Addressing SUD-related Comorbidities, such as Hepatitis, HIV, Depression, Anxiety,

and PTSDDevelopers:

Karla Thornton, MD, MPH, University of New Mexico Brant Hager MD, University of New Mexico Richard Ries MD, University of Washington

This project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under contract number HHSH250201600015C. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government.

DisclosuresDr. Karla Thornton has no information to disclose Dr. Hager has no conflicts of interest to disclose Dr Ries has Grant funding from:

NIH- NIDA-AFSP Harm Reduction Counseling and Injectable Naltrexone in Homeless persons with Severe Alcohol Dep. Preventing Addiction Related Suicide PTSD Treatment in Persons with Severe Cannabis Dep Contingency Management of Alcohol in Mentally Ill Comparing CAMS to TAU after recent suicide attempts

Dept of Defense Suicide Prevention in Active Duty Soldiers

Medical co-occurring disorders: focus on Hepatitis C

Hepatitis C

Karla Thornton, MD, MPHProfessor, Infectious Diseases

Associate Director, Project ECHOUniversity of New Mexico Health Sciences Center

Learning Objectives

• Describe the epidemiology of HCV in the United States

• Interpret HCV testing • Recognize the importance of addressing HCV

in the primary care setting

HCV Deaths and Deaths from Other Nationally Notifiable Infectious Diseases,* 2003- 2013

* TB, HIV, Hepatitis B and 57 other infectious conditions reported to CDC

Holmberg S, et al. “Continued Rising Mortality from Hepatitis C Virus in the United States, 2003-2013 ”Presented at ID Week 2015, October 10, 2015, San Diego, CA

Speaker Notes: HCV Is national epidemic. Although the number of

deaths caused by reportable infectious diseases, including HIV/AIDS, has

decreased substantially over the past decade, deaths from HCV are on the rise. HCV-associated deaths surpassed those from other infections several years ago.

Population Estimated Size Prevalence (anti-HCV, %) Number Chronically InfectedIncarcerated 2,186,230 23.1 505,350Homeless 691,899 32.1 222,100Hospitalized 478,054 15.6 74,576Nursing homes 1,446,959 4.5 65,113Active-duty military 1,404,060 0.5 7,020Indian reservations 1,069,411 11.5 123,224Total 997,384

Hepatitis C Prevalence in the United States

• NHANES (2003-2010)– 3.6 million chronically infected (anti-HCV)– 2.7 million currently infected (82% of anti-HCV positive)

• Populations not included in NHANES:

Denniston, Ann. Int. Med. 2014, Edlin, Hepatology 2015; Armstrong GL, Ann Int. Med. 2006;144:705-14

NHANES SURVEY: UNITED STATES, 1988-1994 AND 1999-2002PREVALENCE OF HCV ANTIBODY, BY YEAR OF BIRTH

Source: Armstrong GL, et al. Ann Intern Med. 2006;144:705-14.

Speaker Notes: More than 80% of all HCV-infected adults are persons in the 1945-1965 birth cohort. It is estimated that 70% have moderate-severe liver disease This is an ill cohort. These high rates of morbidity translate to high rates of mortality

Reported Number of Acute Hepatitis C cases — United States, 2000–2015

Source: National Notifiable Diseases Surveillance System (NNDSS)

Speaker Notes: The number of reported cases of acute hepatitis C declined until 2003 and remained steady until 2010. However, from

2010-2015, there was an approximate 2.9-fold increase in the number of reported acute hepatitis C cases from 850 to 2,436 cases.

Injection drug use is the main risk factor for Hepatitis C virus (HCV) transmission in industrialized countries.

60–80% of new cases of HV infection occur among PWIDMost (60%) of existing infections are among former and current PWID.

Many of these patients will be seen by you for treatment of SUD

Role of the Primary Care Clinician in HCV

• Screening for HCV • Counseling on modifiable risk factors important in disease

progression • Staging of liver disease • HCC surveillance • Recognition of extra-hepatic manifestations • HCV treatment (with mentoring) or referral

Speaker Notes: There is very important

role for primary care providers in the HCV epidemic as seen in this slide. We do not have time to go over all of them but will focus on the first and last.

NHANES SURVEY, UNITED STATES, 2001-2008AWARENESS OF HCV INFECTION STATUS

Source: Denniston M, et al. Hepatology. 2012:55:1652-61.

Speaker Notes: At least 50 % of persons with chronic HCV are unaware of their infection. It is extremely important to screen in the setting of primary care.Other surveys have even more disappointing results: Smith B et al MMWR 2012; 61 (RR-4): 1-3245-85% unaware of their status Among high-risk populations, testing rates are 17%-87%~70% of IDU’s with HCV are unaware of their status

Recommended Testing Sequence for Identifying Current Hepatitis C Virus (HCV) Infection

* For persons who might have been exposed to HCV within the past 6 months, testing for HCV RNA or follow-up testing for HCV antibody is recommended. For persons who are immunocompromised, testing for HCV RNA can be considered.

† To differentiate past, resolved HCV infection from biologic false positivity for HCV antibody, testing with another HCV antibody assay can be considered. Repeat HCV RNA testing if the person tested is suspected to have had HCV exposure within the past 6 months or has clinical evidence of HCV disease, or if there is concern regarding the handling or storage of the test specimen.

Slide courtesy AASLD Curriculum & Training Source: CDC. Testing for HCV infection: An update of guidance for clinicians and laboratorians. MMWR. 2013;62(18).

Speaker Notes: This HCV testing algorithm is available on the CDC website and it is crucial that it be followed in primary care. Confirmatory HCV RNA is mandatory and if possible exclusively order HCV antibody that reflexes to RNA.

The Evolution of Highly Effective TreatmentSpeaker Notes: Treatment for HCV has evolved dramatically. For nearly two decades the standard of care was an interferon based regimen for 6-12 months, combined with ribavirin resulting in, at best, 50% of patients achieving cure with a year’s worth of treatment. In 2011, the first generation of direct-acting antivirals were approved. Although these agents markedly improved SVR rates, in addition to the toxicities and laboratory abnormalities of interferon, these early agents were also plagued by substantial side effects and a high pill burden. By 2014, we entered a new era of therapy hallmarked by the ability to treat with an all-oral regimen, sparing the need for interferon, with few side effects and, more importantly high cure rates with abbreviated courses of treatment.

WHAT DO WE GET WITH HCV TREATMENT?

SVR (cure) of HCV is associated with:

•70% Reduction of Liver Cancer •50% Reduction in All-cause Mortality •90% Reduction in Liver Failure

Lok A. NEJM 2012; Ghany M. Hepatol 2009; Van der Meer AJ. JAMA 2012

Speaker Notes: Benefits of HCV cure are dramatic even in the setting of baseline cirrhosis as seen in this slide. We also know now that cirrhosis improves in many patients. In paired biopsy studies as many as 60% of cirrhotic patient showed some degree of cirrhosis regression. D’Ambrosio R, et al. Hepatology. 2012;56:532-543

HEPATITIS C CASCADE OF CARE IN UNITED STATES

Source: Holmberg SD, et al. N Engl J Med. 2013;368:1859-61.

Speaker Notes: Now we know how widespread the HCV epidemic is. We have excellent tests to diagnose the disease and can cure it in over 90% of patients. However, the care cascade is dismal. You can help improve this situation by testing and treating these patients.

HCV Treatment in PWID

• Treatment of HCV in PWID has been very limited – Stigma – Drug use status as a criterion for treatment exclusion – Incarceration in prisons where treatment is limited – Concern for HCV reinfection

• Current AASLD/IDSA HCV Treatment Guidelines recommend HCV treatment for all persons including PWID

• PWID can be successfully treated for HCV on-site in an opioid treatment program rather than being referred

Mehta et al., 2008;Grebely, Oser, Taylor, & Dore, 2013; Oramasionwu, Moore, & Toliver, 2014; Wolfe et al., 2015; Butner, 2017.

Speaker Notes: We do not know the care cascade for PWID but is almost certainly more diamal than the NHANES care cascade. Treatment of HCV in PWID has been very limited, particularly in the interferon era. Stigma and unrealistic restrictions still limit treatment. Reinfection occurs in around 5% of PWID and this has to be anticipated. It is recommended to treat all persons living with HCV in national guidelines. New DAA’s present a unique opportunity to treat much more broadly and feasible to treat in primary care and addiction treatment centers.

Co-Occurring Psychiatric and Substance Use Disorder in OUD

Brant Hager MD, University of New MexicoRichard Ries MD, University of Washington

Questions for Co-Occurring Disorders in Primary Care Settings

• Are psychiatric symptoms present only during substance use disorder?

→Likely psychiatric disorder due to substance

• Are psychiatric symptoms present before substance use disorder, and/or during extended periods of sobriety?

→ Likely co-occurring psychiatric disorder

• Are psychiatric symptoms present before substance use disorder, and/or during extended periods of sobriety, as well as during substance use disorder?

→ Likely co-occurring psychiatric disorder, +/- psychiatric disorder due to substance

-Speaker Notes: General approach to psychiatric disorder due to substance: treat substance use disorder-General approach to co-occurring disorders: treat substance use disorder and co-occurring disorder simultaneously

Lifetime Prevalence of Psychiatric Disorders: General Population vs OUD

0%

10%

20%

30%

40%

50%

60%

MajorDepression

Dysthymia Bipolar I-II Panic Disorder Social Phobia GeneralizedAnxietyDisorder

PersonalityDisorder

PTSD

General Population Persons with OUDGrant et al 2004, Grella et al 2009, Hasin et al 2015, Mills et al 2004

Speaker Notes: (You will not have time to go through every item on this slide; point out highlights)

-Data on disorders other than PTSD are from the National Epidemiologic Survey on Alcohol and Related Conditions-Data on PTSD are from the Australian Treatment Outcome Study. There are no large sample epidemiologic data on PTSD in OUD from the US.

Lifetime Prevalence of Substance Use Disorders: General Population vs OUD

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Alcohol UseDisorder

Cannabis UseDisorder

Cocaine UseDisorder

Stimulant UseDisorder

Sedative UseDisorder

Inhalant UseDisorder

HallucinogenUse Disorder

General Population Persons with OUD

Grant et al 2004, Grant et al 2016, Grella et al 2009, Hasin et al 2015

Speaker Notes: (You will not have time to go through every item on this slide; point

out highlights) -Data are from the National Epidemiologic Survey of Alcohol and

Related Conditions

Psychiatric Disorders and Opioid Dependence Reciprocally Increase Risk

• Pre-existing psychiatric disorders: • Generalized anxiety disorder: 11x risk of developing opioid dependence • Bipolar I disorder: 10x risk of developing opioid dependence • Panic disorder: 7x risk of developing opioid dependence • Major depression: 5x risk of developing opioid dependence

• Pre-existing opioid dependence: • 9x risk of developing panic disorder • 5x risk of developing major depression • 5x risk of developing bipolar I disorder • 4x risk of developing generalized anxiety disorder

Martins et al 2009

Speaker Notes: (You will not have time to go through every item on this slide; point out highlights)

-Data are from the National Epidemiologic Survey on Alcohol and Related Conditions, which did not include PTSD.-Pre-existing psychiatric disorders increase the risk of developing opioid dependence following nonmedical opioid use.-Note the particularly strong relationship between pre-existing anxiety disorders and the development of opioid use disorder.-In turn, pre-existing opioid dependence increases the risk of developing psychiatric disorders.

Co-Occurring Psychiatric Disorders: Treatment Goals

• Acute Phase: 1-3 months • Non-response: <25% reduction in symptoms • Partial response: 25-50% reduction in symptoms • Response: >50% reduction in symptoms • Remission: no symptoms, e.g. PHQ-9 <5

• Continuation Phase: 3-12 months • Prevent relapse: another episode within 6 months of remission

• Maintenance Phase: 1-3 years • Prevent recurrence: another episode after 6 months of remission

• Treatment Goal: Durable remission

Speaker Notes: (You will not have time to go through every item on this slide; point out highlights)

-The described phases stem from guidelines on the treatment of depression, and may be adapted to other psychiatric disorders.

Co-Occurring Depressive Disorders

• Co-occurring depressive disorders treatment in OUD • Positive RCTs in methadone MAT: imipramine, doxepin • Negative RCTs in methadone MAT: imipramine, doxepin, bupropion,

sertraline, fluoxetine • No RCTs in bup MAT

• Bup has empirical support as antidepressant outside OUD • Lifetime major depression correlates positively with abstinence

during bup MAT for OUD • Depressive symptoms in OUD

• Bup and methadone MAT equally improve depressive symptoms in patients with OUD – ~50% reduction

• Naltrexone MAT does not appear to worsen depressive sx

-Speaker Notes: Note the mixed evidence for treatment of co-occurring depressive disorders in methadone MAT, and the dearth of studies on the treatment of co-occurring depressive disorders in buprenorphine MAT.-Co-occurring major depressive disorder appears to be a positive prognostic feature for buprenorphine MAT.

Co-Occurring Depressive Disorders: Treatment

• Recommend first stabilizing OUD on MAT for ~6 weeks • Depressive disorder remits?

• Continue MAT as treatment of OUD and depressive disorder • Depressive disorder persists?

• Treat depressive disorder per established guidelines • Measurement based care: track and respond to depression using serial PHQ-9s • Shared decision making and patient activation: educated patient choses treatment

direction, team uses behavioral activation • Systematic follow up: team contacts patient proactively to address symptoms and

concerns • Stepped care: proactive treatment titration, consultation with behavioral health in

resistant illness • Treat to target: remission defined as PHQ-9 score <5

Dean et al 2004, Dreifuss et al 2013, Fava et al 2016, Krupitsky et al 2016, Nunes et al 2004

Speaker Notes: (You will not have time to go through every item on this slide; point out highlights)

-Earlier in the talk, the general approach of treating co-occurring disorders simultaneously was mentioned. In the case of depressive disorders, given the evidence for MAT having a strong secondary effect on reduction of depressive symptoms, the authors recommend first stabilizing on MAT prior to pursuing antidepressant treatment per se.-The established guidelines for treatment of depressive disorders stem from the collaborative care model. More information can be found at the University of Washington AIMS center, at https://aims.uw.edu.

Co-Occurring Major Depression: Treatment

• Major Depressive Disorder • Psychotherapy, e.g.: IPT, CBT, Behavioral Activation • Medication • Psychotherapy plus medication • General treatment sequence: Psychotherapy → SSRI → SNRI →

Bupropion → Mirtazapine → TCA → rTMS → ECT → MAOI

Huhn et al 2014, Rush et al 2006

-Speaker Notes: In general, psychotherapy and medication are equally effective for the treatment of acute depression, and their combination is more effective than either one alone.-As acute depression severity increases, medication, psychotherapy, and their combination, each become more effective.-Chronic forms of depression, such as dysthymia, tend to respond better to medication treatment.-IPT is Interpersonal Psychotherapy, CBT is Cognitive Behavioral Therapy. SSRI=selective serotonin reuptake inhibitor SNRI= Serotonin/norepinephrine reuptake inhibitor TCA=tricyclic antidepressant rTMS= repetitive Transmagnetic Stimulation Therapy ECT=Electroconvuslive therapy MAOI=Monoamine oxidase inhibitor

Co-Occurring Anxiety Disorders: Treatment

• Panic Disorder • Psychotherapy • Medication • General treatment sequence: Psychotherapy → SSRI → SNRI →

Imipramine

• Social Phobia • Psychotherapy • Medication • General treatment sequence: Psychotherapy → SSRI → SNRI

• Avoid benzos in MAT: 2x risk of all-cause mortality • Avoid MAOIs in MAT: risk of serotonin syndrome

Huhn et al 2014, Abrahamsson et al 2017

-Speaker Notes: In general, psychotherapy and medication are equally effective for the treatment of panic disorder, and for the treatment of social phobia.-Risk of death from benzos drawn from a large Scandinavian registry-based cohort study; this finding also applies to the “Z-drugs” (e.g. zolpidem) and pre-gabalin

Co-Occurring Anxiety Disorders: Treatment

• Generalized Anxiety Disorder • Psychotherapy • Medication

• Pregabalin • Hydroxyzine • SNRI or SSRI • Buspirone

• General treatment sequence: Psychotherapy → Hydroxyzine → SNRI → SSRI → Pregabalin → Buspirone

• Avoid benzos in MAT: 2x risk of all-cause mortality • Caution pregabalin in MAT: 3x risk of overdose death

Huhn et al 2014, Hidalgo et al 2007, Abrahamsson et al 2017

-Speaker Notes: In general, psychotherapy and medication are equally effective for the treatment of generalized anxiety disorder.-Medications are listed in order of decreasing effectiveness. Note the high effectiveness of hydroxyzine, and the low effectiveness of buspirone.-Risks of death from benzos and pregabalin drawn from a large Scandinavian registry-based cohort study.

Co-Occurring PTSD: Treatment

• Psychotherapy, e.g.: CBT, PE, EMDR, SS • Positive RCT of PE for PTSD in methadone MAT • CBT for PTSD in buprenorphine MAT reduces positive urines

• Medication • Prazosin reduces nighmares and hyper-arousal assoc w PTSD • Note: prazosin only studied as augmentation of other PTSD treatment

• General treatment sequence: Psychotherapy → SSRI → SNRI → Prazosin Augmentation → TCA

Huhn et al 2014, Sunders et al 2015, Schiff et al 2015, Seal et al 2016, Peirce et al 2016

-Speaker Notes: In general, psychotherapy is more effective than medication for the treatment of PTSD the top line lists evidence-based therapies for PTSD-Psychotherapies are listed in order of decreasing effectiveness.-CBT is Cognitive Behavioral Therapy, PE is Prolonged Exposure therapy, EMDR is Eye Movement Desensitization Reprocessing therapy, and SS is Seeking Safety.Prazosin augmentation in civilians: ~3mg PO QHSPrazosin augmentation in veterans: ~20mg TDD in men, ~9mg TDD in women

Insomnia

• Reported in up to 21% of patients on buprenorphine MAT • Central sleep apnea demonstrated in 33% • Nocturnal hypoxemia demonstrated in 39% • No RCTs examining insomnia treatment in buprenorphine MAT

• Reported in up to 84% of patients on methadone MAT • Central sleep apnea in up to 60% • Positive RCTs of insomnia treatment in methadone MAT

• Cognitive behavioral therapy for insomnia (CBTI) • Suan Zao Ren Tang (sour jujube concoction) *GABA-ergic • Acupuncture

• Negative RCTs of insomnia treatment in methadone MAT • Trazodone

Robabeh et al 2015, Farney et al 2013; Chan et al 2015; Li et al 2012

-Speaker Notes: When assessing sleep in patients on MAT, a high index of suspicion for central sleep apnea must be maintained.

-MAT may also worsen obstructive sleep apnea.-The authors recommend a low threshold for sleep medicine consultation and sleep study.

Insomnia: Treatment• Assess for sleep disordered breathing and treat!

• Psychotherapy • CBT-I: stimulus control, sleep restriction, sleep hygiene, relaxation,

cognitive restructuring • Medication

• General treatment sequence: Psychotherapy → Doxepin → Ramelteon → Trazodone → Melatonin

• Caution z-drugs in MAT: 1.6x risk of overdose death

Sateia et al 2017, Smith et al 2002; Schutte-Rodin et al 2008, Abrahamsson et al 2017

-Speaker Notes: In general, psychotherapy is more effective than medication for treatment of insomnia.-Stimulus control means increasing association of the bed with sleep, and decreasing association of the bed with wakefulness.-Cognitive restructuring means observing and reshaping maladaptive thoughts, such as catastrophic thinking associated with insomnia.-Risk of death from z-drugs drawn from a large Scandinavian registry-based cohort study.

Summary

• Psychiatric disorders strikingly common in OUD • Psychiatric disorders and OUD reciprocally increase risk • Limited direct literature on psychiatric disorders treatment in

OUD or MAT • Stabilize OUD with MAT • Psychotherapy first line in major depression, anxiety

disorders, PTSD, and insomnia • Medication first line in dysthymia • Caution pregabalin, z-drugs • Avoid benzos

References

• Abrahamsson T, Berge J, Ojehagen A, et al. Benzodiazepine, z-drug and pregabalin prescriptions and mortality among patients in opioid maintenance treatment-–a nation-wide register-based open cohort study. Drug Alcohol Depend 2017; http://dx.doi.org/doi:10.1016/j.drugalcdep.2017.01.013

• Chan YY, Chen YH, Yang SN, et al. Clinical efficacy of traditional Chinese medicine, suan zao ren tang, for sleep disturbance during methadone maintenance: a randomized, double-blind, placebo-controlled trial. Evid Based Complement Alternat Med 2015; 2015:710895. doi: 10.1155/2015/710895. Epub 2015 Aug 4

• Dean AJ, Bell J, Christie MJ, et al. Depressive symptoms during buprenorphine vs. methadone maintenance: findings from a randomised, controlled trial in opioid dependence. European Psychiatry 2004;19:510-513

• Dreifuss JA, Griffin ML, Frost K, et al. Patient characteristics associated with buprenorphine/naloxone treatment outcome for prescription opioid dependence: results from a multisite study. Drug Alcohol Dep 2013;131:112-118

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• Grella CE, Karno MP, Warda US, et al. Gender and comorbidity among individuals with opioid use disorders in the NESARC study

• Hasin DS, Grant BF. The National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) waves 1 and 2: review and summary of findings. Soc Psychiatry Psychiatr Epidemiol 2015;50:1609-1640

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This project is supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) under contract number HHSH250201600015C. This information or content and conclusions are those of the author and should not be construed as the official position or policy of, nor should any endorsements be inferred by HRSA, HHS or the U.S. Government.