescribing this PAMORA over no treatment.

The guideline also makes no recommendation on the use of the intestinal secretagogue lubiprostone or the 5HT agonist prucalopride. Studies of lubiprostone were limited by possible reporting bias and showed no clear treatment benefit, the authors state. They describe a similar evidence gap for prucalopride, noting that at least one trial ended early without publication of the findings. They recommend further studying lubiprostone as well as prucalopride and other highly selective 5-HT4 agonists for treating OIC. Head-to-head trials would help guide treatment choice for patients with laxative-refractory OIC, they add. “Cost-effectiveness studies are also lacking in this field, which could inform prescribing strategy, particularly for newer, more expensive agents.”

For patients with suspected opioid-induced constipation, start by taking a careful history of defecation and dietary patterns, stool consistency, incomplete evacuation, and “alarm symptoms,” such as bloody stools or weight loss, state new guidelines from the American Gastroenterological Association in Gastroenterology.

Hemera/thinkstock

Clinicians also should rule out other causes of constipation, such as pelvic outlet dysfunction, mechanical obstruction, metabolic abnormalities, and comorbidities or concurrent medications, wrote Seth D. Crockett, MD, MPH, of the University of North Carolina at Chapel Hill, together with his associates. The guideline was published online Sept. 1.

Opioid therapy can lead to a range of gastrointestinal symptoms, such as constipation, gastroesophageal reflux, nausea and vomiting, bloating, and abdominal pain. Among these, constipation is by far the most common and debilitating, the guideline notes. In past studies, 40%-80% of patients who received opioids developed opioid-induced constipation (OIC), a more severe presentation that involves a combination of reduced stool frequency in addition to other symptoms, such as harder stools, new or worsening straining during defecation, and a sense of incomplete rectal evacuation.

Treating OIC should start with lifestyle interventions, such as drinking more fluids, toileting as soon as possible when feeling the urge to defecate, and adding regular moderate exercise whenever tolerable, the guideline advises. For patients on oral or parenteral therapy, consider switching to an equianalgesic dose of a less-constipating opioid, such as transdermal fentanyl or oxycodone-naloxone combination therapy.

Many patients with OIC require interventions beyond lifestyle changes or opioid switching. For these patients, the guideline advises starting with conventional laxative therapies based on their safety, low cost, and “established efficacy” in the OIC setting. Options include stool softeners (docusate sodium), osmotic laxatives (polyethylene glycol, magnesium hydroxide, magnesium citrate, and lactulose), lubricants (mineral oil), and stimulant laxatives (bisacodyl, sodium picosulfate, and senna). “Of note, there is little evidence that routine use of stimulant laxatives is harmful to the colon, despite widespread concern to the contrary,” the guideline states. Although randomized, controlled trials have not evaluated particular laxative combinations or titrations for OIC, the best evidence supports stimulant and osmotic laxative therapy, the authors note.

Before deeming any case of OIC laxative refractory, ensure that a patient receives an adequate trial of at least two classes of laxatives administered on a regular schedule, not just “as needed,” the guideline specifies. For example, a patient might receive a 2-week trial of a daily osmotic laxative plus a stimulant laxative two to three times weekly. The guideline authors suggest restricting the use of enemas to rescue therapy. They also note that consuming more fiber tends not to help patients with OIC because fiber does not affect colonic motility.

For truly laxative-refractory OIC, the guidelines recommend escalating treatment to peripherally acting mu-opioid receptor antagonists (PAMORAs). These drugs restore the function of the enteric nervous system by blocking mu-opioid receptors in the gut. Among the PAMORAs, the guideline strongly recommends the use of naldemedine or naloxegol over no treatment, based on robust data from randomized, double-blind, placebo-controlled trials. In the phase 3 COMPOSE 1, 2, and 3 trials, about 52% of patients who received naldemedine achieved at least three spontaneous bowel movements per week, compared with 35% of patients who received placebo. Additionally, in a 52-week safety and efficacy study (COMPOSE 3), naldemedine was associated with one more spontaneous bowel movement per week versus placebo and with a low absolute increase in adverse events.

The guideline bases its strong recommendation for naloxegol on moderate-quality data from three studies, including two phase 3, double-blind, randomized, placebo-controlled trials. Although at least five randomized, controlled trials have evaluated methylnaltrexone, the evidence was low quality and therefore the guideline only conditionally recommends prescribing this PAMORA over no treatment.

The guideline also makes no recommendation on the use of the intestinal secretagogue lubiprostone or the 5HT agonist prucalopride. Studies of lubiprostone were limited by possible reporting bias and showed no clear treatment benefit, the authors state. They describe a similar evidence gap for prucalopride, noting that at least one trial ended early without publication of the findings. They recommend further studying lubiprostone as well as prucalopride and other highly selective 5-HT4 agonists for treating OIC. Head-to-head trials would help guide treatment choice for patients with laxative-refractory OIC, they add. “Cost-effectiveness studies are also lacking in this field, which could inform prescribing strategy, particularly for newer, more expensive agents.”

For patients with suspected opioid-induced constipation, start by taking a careful history of defecation and dietary patterns, stool consistency, incomplete evacuation, and “alarm symptoms,” such as bloody stools or weight loss, state new guidelines from the American Gastroenterological Association in Gastroenterology.

Hemera/thinkstock

Clinicians also should rule out other causes of constipation, such as pelvic outlet dysfunction, mechanical obstruction, metabolic abnormalities, and comorbidities or concurrent medications, wrote Seth D. Crockett, MD, MPH, of the University of North Carolina at Chapel Hill, together with his associates. The guideline was published online Sept. 1.

Opioid therapy can lead to a range of gastrointestinal symptoms, such as constipation, gastroesophageal reflux, nausea and vomiting, bloating, and abdominal pain. Among these, constipation is by far the most common and debilitating, the guideline notes. In past studies, 40%-80% of patients who received opioids developed opioid-induced constipation (OIC), a more severe presentation that involves a combination of reduced stool frequency in addition to other symptoms, such as harder stools, new or worsening straining during defecation, and a sense of incomplete rectal evacuation.

Treating OIC should start with lifestyle interventions, such as drinking more fluids, toileting as soon as possible when feeling the urge to defecate, and adding regular moderate exercise whenever tolerable, the guideline advises. For patients on oral or parenteral therapy, consider switching to an equianalgesic dose of a less-constipating opioid, such as transdermal fentanyl or oxycodone-naloxone combination therapy.

Many patients with OIC require interventions beyond lifestyle changes or opioid switching. For these patients, the guideline advises starting with conventional laxative therapies based on their safety, low cost, and “established efficacy” in the OIC setting. Options include stool softeners (docusate sodium), osmotic laxatives (polyethylene glycol, magnesium hydroxide, magnesium citrate, and lactulose), lubricants (mineral oil), and stimulant laxatives (bisacodyl, sodium picosulfate, and senna). “Of note, there is little evidence that routine use of stimulant laxatives is harmful to the colon, despite widespread concern to the contrary,” the guideline states. Although randomized, controlled trials have not evaluated particular laxative combinations or titrations for OIC, the best evidence supports stimulant and osmotic laxative therapy, the authors note.

Before deeming any case of OIC laxative refractory, ensure that a patient receives an adequate trial of at least two classes of laxatives administered on a regular schedule, not just “as needed,” the guideline specifies. For example, a patient might receive a 2-week trial of a daily osmotic laxative plus a stimulant laxative two to three times weekly. The guideline authors suggest restricting the use of enemas to rescue therapy. They also note that consuming more fiber tends not to help patients with OIC because fiber does not affect colonic motility.

For truly laxative-refractory OIC, the guidelines recommend escalating treatment to peripherally acting mu-opioid receptor antagonists (PAMORAs). These drugs restore the function of the enteric nervous system by blocking mu-opioid receptors in the gut. Among the PAMORAs, the guideline strongly recommends the use of naldemedine or naloxegol over no treatment, based on robust data from randomized, double-blind, placebo-controlled trials. In the phase 3 COMPOSE 1, 2, and 3 trials, about 52% of patients who received naldemedine achieved at least three spontaneous bowel movements per week, compared with 35% of patients who received placebo. Additionally, in a 52-week safety and efficacy study (COMPOSE 3), naldemedine was associated with one more spontaneous bowel movement per week versus placebo and with a low absolute increase in adverse events.

The guideline bases its strong recommendation for naloxegol on moderate-quality data from three studies, including two phase 3, double-blind, randomized, placebo-controlled trials. Although at least five randomized, controlled trials have evaluated methylnaltrexone, the evidence was low quality and therefore the guideline only conditionally recommends prescribing this PAMORA over no treatment.

The guideline also makes no recommendation on the use of the intestinal secretagogue lubiprostone or the 5HT agonist prucalopride. Studies of lubiprostone were limited by possible reporting bias and showed no clear treatment benefit, the authors state. They describe a similar evidence gap for prucalopride, noting that at least one trial ended early without publication of the findings. They recommend further studying lubiprostone as well as prucalopride and other highly selective 5-HT4 agonists for treating OIC. Head-to-head trials would help guide treatment choice for patients with laxative-refractory OIC, they add. “Cost-effectiveness studies are also lacking in this field, which could inform prescribing strategy, particularly for newer, more expensive agents.”

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

Nerve growth factor (NGF) therapy in aging rats improves angiogenesis and speeds gastric ulcer healing, which suggests possible applications in human medicine, a recent study found.

Compared with young individuals, elderly people have significantly lower levels of NGF in gastric endothelial cells (GECs), a finding that is associated with impaired angiogenesis and delayed gastric ulcer healing.

“Our previous studies have shown that the gastric mucosa of aging individuals ... has increased susceptibility to injury and delayed healing owing to impaired angiogenesis, but the mechanisms are not fully elucidated,” wrote Amrita Ahluwalia, PhD, of Medical and Research Services at the Veterans Affairs Long Beach (Calif.) Healthcare System and her coauthors.

Mapping the drivers of angiogenesis in the gastric mucosa could lead to treatment options for elderly patients with injured or ulcerated gastric tissue. In prior trials (with rats), “treatment with VEGF [vascular endothelial growth factor] only partly reversed impaired angiogenesis in aging [GECs], indicating an essential role for other factor(s) in addition to VEGF,” the investigators wrote in the September issue of Cellular and Molecular Gastroenterology and Hepatology. They looked to NGF as another possible factor because recent studies had shown it could improve angiogenesis in the brain.

The present study measured NGF expression in rats and humans of varying ages, with NGF treatment and gene therapy performed in rats (in vitro and in vivo).

In vitro angiogenesis was 4.1-fold lower in GECs from aging rats (24 months of age) than it was in GECs from young rats (3 months of age; P less than .001). NGF protein and NGF mRNA levels were also significantly lower in aging GECs than they were with young GECs (NGF protein, 3.0-fold lower; NGF mRNA, 4.2-fold lower; P less than .001).

Treatment of aging rat GECs with exogenous NGF increased angiogenesis by 1.5-fold (P less than .001). Pretreatment with a PI3 kinase inhibitor or an mTOR inhibitor abolished this improvement, suggesting that the PI3 kinase/Akt and mTOR pathways are involved.

When NGF gene therapy was performed in aging GECs, NGF levels rose to the level of that in young GECs, with an accompanying restoration of angiogenesis (threefold increase; P less than .001). Proliferation of aging GECs also increased with gene therapy (P less than .001).

In vivo studies revealed that NGF expression and cell proliferation in aging rat gastric mucosa were lower than in younger rats. Of note, older rats treated with local NGF protein showed increased gastric mucosa angiogenesis and faster ulcer healing, compared with phosphate-buffered saline treatment.

Similar age-related NGF declines were found in humans. When gastric mucosa biopsies were collected from younger individuals (younger than 40 years old; n = 10) and compared with samples from an older population (at least 70 years old; n = 10), the investigators found that NGF expression was 5.5-fold lower in the older people (P less than .001).

“This clearly indicates human relevance of our experimental findings and also can explain impaired angiogenesis and delayed healing of injured gastric mucosa in aging individuals,” the investigators wrote.

“Aging gastropathy and its consequences are clinically critical issues,” the investigators noted, “especially because the aging U.S. population is growing rapidly and it is estimated that, by the year 2030, approximately 70 million Americans will be older than 65 years of age.” Gastric ulcers become more common with age, and individuals 70 years or older have an eightfold increased risk of associated complications, compared with people under 50 years.

The investigators noted that multiple growth factors likely play a role in stimulation of angiogenesis, including NGF, VEGF, epidermal growth factor, and basic fibroblast growth factor. “Further studies are necessary to investigate the role of other growth factors and cytokines in angiogenesis, [gastric ulcer] healing, and their impairment in aging,” the investigators concluded.

The study was funded by the Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The authors declared no conflicts of interest.
 

SOURCE: Ahluwalia A et al. CMGH. 2018 May 17. doi: 10.1016/j.jcmgh.2018.05.003

A proactive side-effect management strategy enabled many patients with high-risk renal cell carcinoma (RCC) to stay on adjuvant sunitinib therapy in a recent clinical trial, researchers report.

With dose interruptions, dose reductions, and supportive medical therapy, adverse events on adjuvant sunitinib were predictable, manageable, and reversible, according to their report on the S-TRAC (Sunitinib as Adjuvant Treatment for High-Risk Renal Cell Carcinoma Following Nephrectomy) trial.

Patients did report reduced health-related quality of life, but with the exception of diarrhea and loss of appetite, those changes were generally not clinically significant, the investigators wrote. The report is in Annals of Oncology.

The safety profile for sunitinib was acceptable in adjuvant RCC treatment in S-TRAC, with no safety signals observed, said Michael Staehler, MD, PhD, department of urology, Ludwig Maximilian University of Munich, and his coauthors.

“It is likely proactive management contributed to preservation of global health status and quality of life, and alleviation of treatment-related symptoms, thereby enabling patients to remain on effective adjuvant therapy,” Dr. Staehler and his coauthors said.

Sunitinib is approved by the Food and Drug Administration for adjuvant treatment of patients at high risk of recurrent RCC after nephrectomy. That was based in part on previously reported results of the phase 3 S-TRAC study, which showed a 24% reduction in risk of a disease-free survival event versus placebo.

For the 306 patients randomized to sunitinib, 71% stayed on treatment for at least 8 months, reaching cycle 6 of therapy, while 56% finished the full year of treatment, Dr. Staehler and his coauthors said in this new report on S-TRAC focused on adverse events and patient-reported outcomes.

The most common adverse events in the sunitinib arm of S-TRAC included diarrhea in 56.9%, versus 21.4% in the placebo arm, palmar-plantar erythrodysesthesia (PPE) in 50.3% versus 10.2% for placebo, and hypertension in 36.9% versus 11.8% for placebo. The frequency of serious adverse events was similar between arms, according to the investigators, at 21.9% for sunitinib and 17.1% for placebo.

Adverse events were the most common reason for dose reduction, cited in 34.6% of cases, and for dose interruption, reported in 46.4%, they said.

Treatment discontinuations due to adverse events occurred in 28.1%, usually because of PPE.

The S-TRAC study investigators used the EORTC QLQ-C30 instrument to evaluate patient experience during treatment.

That evaluation included an analysis of global health status/quality of life score that favored placebo, with a mean difference in the overall means of –4.76. Although statistically significant (P greater than or equal to .0001), the point estimate of the difference was below the commonly accepted threshold that would indicate clinically meaningful deterioration, investigators said.

Similar patterns that were statistically significant but not clinically meaningful were seen for symptoms including fatigue and pain. However, patient-reported scores for diarrhea and loss of appetite did reach the level of a clinically meaningful difference.

But only one patient permanently discontinued sunitinib because of diarrhea, and none permanently discontinued because of loss of appetite, Dr. Staehler and his coauthors noted.

The work was sponsored by Pfizer. Dr. Staehler reported honoraria, consulting fees, and research grants from Pfizer, Bayer, GSK, Roche, BMS, Novartis, Exelixis, and AVEO. Coauthors reported disclosures related to Merck, Sanofi, Astellas, Celldex, Acerta, Janssen, and others.

SOURCE: Staehler M et al. Ann Oncol. 2018 Aug 23. doi: 10.1093/annonc/mdy329.

A proactive side-effect management strategy enabled many patients with high-risk renal cell carcinoma (RCC) to stay on adjuvant sunitinib therapy in a recent clinical trial, researchers report.

With dose interruptions, dose reductions, and supportive medical therapy, adverse events on adjuvant sunitinib were predictable, manageable, and reversible, according to their report on the S-TRAC (Sunitinib as Adjuvant Treatment for High-Risk Renal Cell Carcinoma Following Nephrectomy) trial.

Patients did report reduced health-related quality of life, but with the exception of diarrhea and loss of appetite, those changes were generally not clinically significant, the investigators wrote. The report is in Annals of Oncology.

The safety profile for sunitinib was acceptable in adjuvant RCC treatment in S-TRAC, with no safety signals observed, said Michael Staehler, MD, PhD, department of urology, Ludwig Maximilian University of Munich, and his coauthors.

“It is likely proactive management contributed to preservation of global health status and quality of life, and alleviation of treatment-related symptoms, thereby enabling patients to remain on effective adjuvant therapy,” Dr. Staehler and his coauthors said.

Sunitinib is approved by the Food and Drug Administration for adjuvant treatment of patients at high risk of recurrent RCC after nephrectomy. That was based in part on previously reported results of the phase 3 S-TRAC study, which showed a 24% reduction in risk of a disease-free survival event versus placebo.

For the 306 patients randomized to sunitinib, 71% stayed on treatment for at least 8 months, reaching cycle 6 of therapy, while 56% finished the full year of treatment, Dr. Staehler and his coauthors said in this new report on S-TRAC focused on adverse events and patient-reported outcomes.

The most common adverse events in the sunitinib arm of S-TRAC included diarrhea in 56.9%, versus 21.4% in the placebo arm, palmar-plantar erythrodysesthesia (PPE) in 50.3% versus 10.2% for placebo, and hypertension in 36.9% versus 11.8% for placebo. The frequency of serious adverse events was similar between arms, according to the investigators, at 21.9% for sunitinib and 17.1% for placebo.

Adverse events were the most common reason for dose reduction, cited in 34.6% of cases, and for dose interruption, reported in 46.4%, they said.

Treatment discontinuations due to adverse events occurred in 28.1%, usually because of PPE.

The S-TRAC study investigators used the EORTC QLQ-C30 instrument to evaluate patient experience during treatment.

That evaluation included an analysis of global health status/quality of life score that favored placebo, with a mean difference in the overall means of –4.76. Although statistically significant (P greater than or equal to .0001), the point estimate of the difference was below the commonly accepted threshold that would indicate clinically meaningful deterioration, investigators said.

Similar patterns that were statistically significant but not clinically meaningful were seen for symptoms including fatigue and pain. However, patient-reported scores for diarrhea and loss of appetite did reach the level of a clinically meaningful difference.

But only one patient permanently discontinued sunitinib because of diarrhea, and none permanently discontinued because of loss of appetite, Dr. Staehler and his coauthors noted.

The work was sponsored by Pfizer. Dr. Staehler reported honoraria, consulting fees, and research grants from Pfizer, Bayer, GSK, Roche, BMS, Novartis, Exelixis, and AVEO. Coauthors reported disclosures related to Merck, Sanofi, Astellas, Celldex, Acerta, Janssen, and others.

SOURCE: Staehler M et al. Ann Oncol. 2018 Aug 23. doi: 10.1093/annonc/mdy329.

A proactive side-effect management strategy enabled many patients with high-risk renal cell carcinoma (RCC) to stay on adjuvant sunitinib therapy in a recent clinical trial, researchers report.

With dose interruptions, dose reductions, and supportive medical therapy, adverse events on adjuvant sunitinib were predictable, manageable, and reversible, according to their report on the S-TRAC (Sunitinib as Adjuvant Treatment for High-Risk Renal Cell Carcinoma Following Nephrectomy) trial.

Patients did report reduced health-related quality of life, but with the exception of diarrhea and loss of appetite, those changes were generally not clinically significant, the investigators wrote. The report is in Annals of Oncology.

The safety profile for sunitinib was acceptable in adjuvant RCC treatment in S-TRAC, with no safety signals observed, said Michael Staehler, MD, PhD, department of urology, Ludwig Maximilian University of Munich, and his coauthors.

“It is likely proactive management contributed to preservation of global health status and quality of life, and alleviation of treatment-related symptoms, thereby enabling patients to remain on effective adjuvant therapy,” Dr. Staehler and his coauthors said.

Sunitinib is approved by the Food and Drug Administration for adjuvant treatment of patients at high risk of recurrent RCC after nephrectomy. That was based in part on previously reported results of the phase 3 S-TRAC study, which showed a 24% reduction in risk of a disease-free survival event versus placebo.

For the 306 patients randomized to sunitinib, 71% stayed on treatment for at least 8 months, reaching cycle 6 of therapy, while 56% finished the full year of treatment, Dr. Staehler and his coauthors said in this new report on S-TRAC focused on adverse events and patient-reported outcomes.

The most common adverse events in the sunitinib arm of S-TRAC included diarrhea in 56.9%, versus 21.4% in the placebo arm, palmar-plantar erythrodysesthesia (PPE) in 50.3% versus 10.2% for placebo, and hypertension in 36.9% versus 11.8% for placebo. The frequency of serious adverse events was similar between arms, according to the investigators, at 21.9% for sunitinib and 17.1% for placebo.

Adverse events were the most common reason for dose reduction, cited in 34.6% of cases, and for dose interruption, reported in 46.4%, they said.

Treatment discontinuations due to adverse events occurred in 28.1%, usually because of PPE.

The S-TRAC study investigators used the EORTC QLQ-C30 instrument to evaluate patient experience during treatment.

That evaluation included an analysis of global health status/quality of life score that favored placebo, with a mean difference in the overall means of –4.76. Although statistically significant (P greater than or equal to .0001), the point estimate of the difference was below the commonly accepted threshold that would indicate clinically meaningful deterioration, investigators said.

Similar patterns that were statistically significant but not clinically meaningful were seen for symptoms including fatigue and pain. However, patient-reported scores for diarrhea and loss of appetite did reach the level of a clinically meaningful difference.

But only one patient permanently discontinued sunitinib because of diarrhea, and none permanently discontinued because of loss of appetite, Dr. Staehler and his coauthors noted.

The work was sponsored by Pfizer. Dr. Staehler reported honoraria, consulting fees, and research grants from Pfizer, Bayer, GSK, Roche, BMS, Novartis, Exelixis, and AVEO. Coauthors reported disclosures related to Merck, Sanofi, Astellas, Celldex, Acerta, Janssen, and others.

SOURCE: Staehler M et al. Ann Oncol. 2018 Aug 23. doi: 10.1093/annonc/mdy329.

Two once-daily oral HIV-1 medicines have been approved by the Food and Drug Administration, according to Merck: Delstrigo, a fixed-dose combination tablet of doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg), and Pifeltro (doravirine, 100 mg). Both drugs are indicated for treating HIV-1 infection in adult patients with no prior antiretroviral treatment.

Pifeltro is a nonnucleoside reverse transcriptase inhibitor to be used in combination with other antiretroviral medicines. Delstrigo contains a boxed warning regarding posttreatment acute exacerbation of hepatitis B infection.

Delstrigo and Pifeltro are not curative, according to the announcement by Merck, which manufactures both drugs.

The FDA approval of Delstrigo was based on findings from the DRIVE-AHEAD trial (NCT02403674), which randomized 728 participants with no history of antiretroviral treatment to receive once daily either Delstrigo or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV 600 mg/FTC 200 mg/TDF 300 mg). Delstrigo was associated with sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferior efficacy when compared with EFV/FTC/TDF (84% vs. 81%, respectively), according to Merck.

Pifeltro was approved based on the results of the DRIVE-FORWARD trial (NCT02275780), which randomized 766 participants with no history of antiretroviral treatment to receive either Pifeltro once daily or darunavir 800 mg plus ritonavir 100 mg (DRV+r) once daily, each in combination with either emtricitabine (FTC)/TDF or abacavir (ABC)/lamivudine (3TC), as selected by the investigator. Pifeltro was associated with sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferior efficacy when compared with DRV+r, each in combination with FTC/TDF or ABC/3TC (84% vs. 80%, respectively), according to the Merck announcement.

[email protected]

Two once-daily oral HIV-1 medicines have been approved by the Food and Drug Administration, according to Merck: Delstrigo, a fixed-dose combination tablet of doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg), and Pifeltro (doravirine, 100 mg). Both drugs are indicated for treating HIV-1 infection in adult patients with no prior antiretroviral treatment.

Pifeltro is a nonnucleoside reverse transcriptase inhibitor to be used in combination with other antiretroviral medicines. Delstrigo contains a boxed warning regarding posttreatment acute exacerbation of hepatitis B infection.

Delstrigo and Pifeltro are not curative, according to the announcement by Merck, which manufactures both drugs.

The FDA approval of Delstrigo was based on findings from the DRIVE-AHEAD trial (NCT02403674), which randomized 728 participants with no history of antiretroviral treatment to receive once daily either Delstrigo or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV 600 mg/FTC 200 mg/TDF 300 mg). Delstrigo was associated with sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferior efficacy when compared with EFV/FTC/TDF (84% vs. 81%, respectively), according to Merck.

Pifeltro was approved based on the results of the DRIVE-FORWARD trial (NCT02275780), which randomized 766 participants with no history of antiretroviral treatment to receive either Pifeltro once daily or darunavir 800 mg plus ritonavir 100 mg (DRV+r) once daily, each in combination with either emtricitabine (FTC)/TDF or abacavir (ABC)/lamivudine (3TC), as selected by the investigator. Pifeltro was associated with sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferior efficacy when compared with DRV+r, each in combination with FTC/TDF or ABC/3TC (84% vs. 80%, respectively), according to the Merck announcement.

[email protected]

Two once-daily oral HIV-1 medicines have been approved by the Food and Drug Administration, according to Merck: Delstrigo, a fixed-dose combination tablet of doravirine (100 mg), lamivudine (300 mg), and tenofovir disoproxil fumarate (300 mg), and Pifeltro (doravirine, 100 mg). Both drugs are indicated for treating HIV-1 infection in adult patients with no prior antiretroviral treatment.

Pifeltro is a nonnucleoside reverse transcriptase inhibitor to be used in combination with other antiretroviral medicines. Delstrigo contains a boxed warning regarding posttreatment acute exacerbation of hepatitis B infection.

Delstrigo and Pifeltro are not curative, according to the announcement by Merck, which manufactures both drugs.

The FDA approval of Delstrigo was based on findings from the DRIVE-AHEAD trial (NCT02403674), which randomized 728 participants with no history of antiretroviral treatment to receive once daily either Delstrigo or efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV 600 mg/FTC 200 mg/TDF 300 mg). Delstrigo was associated with sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferior efficacy when compared with EFV/FTC/TDF (84% vs. 81%, respectively), according to Merck.

Pifeltro was approved based on the results of the DRIVE-FORWARD trial (NCT02275780), which randomized 766 participants with no history of antiretroviral treatment to receive either Pifeltro once daily or darunavir 800 mg plus ritonavir 100 mg (DRV+r) once daily, each in combination with either emtricitabine (FTC)/TDF or abacavir (ABC)/lamivudine (3TC), as selected by the investigator. Pifeltro was associated with sustained viral suppression through 48 weeks, meeting its primary endpoint of noninferior efficacy when compared with DRV+r, each in combination with FTC/TDF or ABC/3TC (84% vs. 80%, respectively), according to the Merck announcement.

[email protected]

In patients with muscle-invasive bladder cancer, a dose-dense neoadjuvant chemotherapy regimen followed by cystectomy was associated with a higher rate of complete responses, compared with standard gemcitabine-platinum neoadjuvant chemotherapy and cystectomy, results of a retrospective analysis indicate.

Among 1,113 patients who underwent neoadjuvant chemotherapy (NAC) and cystectomy, a regimen of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) was associated with a nearly threefold greater likelihood that patients would have a complete response, compared with gemcitabine and cisplatin, reported Scott M. Gilbert, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues.

“We also found that ddMVAC was associated with longer survival intervals and a lower risk of death than the other treatments examined, although those findings did not reach statistical significance, indicating that larger comparative studies are needed to definitively answer questions regarding survival,” they wrote in JAMA Oncology.

The investigators noted that, despite clear evidence of a survival benefit associated with neoadjuvant chemotherapy followed by cystectomy, compared with cystectomy alone in patients with muscle-invasive bladder cancer, “the rates of adoption and routine use of NAC have been modest.”

Gemcitabine and cisplatin have become the de facto standard of care because of favorable toxicity profile and response rates comparable to those seen with ddMVAC. Yet there are few studies comparing disease control and survival outcomes for different neoadjuvant chemotherapy regimens, they noted, which prompted the current study.

The investigators conducted a cross-sectional analysis of data on 1,113 patients with bladder cancer treated with cystectomy at their center from January 2007 through May 2017. They compared rates of downstaging, complete responses, and overall survival with ddMVAC, compared with gemcitabine combined with either cisplatin or carboplatin, other neoadjuvant combinations (including etoposide- fluorouracil- and paclitaxel-based regimens) or no neoadjuvant chemotherapy.

Of the 1,113 patients, 824 had disease stage T2 or greater, and of this group, 332 had received neoadjuvant chemotherapy.

They found that ddMVAC was associated with a 52.2% downstaging rate, compared with 41.3% for gemcitabine-cisplatin, and 27% for gemcitabine-carboplatin. Respective pathologic complete response rates were 41.3%, 24.5%, and 9.4% (P less than .001).

Downstaging rates for patients treated with other regimens and patients who did not receive neoadjuvant chemotherapy were 42% and 25.7%, respectively. Complete response rates (downstaging to pT0N0) were 24% and 10.7%.

In a multivariable logistic regression model controlling for age, comorbidities, sex, clinical stage, and chemotherapy regimen, ddMVAC was associated with a significantly higher likelihood of pathologic complete response, with an odds ratio of 2.67 (P less than .001). Similarly, a propensity-score model weighted for clinical and demographic characteristics showed an OR for complete response with ddMVAC of 1.52 (P = .05).

The 2-year Kaplan-Meier survival probability estimate for ddMVAC was 73.3%, compared with 62% for gemcitabine-cisplatin and 34.8% for gemcitabine-carboplatin (P = .002).

Regardless of chemotherapy type, a complete pathologic response was a significant predictor for overall survival (P less than .001).

Although ddMVAC showed a trend toward better overall survival in both logistic regression and propensity score models, neither reached statistical significance.

The authors did not report survival results for patients who did not receive neoadjuvant chemotherapy.

The investigators acknowledged that the study is limited by its nonrandomized design and the relatively small sample of patients treated with ddMVAC (46 patients).

The study was supported in part by a National Cancer Institute grant to the H. Lee Moffitt Cancer Center. The authors reported having no conflicts of interest.

SOURCE: Peyton CC et al. JAMA Oncology. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3542.
 

In patients with muscle-invasive bladder cancer, a dose-dense neoadjuvant chemotherapy regimen followed by cystectomy was associated with a higher rate of complete responses, compared with standard gemcitabine-platinum neoadjuvant chemotherapy and cystectomy, results of a retrospective analysis indicate.

Among 1,113 patients who underwent neoadjuvant chemotherapy (NAC) and cystectomy, a regimen of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) was associated with a nearly threefold greater likelihood that patients would have a complete response, compared with gemcitabine and cisplatin, reported Scott M. Gilbert, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues.

“We also found that ddMVAC was associated with longer survival intervals and a lower risk of death than the other treatments examined, although those findings did not reach statistical significance, indicating that larger comparative studies are needed to definitively answer questions regarding survival,” they wrote in JAMA Oncology.

The investigators noted that, despite clear evidence of a survival benefit associated with neoadjuvant chemotherapy followed by cystectomy, compared with cystectomy alone in patients with muscle-invasive bladder cancer, “the rates of adoption and routine use of NAC have been modest.”

Gemcitabine and cisplatin have become the de facto standard of care because of favorable toxicity profile and response rates comparable to those seen with ddMVAC. Yet there are few studies comparing disease control and survival outcomes for different neoadjuvant chemotherapy regimens, they noted, which prompted the current study.

The investigators conducted a cross-sectional analysis of data on 1,113 patients with bladder cancer treated with cystectomy at their center from January 2007 through May 2017. They compared rates of downstaging, complete responses, and overall survival with ddMVAC, compared with gemcitabine combined with either cisplatin or carboplatin, other neoadjuvant combinations (including etoposide- fluorouracil- and paclitaxel-based regimens) or no neoadjuvant chemotherapy.

Of the 1,113 patients, 824 had disease stage T2 or greater, and of this group, 332 had received neoadjuvant chemotherapy.

They found that ddMVAC was associated with a 52.2% downstaging rate, compared with 41.3% for gemcitabine-cisplatin, and 27% for gemcitabine-carboplatin. Respective pathologic complete response rates were 41.3%, 24.5%, and 9.4% (P less than .001).

Downstaging rates for patients treated with other regimens and patients who did not receive neoadjuvant chemotherapy were 42% and 25.7%, respectively. Complete response rates (downstaging to pT0N0) were 24% and 10.7%.

In a multivariable logistic regression model controlling for age, comorbidities, sex, clinical stage, and chemotherapy regimen, ddMVAC was associated with a significantly higher likelihood of pathologic complete response, with an odds ratio of 2.67 (P less than .001). Similarly, a propensity-score model weighted for clinical and demographic characteristics showed an OR for complete response with ddMVAC of 1.52 (P = .05).

The 2-year Kaplan-Meier survival probability estimate for ddMVAC was 73.3%, compared with 62% for gemcitabine-cisplatin and 34.8% for gemcitabine-carboplatin (P = .002).

Regardless of chemotherapy type, a complete pathologic response was a significant predictor for overall survival (P less than .001).

Although ddMVAC showed a trend toward better overall survival in both logistic regression and propensity score models, neither reached statistical significance.

The authors did not report survival results for patients who did not receive neoadjuvant chemotherapy.

The investigators acknowledged that the study is limited by its nonrandomized design and the relatively small sample of patients treated with ddMVAC (46 patients).

The study was supported in part by a National Cancer Institute grant to the H. Lee Moffitt Cancer Center. The authors reported having no conflicts of interest.

SOURCE: Peyton CC et al. JAMA Oncology. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3542.
 

In patients with muscle-invasive bladder cancer, a dose-dense neoadjuvant chemotherapy regimen followed by cystectomy was associated with a higher rate of complete responses, compared with standard gemcitabine-platinum neoadjuvant chemotherapy and cystectomy, results of a retrospective analysis indicate.

Among 1,113 patients who underwent neoadjuvant chemotherapy (NAC) and cystectomy, a regimen of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) was associated with a nearly threefold greater likelihood that patients would have a complete response, compared with gemcitabine and cisplatin, reported Scott M. Gilbert, MD, of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, and colleagues.

“We also found that ddMVAC was associated with longer survival intervals and a lower risk of death than the other treatments examined, although those findings did not reach statistical significance, indicating that larger comparative studies are needed to definitively answer questions regarding survival,” they wrote in JAMA Oncology.

The investigators noted that, despite clear evidence of a survival benefit associated with neoadjuvant chemotherapy followed by cystectomy, compared with cystectomy alone in patients with muscle-invasive bladder cancer, “the rates of adoption and routine use of NAC have been modest.”

Gemcitabine and cisplatin have become the de facto standard of care because of favorable toxicity profile and response rates comparable to those seen with ddMVAC. Yet there are few studies comparing disease control and survival outcomes for different neoadjuvant chemotherapy regimens, they noted, which prompted the current study.

The investigators conducted a cross-sectional analysis of data on 1,113 patients with bladder cancer treated with cystectomy at their center from January 2007 through May 2017. They compared rates of downstaging, complete responses, and overall survival with ddMVAC, compared with gemcitabine combined with either cisplatin or carboplatin, other neoadjuvant combinations (including etoposide- fluorouracil- and paclitaxel-based regimens) or no neoadjuvant chemotherapy.

Of the 1,113 patients, 824 had disease stage T2 or greater, and of this group, 332 had received neoadjuvant chemotherapy.

They found that ddMVAC was associated with a 52.2% downstaging rate, compared with 41.3% for gemcitabine-cisplatin, and 27% for gemcitabine-carboplatin. Respective pathologic complete response rates were 41.3%, 24.5%, and 9.4% (P less than .001).

Downstaging rates for patients treated with other regimens and patients who did not receive neoadjuvant chemotherapy were 42% and 25.7%, respectively. Complete response rates (downstaging to pT0N0) were 24% and 10.7%.

In a multivariable logistic regression model controlling for age, comorbidities, sex, clinical stage, and chemotherapy regimen, ddMVAC was associated with a significantly higher likelihood of pathologic complete response, with an odds ratio of 2.67 (P less than .001). Similarly, a propensity-score model weighted for clinical and demographic characteristics showed an OR for complete response with ddMVAC of 1.52 (P = .05).

The 2-year Kaplan-Meier survival probability estimate for ddMVAC was 73.3%, compared with 62% for gemcitabine-cisplatin and 34.8% for gemcitabine-carboplatin (P = .002).

Regardless of chemotherapy type, a complete pathologic response was a significant predictor for overall survival (P less than .001).

Although ddMVAC showed a trend toward better overall survival in both logistic regression and propensity score models, neither reached statistical significance.

The authors did not report survival results for patients who did not receive neoadjuvant chemotherapy.

The investigators acknowledged that the study is limited by its nonrandomized design and the relatively small sample of patients treated with ddMVAC (46 patients).

The study was supported in part by a National Cancer Institute grant to the H. Lee Moffitt Cancer Center. The authors reported having no conflicts of interest.

SOURCE: Peyton CC et al. JAMA Oncology. 2018 Aug 30. doi: 10.1001/jamaoncol.2018.3542.
 

“Alex, I understand that you are upset that you left your little bulldozer at home. Let’s try to think of something else you can play with here at the restaurant that is kind of like a bulldozer.”

Ambernectar 13/CC BY-ND 2.0

Sounds like a reasonable strategy to calm an unruly preschooler, and it might have been had it not been the fifth attempt in a 45-minute dialogue between a mother and her overtired, misbehaving 3-year-old. There had been a lot of “I understand how you feel” and “use your words” woven into a gag-worthy and futile effort to forge a collaborative parent-child solution to the problem of an exhausted preschooler who is up past his bedtime in a public place.

My wife and I enjoy a night out with friends and prefer a quiet dining atmosphere. However, some evenings we eat earlier and choose a restaurant we know appeals to families with young children. At those meals, we anticipate being serenaded by a loud background buzz punctuated by the occasional shriek or short bout of crying. We expect a degree of childish behavior to come with the territory, and watching the dramas unfold brings back fond “been there, done that” memories. But, listening to those behaviors being horribly mismanaged can ruin even the most tolerant adult’s appetite in less time than it takes a parent to say, “I can see you’re unhappy, and we need to talk about why.”

In an op-ed piece, a psychotherapist asks the legitimate question, and provides the correct quick answer (“Which Is Better, Rewards or Punishments? Neither,” New York Times, Aug. 21, 2018). I couldn’t agree more. In my experience, rewards have a very short half-life and can become disastrously inflationary in the blink of an eye. On the other hand, punishments can be either too heavy-handed or so irrational that the child fails to make a logical connection between his misbehavior and his sentence.

Unfortunately, many child behavior advisers, including the op-ed author, offer alternatives to rewards and punishment that are unworkable in real-world circumstances, such as the restaurant scenario my wife and I endured.

While it sounds very democratic to ask a 3-year-old why he is misbehaving, more often than not it should be the parent who is asking what he or she could have done differently to avoid the situation. It is likely the child has been allowed to become overtired and/or the parent may be in denial about his/her child’s intolerance for stimulating environments.

Too often the parent takes too long to realize that the water is spilling over the dam and it is time to head for shore. Children who are overtired and having a tantrum can’t participate in a rational discussion about their feelings. If that dialogue needs to happen, and that is seldom, it should be the next day after the parent has time to consider his or her own mistakes.

When it comes to managing misbehaving children, I prefer well-tailored consequences and my favorite is a humanely crafted time-out. When presented and executed properly, a time-out can break the cycle of misbehavior and give both parent and child a chance to reconsider their positions.

But at 7 p.m. on a Friday evening in a busy restaurant, neither a time-out nor philosophizing with a 3-year-old is going to work. It’s time to ask for the check and head home to bed.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

“Alex, I understand that you are upset that you left your little bulldozer at home. Let’s try to think of something else you can play with here at the restaurant that is kind of like a bulldozer.”

Ambernectar 13/CC BY-ND 2.0

Sounds like a reasonable strategy to calm an unruly preschooler, and it might have been had it not been the fifth attempt in a 45-minute dialogue between a mother and her overtired, misbehaving 3-year-old. There had been a lot of “I understand how you feel” and “use your words” woven into a gag-worthy and futile effort to forge a collaborative parent-child solution to the problem of an exhausted preschooler who is up past his bedtime in a public place.

My wife and I enjoy a night out with friends and prefer a quiet dining atmosphere. However, some evenings we eat earlier and choose a restaurant we know appeals to families with young children. At those meals, we anticipate being serenaded by a loud background buzz punctuated by the occasional shriek or short bout of crying. We expect a degree of childish behavior to come with the territory, and watching the dramas unfold brings back fond “been there, done that” memories. But, listening to those behaviors being horribly mismanaged can ruin even the most tolerant adult’s appetite in less time than it takes a parent to say, “I can see you’re unhappy, and we need to talk about why.”

In an op-ed piece, a psychotherapist asks the legitimate question, and provides the correct quick answer (“Which Is Better, Rewards or Punishments? Neither,” New York Times, Aug. 21, 2018). I couldn’t agree more. In my experience, rewards have a very short half-life and can become disastrously inflationary in the blink of an eye. On the other hand, punishments can be either too heavy-handed or so irrational that the child fails to make a logical connection between his misbehavior and his sentence.

Unfortunately, many child behavior advisers, including the op-ed author, offer alternatives to rewards and punishment that are unworkable in real-world circumstances, such as the restaurant scenario my wife and I endured.

While it sounds very democratic to ask a 3-year-old why he is misbehaving, more often than not it should be the parent who is asking what he or she could have done differently to avoid the situation. It is likely the child has been allowed to become overtired and/or the parent may be in denial about his/her child’s intolerance for stimulating environments.

Too often the parent takes too long to realize that the water is spilling over the dam and it is time to head for shore. Children who are overtired and having a tantrum can’t participate in a rational discussion about their feelings. If that dialogue needs to happen, and that is seldom, it should be the next day after the parent has time to consider his or her own mistakes.

When it comes to managing misbehaving children, I prefer well-tailored consequences and my favorite is a humanely crafted time-out. When presented and executed properly, a time-out can break the cycle of misbehavior and give both parent and child a chance to reconsider their positions.

But at 7 p.m. on a Friday evening in a busy restaurant, neither a time-out nor philosophizing with a 3-year-old is going to work. It’s time to ask for the check and head home to bed.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

“Alex, I understand that you are upset that you left your little bulldozer at home. Let’s try to think of something else you can play with here at the restaurant that is kind of like a bulldozer.”

Ambernectar 13/CC BY-ND 2.0

Sounds like a reasonable strategy to calm an unruly preschooler, and it might have been had it not been the fifth attempt in a 45-minute dialogue between a mother and her overtired, misbehaving 3-year-old. There had been a lot of “I understand how you feel” and “use your words” woven into a gag-worthy and futile effort to forge a collaborative parent-child solution to the problem of an exhausted preschooler who is up past his bedtime in a public place.

My wife and I enjoy a night out with friends and prefer a quiet dining atmosphere. However, some evenings we eat earlier and choose a restaurant we know appeals to families with young children. At those meals, we anticipate being serenaded by a loud background buzz punctuated by the occasional shriek or short bout of crying. We expect a degree of childish behavior to come with the territory, and watching the dramas unfold brings back fond “been there, done that” memories. But, listening to those behaviors being horribly mismanaged can ruin even the most tolerant adult’s appetite in less time than it takes a parent to say, “I can see you’re unhappy, and we need to talk about why.”

In an op-ed piece, a psychotherapist asks the legitimate question, and provides the correct quick answer (“Which Is Better, Rewards or Punishments? Neither,” New York Times, Aug. 21, 2018). I couldn’t agree more. In my experience, rewards have a very short half-life and can become disastrously inflationary in the blink of an eye. On the other hand, punishments can be either too heavy-handed or so irrational that the child fails to make a logical connection between his misbehavior and his sentence.

Unfortunately, many child behavior advisers, including the op-ed author, offer alternatives to rewards and punishment that are unworkable in real-world circumstances, such as the restaurant scenario my wife and I endured.

While it sounds very democratic to ask a 3-year-old why he is misbehaving, more often than not it should be the parent who is asking what he or she could have done differently to avoid the situation. It is likely the child has been allowed to become overtired and/or the parent may be in denial about his/her child’s intolerance for stimulating environments.

Too often the parent takes too long to realize that the water is spilling over the dam and it is time to head for shore. Children who are overtired and having a tantrum can’t participate in a rational discussion about their feelings. If that dialogue needs to happen, and that is seldom, it should be the next day after the parent has time to consider his or her own mistakes.

When it comes to managing misbehaving children, I prefer well-tailored consequences and my favorite is a humanely crafted time-out. When presented and executed properly, a time-out can break the cycle of misbehavior and give both parent and child a chance to reconsider their positions.

But at 7 p.m. on a Friday evening in a busy restaurant, neither a time-out nor philosophizing with a 3-year-old is going to work. It’s time to ask for the check and head home to bed.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

ABSTRACT

The injury parameters and patient characteristics that affect function after scapular fracture are poorly defined. We performed a retrospective review of 594 adult patients with a minimum 12-month follow-up after scapular fracture. Functional outcomes were prospectively assessed using the American Shoulder and Elbow Surgeons (ASES) survey in 153 patients after a mean of 62 months of follow-up. The population was 78% male, and 88% had injuries caused by a high-energy event. Only 4.6% had injuries isolated to the scapula. All fractures healed primarily and the mean ASES score was 79.3, indicating minimal functional impairment. However, 7 patients (4.6%) reported severe functional deficits. Fifteen patients (9.8%) underwent open reduction and internal fixation. These patients had a better mean ASES score than those who were treated nonoperatively (92.1 vs 77.9, P = .03). When fracture types were analyzed individually, there was an advantage to surgery in fractures involving the glenoid (96.0 vs 75.7, P < .05). Concomitant chest wall injury or the presence of adjacent fractures did not affect functional outcomes. Smokers had a worse mean score (73.3 vs 84.5, P = .01), as did patients with a history of alcohol abuse (70.3 vs 83.9, P < .05). In conclusion, mean ASES scores indicated good function overall. Patients with a history of tobacco use or alcohol abuse had worse outcome scores.

Continue to: Scapular fractures occur frequently due to high-energy trauma...

Scapular fractures occur frequently due to high-energy trauma, with concomitant injuries seen in approximately 90% of cases.^1-4 As a result, treatment is often surrounded by other difficult medical decisions, and factors affecting outcomes can be multifaceted. The gaps in our understanding of long-term outcomes with current treatment modalities have recently come to light, especially when it comes to determining indications for surgery.

Specifically, there is very little literature on radiographic healing and long-term shoulder function in larger samples of scapular fractures; additionally, there is evidence that some patients do not experience full functional recovery.^3,5-7 Studies assessing return of function in patients treated nonoperatively have shown decreased mobility and persistence of pain.⁷ Some of these findings could be due to variability in surgical indications.^2,4 While the majority of fractures are treated nonoperatively, the decision to operate has recently been one of debate. Prior literature has suggested highly variable measurements of angulation and extra-articular displacement at which surgery is recommended.¹ For example, indications for surgery measured by the medial displacement of extra-articular fractures range from >10 mm to >20 mm;^8-11 similarly, the displacement of intra-articular fractures meriting surgery ranges from >2 mm to >5 mm, depending on the author.^12-16

The current debate over surgical indications for less severe scapular fractures, as well as the potential for chronic pain and stiffness calls for a thorough examination of factors affecting functional outcomes. The purpose of this study is to determine which patient factors, fracture patterns, and treatment modalities were associated with differences in healing and return of shoulder function. We hypothesized that certain aspects of the patient’s social history (tobacco, alcohol) as well as concomitant chest wall injuries may be associated with poor outcome scores and lower levels of function. We further hypothesized that glenoid fractures would affect function more than body fractures, and we did not expect to see a significant difference in outcomes between operative and nonoperative treatment.

MATERIALS AND METHODS

This study was approved by the Institutional Review Board. A registry at our level 1 trauma center was queried to identify 663 skeletally mature patients with scapular fractures between 1999 and 2011. Forty-eight patients had died prior to the study, and 21 patients had insufficient radiography and/or clinical follow-up (Figure 1). To be included, patients were required to have at least 1 year of follow-up to assess healing. Data on patient demographics, fracture classification, etiology of injury, concomitant injuries (clavicle fractures, rib fractures, pulmonary injuries), comorbidities, alcohol use, and tobacco use were collected retrospectively for the remaining 594 patients. Patients were then prospectively contacted via telephone and mail, employing 3 Internet search engines as needed, in an attempt to obtain current contact information. Three patients declined to participate, and 438 were not reachable after multiple attempts. Outcome scores for the remaining 153 patients were determined with the Modified American Shoulder and Elbow Surgeons (ASES) Shoulder Form.¹⁷ Scores were measured out of 100, with 0 to 30 representing maximally impaired, 31 to 60 representing moderately impaired, and 61 to 100 representing minimally impaired shoulder function.¹⁸ Due to the retrospective identification of the patients, no pre-injury shoulder function scores were collected. Given that many patients were unreachable, or reachable but not living in close proximity to the hospital, patients did not routinely return for re-evaluation for this study.

Nonoperative management consisted of sling immobilization for comfort for up to 2 weeks, during which time Codman’s exercises and elbow, forearm, wrist, and hand motion were encouraged. Active and passive shoulder mobility without restriction were also recommended progressively as tolerated. Strengthening and unrestricted lifting activities were allowed after approximately 8 to 10 weeks following the injury. Decision for surgery was at the surgeon’s discretion. Surgical indications included articular displacement and severely displaced glenoid neck fractures. Open reduction and internal fixation was performed by 1 of 4 fellowship-trained surgeons. Concomitant surgical procedures were not undertaken in the same setting. Postoperative activity consisted of sling immobilization for comfort for up to 6 weeks, during which time active and passive shoulder mobility without restriction were also recommended progressively as tolerated. Strengthening and unrestricted lifting activities were allowed after approximately 12 weeks following surgery. We considered fractures as healed if either X-rays showed healing progression to complete union or early X-rays showing signs of healing with subsequent follow-up visits indicating clinical healing (absence of pain, absence of shoulder dysfunction).

Continue to: STATISTICAL ANALYSIS...

STATISTICAL ANALYSIS

Statistical analysis was undertaken with GraphPad software. Associations were tested between positive predictive variables and functional outcomes. Variables included gender, mechanism, fracture classification, patient comorbidities, social factors, associated injuries, and type of treatment. A Mann-Whitney rank test was used to test for associations between nonparametric variables, including patient age. In all cases, P < .05 was considered significant.

RESULTS

Complete clinical and radiographic data were available for 594 patients. This included 462 men and 132 women, with a mean age of 42.8 years (range, 15-92 years). Twenty-four patients (4.0%) sustained bilateral fractures, and 31 fractures (5.0%) were open. All fractures healed primarily. A total of 153 patients completed the ASES questionnaire at a mean of 62 months after injury (Table 1). This group was similar to the entire population with respect to age, gender, and type of treatment. In all, 135 patients had been injured by a high-energy mechanism (88%), and the fracture pattern as per the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) classification consisted of 14A (no glenoid involvement) (n = 139; 91%) and 14B/C (glenoid involvement) (n = 14; 9.2%).¹⁹ The mean ASES score for our entire sample was 79.3 (minimally functionally impaired). In all, 117 patients (76%) reported minimal functional deficit (ASES, 61-100), 29 (19%) reported moderate functional deficit (ASES, 31-60), and only 7 (4.6%) reported maximum functional deficit (ASES, 0-30). Gender and age were not associated with functional outcome scores.

Table 1. Patient Demographics and Etiology of Scapula Fractures.

Fifteen patients (9.8%) were treated surgically. They had a higher mean ASES score vs non-surgically treated patients (92.1 vs 77.9; P = .03) (Table 2). However, when patients were divided into 14A and 14B/C fracture patterns, there was only a significant advantage in outcome scores for operative vs nonoperative care in the 14B/C classification (96.0 vs 75.7; P < .05); meanwhile, surgery for scapular body fractures (14A) was not associated with better outcome scores (90.2 vs 78.3; P = .14). Unfortunately, assessment of these comparisons within classification groups resulted in underpowered analyses for these small groups.

Table 2. Number of ASES Surveys Completed and Mean ASES Score for Each Treatment Type and Fracture Classification

^aP < 0.05.

Abbreviation: ASES, American Shoulder and Elbow Surgeons.

Table 3 shows the ASES scores for patients with various types of associated chest and shoulder injuries. Only 7 patients (4.6%) had injuries isolated to the scapula. Thirty-three patients (22%) had associated clavicle fractures, and 102 patients (67%) sustained concomitant chest wall injuries, including rib fractures (n = 88) and pulmonary injuries (n = 71). Patients with associated chest wall injuries did not have worse mean ASES scores than those without chest wall injuries (80.9 vs 78.2; P = .49). Additionally, patients who had concomitant clavicle fractures did not report worse scores than those who did not (83.2 vs 78.6; P = .46).

Table 3. Concomitant Injuries and Mean American Shoulder and Elbow Surgeons (ASES) Scores

The majority of patients were self-reported smokers (54%) and alcohol drinkers (64%) (Table 4). Aspects of social history were associated with differences in functional outcome scores. Non-smokers had a higher mean ASES score than both current smokers (84.5 vs 72.8; P = .02) and patients with any lifetime history of smoking (84.5 vs 73.3; P = .01) (Figure 2). There was no significant difference in shoulder function scores between patients identified as non-drinkers and those who reported consuming alcohol at moderate levels (83.9 vs 78.9; P = .26); however, patients who had a documented history of alcohol abuse had lower mean ASES scores than those who reported being non-drinkers (70.3 vs 83.9; P < .05).

Table 4. Substance Use and Functional Outcome Scores

^aP < 0.05.

Continue to: DISCUSSION...

DISCUSSION

Patients with scapular fractures often require a complex set of treatment decisions due to high rates of concomitant injuries.^2,20-22 A lack of large studies on long-term scapular function, as well as evidence that some patients treated conservatively for scapular fractures experience functional deficit and pain, inspired us to investigate the recovery process after scapular fractures through radiographs and the ASES survey.⁷ Further, we attempted to identify any factors that may be associated with poor functional results. Our review of long-term outcomes after scapular fractures demonstrates that they not only heal well but also have a good functional outcome in most cases. Over 95% had acceptable ASES scores, with both 14A and 14B/C having similar return of function. While both operatively and nonoperatively treated patients had scores indicating minimal functional impairment, those treated surgically had better scores overall. Surprisingly, concomitant injuries, including chest wall injuries, did not portend a worse shoulder outcome in our patients. The factors that were associated with worse outcome were tobacco use and alcohol abuse.

Beyond these findings, we attempted to comment on surgical indications, which have been highly debated.^2,3 For example, the medial displacement at which studies suggest extra-articular fractures merit surgery ranges from >10 mm to >20 mm;^8-11 similarly, the indication for surgery based on displacement of intra-articular fractures ranges from >2 mm to >5 mm, depending on the author.^12-16 Glenoid articular fractures or neck fractures are other potential indications for operative treatment. In fact, a review of 520 scapular fractures from multiple studies found that 80% of those with glenoid involvement were treated operatively, while only 52% of those with exclusive acromion and/or coracoid involvement, and 1% of those with exclusive scapular body involvement were treated operatively.⁵ Some reports indicate that 14B/C fractures, especially those that are displaced or complex, show good functional outcomes and low complication rates after fixation.^5,23 In this study, articular fractures of the glenoid were treated operatively more often than extra-articular fractures. We attempted to determine the impact of surgical care on functional outcomes according to fracture type, but we were limited by the small number of surgical patients when reviewing the 14A and 14B/C groups. As a whole, surgical patients had better outcomes than non-surgical patients. We believe this difference is clinically relevant and suggests a potential group of patients who may benefit from fixation. Further investigation is needed to better characterize these injuries and to develop specific recommendations.

This study yielded interesting results related to substance abuse. It has previously been shown that tobacco smoking and alcohol abuse have both been associated with poor bone health.²⁴ Studies have suggested that exposure to nicotine and other chemical components in cigarettes can lead to delayed healing, higher rates of nonunion, and decreased mechanical strength of bone.^25-29 Additionally, alcohol abuse has been associated with decreased bone mass and poor bone formation.^24,30,31 Although we did not measure bone density or quantitate time of healing, this study provides added insight in that the healed fractures of smokers and patients with a history of alcohol abuse showed lower levels of shoulder function, as measured by ASES scores after similar initial injuries and similar follow-up periods. These results suggest that chemical, social, or a combination of these factors affect muscular recovery, other aspects of post-fracture recovery, and/or levels of baseline physical or mental impairment beyond those detailed in previous studies of bone health and substance abuse. For example, return to work was a scored category in the ASES survey that we used to asses the return of shoulder function, and several studies have shown that factors such as education level, coping abilities, and baseline functioning (cognitive, social, and physical) all have a significant impact on rates of return to work, independently of injury type.^6,32-35 It is possible, then, that other aspects of the ASES survey are affected by factors that may be more prevalent in populations engaging in substance abuse. From both perspectives, these data highlight the importance of addressing tobacco use and alcohol abuse as a part of caring for all trauma patients, including those with scapular fractures, regardless of their high rates of radiographic healing. They also provide insight for prognosticating and setting patient expectations after scapular fractures.

Continue to: This study addressed the relationship between...

This study addressed the relationship between concomitant chest wall injuries and recovery of shoulder function after scapular fracture. Previous studies have suggested that concomitant chest wall injuries, such as rib fractures, cause more pain and may adversely impact the return of function in patients who have sustained scapular body fractures.¹ These results, however, occurred in the setting of a much shorter follow-up, in which Disability of Arm, Shoulder, and Hand (DASH) surveys were distributed 6 months post-injury, 12 months post-injury, and once at last follow-up (<3 years). At our significantly later average follow-up, chest wall injuries did not portend a worse return of shoulder function, in contrast to our hypothesis. Our lack of findings of a worse return of function in patients with chest wall injuries, in light of previous literature, suggests that this association could become less distinct as the initial injury becomes more remote and has had more time to heal. Farther out from injury, patients seem to function similarly, regardless of chest wall injury history.

This study was limited by several factors. First, the surgically treated group was considerably smaller than the nonoperative group, which made drawing statistically significant comparisons between them challenging. Although there were no apparent differences between the group who completed ASES surveys and those who did not, only collecting ASES data on 153 of the 663 patients introduces a possible selection bias in this analysis. Additionally, due to the retrospective nature of this study, we were not able to ascertain the specific surgical indications used by individual surgeons. Again, the nature of this study also made it implausible to separate fractures beyond the simple 14A vs 14B/C classification. For example, we did not routinely have access to computed tomography scans to provide exact measurements of displacement, angulation, or step-off; therefore, we were unable to compare our fracture parameters to those mentioned in studies with more specific surgical indications. We also did not have information regarding pre-existing shoulder dysfunction, which could negatively affect ASES scores. Finally, accurate measures of certain social history factors can be difficult to achieve; smoking, alcohol consumption, and alcohol abuse may be subject to underreporting.

CONCLUSION

We assessed parameters that may affect return of shoulder function after scapular fracture. Our results indicate that both 14A and 14B/C fractures have similarly high rates of healing and minimal functional impairment. Patients treated operatively typically had better shoulder functional outcomes. Current or past tobacco use or alcohol abuse was associated with worse functional outcome scores. This could suggest chemical, social, or a combination of these factors affecting muscular recovery and/or greater levels of baseline functional impairment. Finally, concomitant chest wall injuries may not negatively affect shoulder outcome, contrasting with data from previous studies on the more immediate post-injury period.

ABSTRACT

The injury parameters and patient characteristics that affect function after scapular fracture are poorly defined. We performed a retrospective review of 594 adult patients with a minimum 12-month follow-up after scapular fracture. Functional outcomes were prospectively assessed using the American Shoulder and Elbow Surgeons (ASES) survey in 153 patients after a mean of 62 months of follow-up. The population was 78% male, and 88% had injuries caused by a high-energy event. Only 4.6% had injuries isolated to the scapula. All fractures healed primarily and the mean ASES score was 79.3, indicating minimal functional impairment. However, 7 patients (4.6%) reported severe functional deficits. Fifteen patients (9.8%) underwent open reduction and internal fixation. These patients had a better mean ASES score than those who were treated nonoperatively (92.1 vs 77.9, P = .03). When fracture types were analyzed individually, there was an advantage to surgery in fractures involving the glenoid (96.0 vs 75.7, P < .05). Concomitant chest wall injury or the presence of adjacent fractures did not affect functional outcomes. Smokers had a worse mean score (73.3 vs 84.5, P = .01), as did patients with a history of alcohol abuse (70.3 vs 83.9, P < .05). In conclusion, mean ASES scores indicated good function overall. Patients with a history of tobacco use or alcohol abuse had worse outcome scores.

Continue to: Scapular fractures occur frequently due to high-energy trauma...

Scapular fractures occur frequently due to high-energy trauma, with concomitant injuries seen in approximately 90% of cases.^1-4 As a result, treatment is often surrounded by other difficult medical decisions, and factors affecting outcomes can be multifaceted. The gaps in our understanding of long-term outcomes with current treatment modalities have recently come to light, especially when it comes to determining indications for surgery.

Specifically, there is very little literature on radiographic healing and long-term shoulder function in larger samples of scapular fractures; additionally, there is evidence that some patients do not experience full functional recovery.^3,5-7 Studies assessing return of function in patients treated nonoperatively have shown decreased mobility and persistence of pain.⁷ Some of these findings could be due to variability in surgical indications.^2,4 While the majority of fractures are treated nonoperatively, the decision to operate has recently been one of debate. Prior literature has suggested highly variable measurements of angulation and extra-articular displacement at which surgery is recommended.¹ For example, indications for surgery measured by the medial displacement of extra-articular fractures range from >10 mm to >20 mm;^8-11 similarly, the displacement of intra-articular fractures meriting surgery ranges from >2 mm to >5 mm, depending on the author.^12-16

The current debate over surgical indications for less severe scapular fractures, as well as the potential for chronic pain and stiffness calls for a thorough examination of factors affecting functional outcomes. The purpose of this study is to determine which patient factors, fracture patterns, and treatment modalities were associated with differences in healing and return of shoulder function. We hypothesized that certain aspects of the patient’s social history (tobacco, alcohol) as well as concomitant chest wall injuries may be associated with poor outcome scores and lower levels of function. We further hypothesized that glenoid fractures would affect function more than body fractures, and we did not expect to see a significant difference in outcomes between operative and nonoperative treatment.

MATERIALS AND METHODS

This study was approved by the Institutional Review Board. A registry at our level 1 trauma center was queried to identify 663 skeletally mature patients with scapular fractures between 1999 and 2011. Forty-eight patients had died prior to the study, and 21 patients had insufficient radiography and/or clinical follow-up (Figure 1). To be included, patients were required to have at least 1 year of follow-up to assess healing. Data on patient demographics, fracture classification, etiology of injury, concomitant injuries (clavicle fractures, rib fractures, pulmonary injuries), comorbidities, alcohol use, and tobacco use were collected retrospectively for the remaining 594 patients. Patients were then prospectively contacted via telephone and mail, employing 3 Internet search engines as needed, in an attempt to obtain current contact information. Three patients declined to participate, and 438 were not reachable after multiple attempts. Outcome scores for the remaining 153 patients were determined with the Modified American Shoulder and Elbow Surgeons (ASES) Shoulder Form.¹⁷ Scores were measured out of 100, with 0 to 30 representing maximally impaired, 31 to 60 representing moderately impaired, and 61 to 100 representing minimally impaired shoulder function.¹⁸ Due to the retrospective identification of the patients, no pre-injury shoulder function scores were collected. Given that many patients were unreachable, or reachable but not living in close proximity to the hospital, patients did not routinely return for re-evaluation for this study.

Nonoperative management consisted of sling immobilization for comfort for up to 2 weeks, during which time Codman’s exercises and elbow, forearm, wrist, and hand motion were encouraged. Active and passive shoulder mobility without restriction were also recommended progressively as tolerated. Strengthening and unrestricted lifting activities were allowed after approximately 8 to 10 weeks following the injury. Decision for surgery was at the surgeon’s discretion. Surgical indications included articular displacement and severely displaced glenoid neck fractures. Open reduction and internal fixation was performed by 1 of 4 fellowship-trained surgeons. Concomitant surgical procedures were not undertaken in the same setting. Postoperative activity consisted of sling immobilization for comfort for up to 6 weeks, during which time active and passive shoulder mobility without restriction were also recommended progressively as tolerated. Strengthening and unrestricted lifting activities were allowed after approximately 12 weeks following surgery. We considered fractures as healed if either X-rays showed healing progression to complete union or early X-rays showing signs of healing with subsequent follow-up visits indicating clinical healing (absence of pain, absence of shoulder dysfunction).

Continue to: STATISTICAL ANALYSIS...

STATISTICAL ANALYSIS

Statistical analysis was undertaken with GraphPad software. Associations were tested between positive predictive variables and functional outcomes. Variables included gender, mechanism, fracture classification, patient comorbidities, social factors, associated injuries, and type of treatment. A Mann-Whitney rank test was used to test for associations between nonparametric variables, including patient age. In all cases, P < .05 was considered significant.

RESULTS

Complete clinical and radiographic data were available for 594 patients. This included 462 men and 132 women, with a mean age of 42.8 years (range, 15-92 years). Twenty-four patients (4.0%) sustained bilateral fractures, and 31 fractures (5.0%) were open. All fractures healed primarily. A total of 153 patients completed the ASES questionnaire at a mean of 62 months after injury (Table 1). This group was similar to the entire population with respect to age, gender, and type of treatment. In all, 135 patients had been injured by a high-energy mechanism (88%), and the fracture pattern as per the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) classification consisted of 14A (no glenoid involvement) (n = 139; 91%) and 14B/C (glenoid involvement) (n = 14; 9.2%).¹⁹ The mean ASES score for our entire sample was 79.3 (minimally functionally impaired). In all, 117 patients (76%) reported minimal functional deficit (ASES, 61-100), 29 (19%) reported moderate functional deficit (ASES, 31-60), and only 7 (4.6%) reported maximum functional deficit (ASES, 0-30). Gender and age were not associated with functional outcome scores.

Table 1. Patient Demographics and Etiology of Scapula Fractures.

Fifteen patients (9.8%) were treated surgically. They had a higher mean ASES score vs non-surgically treated patients (92.1 vs 77.9; P = .03) (Table 2). However, when patients were divided into 14A and 14B/C fracture patterns, there was only a significant advantage in outcome scores for operative vs nonoperative care in the 14B/C classification (96.0 vs 75.7; P < .05); meanwhile, surgery for scapular body fractures (14A) was not associated with better outcome scores (90.2 vs 78.3; P = .14). Unfortunately, assessment of these comparisons within classification groups resulted in underpowered analyses for these small groups.

Table 2. Number of ASES Surveys Completed and Mean ASES Score for Each Treatment Type and Fracture Classification

^aP < 0.05.

Abbreviation: ASES, American Shoulder and Elbow Surgeons.

Table 3 shows the ASES scores for patients with various types of associated chest and shoulder injuries. Only 7 patients (4.6%) had injuries isolated to the scapula. Thirty-three patients (22%) had associated clavicle fractures, and 102 patients (67%) sustained concomitant chest wall injuries, including rib fractures (n = 88) and pulmonary injuries (n = 71). Patients with associated chest wall injuries did not have worse mean ASES scores than those without chest wall injuries (80.9 vs 78.2; P = .49). Additionally, patients who had concomitant clavicle fractures did not report worse scores than those who did not (83.2 vs 78.6; P = .46).

Table 3. Concomitant Injuries and Mean American Shoulder and Elbow Surgeons (ASES) Scores

The majority of patients were self-reported smokers (54%) and alcohol drinkers (64%) (Table 4). Aspects of social history were associated with differences in functional outcome scores. Non-smokers had a higher mean ASES score than both current smokers (84.5 vs 72.8; P = .02) and patients with any lifetime history of smoking (84.5 vs 73.3; P = .01) (Figure 2). There was no significant difference in shoulder function scores between patients identified as non-drinkers and those who reported consuming alcohol at moderate levels (83.9 vs 78.9; P = .26); however, patients who had a documented history of alcohol abuse had lower mean ASES scores than those who reported being non-drinkers (70.3 vs 83.9; P < .05).

Table 4. Substance Use and Functional Outcome Scores

^aP < 0.05.

Continue to: DISCUSSION...

DISCUSSION

Patients with scapular fractures often require a complex set of treatment decisions due to high rates of concomitant injuries.^2,20-22 A lack of large studies on long-term scapular function, as well as evidence that some patients treated conservatively for scapular fractures experience functional deficit and pain, inspired us to investigate the recovery process after scapular fractures through radiographs and the ASES survey.⁷ Further, we attempted to identify any factors that may be associated with poor functional results. Our review of long-term outcomes after scapular fractures demonstrates that they not only heal well but also have a good functional outcome in most cases. Over 95% had acceptable ASES scores, with both 14A and 14B/C having similar return of function. While both operatively and nonoperatively treated patients had scores indicating minimal functional impairment, those treated surgically had better scores overall. Surprisingly, concomitant injuries, including chest wall injuries, did not portend a worse shoulder outcome in our patients. The factors that were associated with worse outcome were tobacco use and alcohol abuse.

Beyond these findings, we attempted to comment on surgical indications, which have been highly debated.^2,3 For example, the medial displacement at which studies suggest extra-articular fractures merit surgery ranges from >10 mm to >20 mm;^8-11 similarly, the indication for surgery based on displacement of intra-articular fractures ranges from >2 mm to >5 mm, depending on the author.^12-16 Glenoid articular fractures or neck fractures are other potential indications for operative treatment. In fact, a review of 520 scapular fractures from multiple studies found that 80% of those with glenoid involvement were treated operatively, while only 52% of those with exclusive acromion and/or coracoid involvement, and 1% of those with exclusive scapular body involvement were treated operatively.⁵ Some reports indicate that 14B/C fractures, especially those that are displaced or complex, show good functional outcomes and low complication rates after fixation.^5,23 In this study, articular fractures of the glenoid were treated operatively more often than extra-articular fractures. We attempted to determine the impact of surgical care on functional outcomes according to fracture type, but we were limited by the small number of surgical patients when reviewing the 14A and 14B/C groups. As a whole, surgical patients had better outcomes than non-surgical patients. We believe this difference is clinically relevant and suggests a potential group of patients who may benefit from fixation. Further investigation is needed to better characterize these injuries and to develop specific recommendations.

This study yielded interesting results related to substance abuse. It has previously been shown that tobacco smoking and alcohol abuse have both been associated with poor bone health.²⁴ Studies have suggested that exposure to nicotine and other chemical components in cigarettes can lead to delayed healing, higher rates of nonunion, and decreased mechanical strength of bone.^25-29 Additionally, alcohol abuse has been associated with decreased bone mass and poor bone formation.^24,30,31 Although we did not measure bone density or quantitate time of healing, this study provides added insight in that the healed fractures of smokers and patients with a history of alcohol abuse showed lower levels of shoulder function, as measured by ASES scores after similar initial injuries and similar follow-up periods. These results suggest that chemical, social, or a combination of these factors affect muscular recovery, other aspects of post-fracture recovery, and/or levels of baseline physical or mental impairment beyond those detailed in previous studies of bone health and substance abuse. For example, return to work was a scored category in the ASES survey that we used to asses the return of shoulder function, and several studies have shown that factors such as education level, coping abilities, and baseline functioning (cognitive, social, and physical) all have a significant impact on rates of return to work, independently of injury type.^6,32-35 It is possible, then, that other aspects of the ASES survey are affected by factors that may be more prevalent in populations engaging in substance abuse. From both perspectives, these data highlight the importance of addressing tobacco use and alcohol abuse as a part of caring for all trauma patients, including those with scapular fractures, regardless of their high rates of radiographic healing. They also provide insight for prognosticating and setting patient expectations after scapular fractures.

Continue to: This study addressed the relationship between...

This study addressed the relationship between concomitant chest wall injuries and recovery of shoulder function after scapular fracture. Previous studies have suggested that concomitant chest wall injuries, such as rib fractures, cause more pain and may adversely impact the return of function in patients who have sustained scapular body fractures.¹ These results, however, occurred in the setting of a much shorter follow-up, in which Disability of Arm, Shoulder, and Hand (DASH) surveys were distributed 6 months post-injury, 12 months post-injury, and once at last follow-up (<3 years). At our significantly later average follow-up, chest wall injuries did not portend a worse return of shoulder function, in contrast to our hypothesis. Our lack of findings of a worse return of function in patients with chest wall injuries, in light of previous literature, suggests that this association could become less distinct as the initial injury becomes more remote and has had more time to heal. Farther out from injury, patients seem to function similarly, regardless of chest wall injury history.

This study was limited by several factors. First, the surgically treated group was considerably smaller than the nonoperative group, which made drawing statistically significant comparisons between them challenging. Although there were no apparent differences between the group who completed ASES surveys and those who did not, only collecting ASES data on 153 of the 663 patients introduces a possible selection bias in this analysis. Additionally, due to the retrospective nature of this study, we were not able to ascertain the specific surgical indications used by individual surgeons. Again, the nature of this study also made it implausible to separate fractures beyond the simple 14A vs 14B/C classification. For example, we did not routinely have access to computed tomography scans to provide exact measurements of displacement, angulation, or step-off; therefore, we were unable to compare our fracture parameters to those mentioned in studies with more specific surgical indications. We also did not have information regarding pre-existing shoulder dysfunction, which could negatively affect ASES scores. Finally, accurate measures of certain social history factors can be difficult to achieve; smoking, alcohol consumption, and alcohol abuse may be subject to underreporting.

CONCLUSION

We assessed parameters that may affect return of shoulder function after scapular fracture. Our results indicate that both 14A and 14B/C fractures have similarly high rates of healing and minimal functional impairment. Patients treated operatively typically had better shoulder functional outcomes. Current or past tobacco use or alcohol abuse was associated with worse functional outcome scores. This could suggest chemical, social, or a combination of these factors affecting muscular recovery and/or greater levels of baseline functional impairment. Finally, concomitant chest wall injuries may not negatively affect shoulder outcome, contrasting with data from previous studies on the more immediate post-injury period.

ABSTRACT

The injury parameters and patient characteristics that affect function after scapular fracture are poorly defined. We performed a retrospective review of 594 adult patients with a minimum 12-month follow-up after scapular fracture. Functional outcomes were prospectively assessed using the American Shoulder and Elbow Surgeons (ASES) survey in 153 patients after a mean of 62 months of follow-up. The population was 78% male, and 88% had injuries caused by a high-energy event. Only 4.6% had injuries isolated to the scapula. All fractures healed primarily and the mean ASES score was 79.3, indicating minimal functional impairment. However, 7 patients (4.6%) reported severe functional deficits. Fifteen patients (9.8%) underwent open reduction and internal fixation. These patients had a better mean ASES score than those who were treated nonoperatively (92.1 vs 77.9, P = .03). When fracture types were analyzed individually, there was an advantage to surgery in fractures involving the glenoid (96.0 vs 75.7, P < .05). Concomitant chest wall injury or the presence of adjacent fractures did not affect functional outcomes. Smokers had a worse mean score (73.3 vs 84.5, P = .01), as did patients with a history of alcohol abuse (70.3 vs 83.9, P < .05). In conclusion, mean ASES scores indicated good function overall. Patients with a history of tobacco use or alcohol abuse had worse outcome scores.

Continue to: Scapular fractures occur frequently due to high-energy trauma...

Scapular fractures occur frequently due to high-energy trauma, with concomitant injuries seen in approximately 90% of cases.^1-4 As a result, treatment is often surrounded by other difficult medical decisions, and factors affecting outcomes can be multifaceted. The gaps in our understanding of long-term outcomes with current treatment modalities have recently come to light, especially when it comes to determining indications for surgery.

Specifically, there is very little literature on radiographic healing and long-term shoulder function in larger samples of scapular fractures; additionally, there is evidence that some patients do not experience full functional recovery.^3,5-7 Studies assessing return of function in patients treated nonoperatively have shown decreased mobility and persistence of pain.⁷ Some of these findings could be due to variability in surgical indications.^2,4 While the majority of fractures are treated nonoperatively, the decision to operate has recently been one of debate. Prior literature has suggested highly variable measurements of angulation and extra-articular displacement at which surgery is recommended.¹ For example, indications for surgery measured by the medial displacement of extra-articular fractures range from >10 mm to >20 mm;^8-11 similarly, the displacement of intra-articular fractures meriting surgery ranges from >2 mm to >5 mm, depending on the author.^12-16

The current debate over surgical indications for less severe scapular fractures, as well as the potential for chronic pain and stiffness calls for a thorough examination of factors affecting functional outcomes. The purpose of this study is to determine which patient factors, fracture patterns, and treatment modalities were associated with differences in healing and return of shoulder function. We hypothesized that certain aspects of the patient’s social history (tobacco, alcohol) as well as concomitant chest wall injuries may be associated with poor outcome scores and lower levels of function. We further hypothesized that glenoid fractures would affect function more than body fractures, and we did not expect to see a significant difference in outcomes between operative and nonoperative treatment.

MATERIALS AND METHODS

This study was approved by the Institutional Review Board. A registry at our level 1 trauma center was queried to identify 663 skeletally mature patients with scapular fractures between 1999 and 2011. Forty-eight patients had died prior to the study, and 21 patients had insufficient radiography and/or clinical follow-up (Figure 1). To be included, patients were required to have at least 1 year of follow-up to assess healing. Data on patient demographics, fracture classification, etiology of injury, concomitant injuries (clavicle fractures, rib fractures, pulmonary injuries), comorbidities, alcohol use, and tobacco use were collected retrospectively for the remaining 594 patients. Patients were then prospectively contacted via telephone and mail, employing 3 Internet search engines as needed, in an attempt to obtain current contact information. Three patients declined to participate, and 438 were not reachable after multiple attempts. Outcome scores for the remaining 153 patients were determined with the Modified American Shoulder and Elbow Surgeons (ASES) Shoulder Form.¹⁷ Scores were measured out of 100, with 0 to 30 representing maximally impaired, 31 to 60 representing moderately impaired, and 61 to 100 representing minimally impaired shoulder function.¹⁸ Due to the retrospective identification of the patients, no pre-injury shoulder function scores were collected. Given that many patients were unreachable, or reachable but not living in close proximity to the hospital, patients did not routinely return for re-evaluation for this study.

Nonoperative management consisted of sling immobilization for comfort for up to 2 weeks, during which time Codman’s exercises and elbow, forearm, wrist, and hand motion were encouraged. Active and passive shoulder mobility without restriction were also recommended progressively as tolerated. Strengthening and unrestricted lifting activities were allowed after approximately 8 to 10 weeks following the injury. Decision for surgery was at the surgeon’s discretion. Surgical indications included articular displacement and severely displaced glenoid neck fractures. Open reduction and internal fixation was performed by 1 of 4 fellowship-trained surgeons. Concomitant surgical procedures were not undertaken in the same setting. Postoperative activity consisted of sling immobilization for comfort for up to 6 weeks, during which time active and passive shoulder mobility without restriction were also recommended progressively as tolerated. Strengthening and unrestricted lifting activities were allowed after approximately 12 weeks following surgery. We considered fractures as healed if either X-rays showed healing progression to complete union or early X-rays showing signs of healing with subsequent follow-up visits indicating clinical healing (absence of pain, absence of shoulder dysfunction).

Continue to: STATISTICAL ANALYSIS...

STATISTICAL ANALYSIS

Statistical analysis was undertaken with GraphPad software. Associations were tested between positive predictive variables and functional outcomes. Variables included gender, mechanism, fracture classification, patient comorbidities, social factors, associated injuries, and type of treatment. A Mann-Whitney rank test was used to test for associations between nonparametric variables, including patient age. In all cases, P < .05 was considered significant.

RESULTS

Complete clinical and radiographic data were available for 594 patients. This included 462 men and 132 women, with a mean age of 42.8 years (range, 15-92 years). Twenty-four patients (4.0%) sustained bilateral fractures, and 31 fractures (5.0%) were open. All fractures healed primarily. A total of 153 patients completed the ASES questionnaire at a mean of 62 months after injury (Table 1). This group was similar to the entire population with respect to age, gender, and type of treatment. In all, 135 patients had been injured by a high-energy mechanism (88%), and the fracture pattern as per the Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association (AO/OTA) classification consisted of 14A (no glenoid involvement) (n = 139; 91%) and 14B/C (glenoid involvement) (n = 14; 9.2%).¹⁹ The mean ASES score for our entire sample was 79.3 (minimally functionally impaired). In all, 117 patients (76%) reported minimal functional deficit (ASES, 61-100), 29 (19%) reported moderate functional deficit (ASES, 31-60), and only 7 (4.6%) reported maximum functional deficit (ASES, 0-30). Gender and age were not associated with functional outcome scores.

Table 1. Patient Demographics and Etiology of Scapula Fractures.

Fifteen patients (9.8%) were treated surgically. They had a higher mean ASES score vs non-surgically treated patients (92.1 vs 77.9; P = .03) (Table 2). However, when patients were divided into 14A and 14B/C fracture patterns, there was only a significant advantage in outcome scores for operative vs nonoperative care in the 14B/C classification (96.0 vs 75.7; P < .05); meanwhile, surgery for scapular body fractures (14A) was not associated with better outcome scores (90.2 vs 78.3; P = .14). Unfortunately, assessment of these comparisons within classification groups resulted in underpowered analyses for these small groups.

Table 2. Number of ASES Surveys Completed and Mean ASES Score for Each Treatment Type and Fracture Classification

^aP < 0.05.

Abbreviation: ASES, American Shoulder and Elbow Surgeons.

Table 3 shows the ASES scores for patients with various types of associated chest and shoulder injuries. Only 7 patients (4.6%) had injuries isolated to the scapula. Thirty-three patients (22%) had associated clavicle fractures, and 102 patients (67%) sustained concomitant chest wall injuries, including rib fractures (n = 88) and pulmonary injuries (n = 71). Patients with associated chest wall injuries did not have worse mean ASES scores than those without chest wall injuries (80.9 vs 78.2; P = .49). Additionally, patients who had concomitant clavicle fractures did not report worse scores than those who did not (83.2 vs 78.6; P = .46).

Table 3. Concomitant Injuries and Mean American Shoulder and Elbow Surgeons (ASES) Scores

The majority of patients were self-reported smokers (54%) and alcohol drinkers (64%) (Table 4). Aspects of social history were associated with differences in functional outcome scores. Non-smokers had a higher mean ASES score than both current smokers (84.5 vs 72.8; P = .02) and patients with any lifetime history of smoking (84.5 vs 73.3; P = .01) (Figure 2). There was no significant difference in shoulder function scores between patients identified as non-drinkers and those who reported consuming alcohol at moderate levels (83.9 vs 78.9; P = .26); however, patients who had a documented history of alcohol abuse had lower mean ASES scores than those who reported being non-drinkers (70.3 vs 83.9; P < .05).

Table 4. Substance Use and Functional Outcome Scores

^aP < 0.05.

Continue to: DISCUSSION...

DISCUSSION

Patients with scapular fractures often require a complex set of treatment decisions due to high rates of concomitant injuries.^2,20-22 A lack of large studies on long-term scapular function, as well as evidence that some patients treated conservatively for scapular fractures experience functional deficit and pain, inspired us to investigate the recovery process after scapular fractures through radiographs and the ASES survey.⁷ Further, we attempted to identify any factors that may be associated with poor functional results. Our review of long-term outcomes after scapular fractures demonstrates that they not only heal well but also have a good functional outcome in most cases. Over 95% had acceptable ASES scores, with both 14A and 14B/C having similar return of function. While both operatively and nonoperatively treated patients had scores indicating minimal functional impairment, those treated surgically had better scores overall. Surprisingly, concomitant injuries, including chest wall injuries, did not portend a worse shoulder outcome in our patients. The factors that were associated with worse outcome were tobacco use and alcohol abuse.

Beyond these findings, we attempted to comment on surgical indications, which have been highly debated.^2,3 For example, the medial displacement at which studies suggest extra-articular fractures merit surgery ranges from >10 mm to >20 mm;^8-11 similarly, the indication for surgery based on displacement of intra-articular fractures ranges from >2 mm to >5 mm, depending on the author.^12-16 Glenoid articular fractures or neck fractures are other potential indications for operative treatment. In fact, a review of 520 scapular fractures from multiple studies found that 80% of those with glenoid involvement were treated operatively, while only 52% of those with exclusive acromion and/or coracoid involvement, and 1% of those with exclusive scapular body involvement were treated operatively.⁵ Some reports indicate that 14B/C fractures, especially those that are displaced or complex, show good functional outcomes and low complication rates after fixation.^5,23 In this study, articular fractures of the glenoid were treated operatively more often than extra-articular fractures. We attempted to determine the impact of surgical care on functional outcomes according to fracture type, but we were limited by the small number of surgical patients when reviewing the 14A and 14B/C groups. As a whole, surgical patients had better outcomes than non-surgical patients. We believe this difference is clinically relevant and suggests a potential group of patients who may benefit from fixation. Further investigation is needed to better characterize these injuries and to develop specific recommendations.

This study yielded interesting results related to substance abuse. It has previously been shown that tobacco smoking and alcohol abuse have both been associated with poor bone health.²⁴ Studies have suggested that exposure to nicotine and other chemical components in cigarettes can lead to delayed healing, higher rates of nonunion, and decreased mechanical strength of bone.^25-29 Additionally, alcohol abuse has been associated with decreased bone mass and poor bone formation.^24,30,31 Although we did not measure bone density or quantitate time of healing, this study provides added insight in that the healed fractures of smokers and patients with a history of alcohol abuse showed lower levels of shoulder function, as measured by ASES scores after similar initial injuries and similar follow-up periods. These results suggest that chemical, social, or a combination of these factors affect muscular recovery, other aspects of post-fracture recovery, and/or levels of baseline physical or mental impairment beyond those detailed in previous studies of bone health and substance abuse. For example, return to work was a scored category in the ASES survey that we used to asses the return of shoulder function, and several studies have shown that factors such as education level, coping abilities, and baseline functioning (cognitive, social, and physical) all have a significant impact on rates of return to work, independently of injury type.^6,32-35 It is possible, then, that other aspects of the ASES survey are affected by factors that may be more prevalent in populations engaging in substance abuse. From both perspectives, these data highlight the importance of addressing tobacco use and alcohol abuse as a part of caring for all trauma patients, including those with scapular fractures, regardless of their high rates of radiographic healing. They also provide insight for prognosticating and setting patient expectations after scapular fractures.

Continue to: This study addressed the relationship between...

This study addressed the relationship between concomitant chest wall injuries and recovery of shoulder function after scapular fracture. Previous studies have suggested that concomitant chest wall injuries, such as rib fractures, cause more pain and may adversely impact the return of function in patients who have sustained scapular body fractures.¹ These results, however, occurred in the setting of a much shorter follow-up, in which Disability of Arm, Shoulder, and Hand (DASH) surveys were distributed 6 months post-injury, 12 months post-injury, and once at last follow-up (<3 years). At our significantly later average follow-up, chest wall injuries did not portend a worse return of shoulder function, in contrast to our hypothesis. Our lack of findings of a worse return of function in patients with chest wall injuries, in light of previous literature, suggests that this association could become less distinct as the initial injury becomes more remote and has had more time to heal. Farther out from injury, patients seem to function similarly, regardless of chest wall injury history.

This study was limited by several factors. First, the surgically treated group was considerably smaller than the nonoperative group, which made drawing statistically significant comparisons between them challenging. Although there were no apparent differences between the group who completed ASES surveys and those who did not, only collecting ASES data on 153 of the 663 patients introduces a possible selection bias in this analysis. Additionally, due to the retrospective nature of this study, we were not able to ascertain the specific surgical indications used by individual surgeons. Again, the nature of this study also made it implausible to separate fractures beyond the simple 14A vs 14B/C classification. For example, we did not routinely have access to computed tomography scans to provide exact measurements of displacement, angulation, or step-off; therefore, we were unable to compare our fracture parameters to those mentioned in studies with more specific surgical indications. We also did not have information regarding pre-existing shoulder dysfunction, which could negatively affect ASES scores. Finally, accurate measures of certain social history factors can be difficult to achieve; smoking, alcohol consumption, and alcohol abuse may be subject to underreporting.

CONCLUSION

We assessed parameters that may affect return of shoulder function after scapular fracture. Our results indicate that both 14A and 14B/C fractures have similarly high rates of healing and minimal functional impairment. Patients treated operatively typically had better shoulder functional outcomes. Current or past tobacco use or alcohol abuse was associated with worse functional outcome scores. This could suggest chemical, social, or a combination of these factors affecting muscular recovery and/or greater levels of baseline functional impairment. Finally, concomitant chest wall injuries may not negatively affect shoulder outcome, contrasting with data from previous studies on the more immediate post-injury period.

Q2. Correct Answer: D 
 
Rationale  
This patient is on nadolol, a nonselective beta-blocker, for the primary prophylaxis of large esophageal varices. The dose of nonselective beta-blockers should be increased in a stepwise manner until the maximum tolerated dose or until a resting heart rate of 50-55/min is met. Since this patient is already at target heart rate, there is no indication to increase the dose. Repeat endoscopy is not indicated to assess change in size of varices once initiated on nonselective beta-blockers and at target heart rate. The choice between beta-blockers or endoscopic variceal ligation depends on local resources and expertise, patient preference and characteristics, side effects, and contraindications. Carvedilol, a nonselective beta-blocker with vasodilatory properties, is a promising alternative therapy that deserves further evaluation. However, given that nadolol has achieved target heart rate and patient is tolerating it, there is no indication to change management. 
 
Reference  
1. Garcia-Tsao G., Sanyal A.J., Grace N.D., Carey W.. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-38.  
2. Tripathi D., Ferguson J.W., Kochar N., et al. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology. 2009;50(3):825-33. 
 
[email protected]

Q2. Correct Answer: D 
 
Rationale  
This patient is on nadolol, a nonselective beta-blocker, for the primary prophylaxis of large esophageal varices. The dose of nonselective beta-blockers should be increased in a stepwise manner until the maximum tolerated dose or until a resting heart rate of 50-55/min is met. Since this patient is already at target heart rate, there is no indication to increase the dose. Repeat endoscopy is not indicated to assess change in size of varices once initiated on nonselective beta-blockers and at target heart rate. The choice between beta-blockers or endoscopic variceal ligation depends on local resources and expertise, patient preference and characteristics, side effects, and contraindications. Carvedilol, a nonselective beta-blocker with vasodilatory properties, is a promising alternative therapy that deserves further evaluation. However, given that nadolol has achieved target heart rate and patient is tolerating it, there is no indication to change management. 
 
Reference  
1. Garcia-Tsao G., Sanyal A.J., Grace N.D., Carey W.. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-38.  
2. Tripathi D., Ferguson J.W., Kochar N., et al. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology. 2009;50(3):825-33. 
 
[email protected]

Q2. Correct Answer: D 
 
Rationale  
This patient is on nadolol, a nonselective beta-blocker, for the primary prophylaxis of large esophageal varices. The dose of nonselective beta-blockers should be increased in a stepwise manner until the maximum tolerated dose or until a resting heart rate of 50-55/min is met. Since this patient is already at target heart rate, there is no indication to increase the dose. Repeat endoscopy is not indicated to assess change in size of varices once initiated on nonselective beta-blockers and at target heart rate. The choice between beta-blockers or endoscopic variceal ligation depends on local resources and expertise, patient preference and characteristics, side effects, and contraindications. Carvedilol, a nonselective beta-blocker with vasodilatory properties, is a promising alternative therapy that deserves further evaluation. However, given that nadolol has achieved target heart rate and patient is tolerating it, there is no indication to change management. 
 
Reference  
1. Garcia-Tsao G., Sanyal A.J., Grace N.D., Carey W.. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46(3):922-38.  
2. Tripathi D., Ferguson J.W., Kochar N., et al. Randomized controlled trial of carvedilol versus variceal band ligation for the prevention of the first variceal bleed. Hepatology. 2009;50(3):825-33. 
 
[email protected]

Q1. Correct Answer: D 
 
Rationale  
There is a risk of perineal trauma with vaginal delivery, and therefore, patients with active perianal Crohn's disease should undergo cesarean delivery to avoid exacerbation of disease. Patients without a history of perianal disease or those with inactive perianal disease have a low rate of relapse, and cesarean delivery is not warranted. Aside from patients with active perineal disease, the mode of delivery should be left to the discretion of the obstetrician. None of the other choices above, including ileal pouch-anal anastomosis, justify the decision to perform cesarean section.

Q1. Correct Answer: D 
 
Rationale  
There is a risk of perineal trauma with vaginal delivery, and therefore, patients with active perianal Crohn's disease should undergo cesarean delivery to avoid exacerbation of disease. Patients without a history of perianal disease or those with inactive perianal disease have a low rate of relapse, and cesarean delivery is not warranted. Aside from patients with active perineal disease, the mode of delivery should be left to the discretion of the obstetrician. None of the other choices above, including ileal pouch-anal anastomosis, justify the decision to perform cesarean section.

Q1. Correct Answer: D 
 
Rationale  
There is a risk of perineal trauma with vaginal delivery, and therefore, patients with active perianal Crohn's disease should undergo cesarean delivery to avoid exacerbation of disease. Patients without a history of perianal disease or those with inactive perianal disease have a low rate of relapse, and cesarean delivery is not warranted. Aside from patients with active perineal disease, the mode of delivery should be left to the discretion of the obstetrician. None of the other choices above, including ileal pouch-anal anastomosis, justify the decision to perform cesarean section.