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Medications to Treat Opioid Addiction: What They Are, Why We Need Them, and How to Use Them

Jessica Gregg, MD, PhDAmanda Wojtusik, PharmD, BCPS

Providence Pain SymposiumDecember 9, 2017

Copyright (C) 2016 Providence Health & Services

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No Disclosures/Conflicts of Interest

Session Objectives

Review the Diagnostic Criteria for Opioid Use Disorder

Discuss the connections between dopamine, craving, dysregulation, and addiction

Understand the role of context in the development and treatment of addiction

Discuss how these concepts relate to opioid use and pain

Understand medications available to treat opioid use disorders

Objective 1

Review the Diagnostic Criteria for an Opioid Use Disorder

Not Just Use Disordered Use

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DSM VDiagnostic and Statistical Manual of Mental Disorders

DSM V: Substance Use Disorder11 criteria

DSM V: Substance Use DisorderCraving / Compulsion

DSM V: Substance Use DisorderTaking in larger amounts or for longer than intended

Unsuccessful efforts to cut down

Spending a lot of time obtaining the substance

Craving or a strong desire to use the substance

DSM V: Substance Use DisorderConsequences

Lack of Control

DSM V: Substance Use Disorder

Continued use despite recurring social or interpersonal problems due to use

Important activities given up or reduced

Recurrent use in physically hazardous situations

Persistent / Recurrent physical or psychological difficulties from use

Recurrent use resulting in a failure to fulfill major role obligations

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DSM V: Substance Use DisorderTolerance*

Withdrawal*

2—3

mild disorder

4—5

moderate disorder

6+

severe disorder

Substance Use DisorderCravingCompulsionConsequencesLoss of Control

Objective 2

Discuss the connections between dopamine, craving, dysregulation, and addiction

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Dopamine

Desire, Drive, Motivation

DSM VDiagnostic and Statistical Manual of Mental Disorders

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Craving

Liking

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Dysregulation

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Discrimination and Prejudice

Poor Outcomes

Addict

Get clean

Dirty urine

Clean urine

Drug abuse

Substance abuse

Objective 3

Understand the role of context in the development and treatment of addiction

BF Skinner

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https://www.youtube.com/watch?v=7kS72J5Nlm8

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?

D1: Activate the nucleus accumbens, cause us to act.

Responsive to big pleasure surges.

D2: Slow down decision making, allow the frontal cortex to step in.

Responsive to smaller pleasures.

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Objective 4

Discuss how these concepts relate to opioid use and pain

63 y/o female with fibromyalgia

Widespread Pain for 20 yearsMedical Hx:

FM, GERD, IBS, insomnia, obesity, OA, pre-diabetic, Hep C Surgical hx:

partial thyroidectomy, THA R, ankle surgery, gastric bypass Mental health hx:

anxiety, depression, bipolar, ADD, PTSDSuicide attempt 8 y ago, trauma history

Medication: Opioids 110 MED, ambien for sleep

Function/ Activity: Spends most of time on couch, now hurts to walk 10’Husband does chores, Use to go to gym 3 years ago with trainer

239 lbs, in weight watchers. “emotional eater”. Gained 40’ over last year

63 y/o female with fibromyalgia

Social:

• Living with husband of 36 yrs, supportive relationship

• Retired real estate broker 20 yrs ago when got “sick”

• Volunteers at church and belongs to bible group

Sleep:

• 5-6 hours/ night of fitful sleep

Substances:

• Smoked age 16-20. Hx of alcohol abuse 21 years ago

• Substance use history in family

Medication: Opioids 110 MED, ambien for sleep

What if?

• Early refills• Multiple prescribers• History of overdose• Terrible constipation• No longer able to babysit her granddaughter due to sedation• Falls asleep driving

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You tell her you are concerned about her opioid use and want to talk to her about a taper

She says……

Are you calling me an addict?

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I’m diagnosing you with a medical problem. I think we need to taper your opioids and I have resources, including medication, that can help.

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Objective 5

Understand medications available to treat opioid use disorders

Medications

• Methadone

• Buprenorphine; Buprenorphine/Naloxone

• Naltrexone

Medications

1960s: Methadone

Drug Addiction Treatment Act of 2000 (DATA 2000)

2002: BuprenorphineFDA approved

1972: Methadone Regulations

1974: Narcotic Addict Treatment Act

1984: Naltrexone FDA approved

2010: Naltrexone ER (Vivitrol®) FDA approved

SAMHSA. Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction. TIP 40.

Fewer than 25% of the individuals with opioid addition receive treatment for it

Methadone

• Full agonist at mu opioid receptor – produces high level of physiological dependence

• Only available via federally approved opioid treatment programs (OTPs)

• Dosed once daily; patients required to attend an OTP, usually on a daily basis at first

– 10 – 30 mg initially

– Maintenance doses of 60 – 120 mg/day

ASAM. National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. 2015.

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Buprenorphine; Buprenorphine/Naloxone

• Partial agonist at mu opioid receptor – produces less physiological dependence vs. methadone

• Available via OTPs or office based treatment programs; must be prescribed by qualifying physicians

• Started when pts experiencing mild-moderate withdrawal

– 6-12 hrs after the last use of heroin/SA opioids

– 24-48 hrs after the last use of methadone/LA opioids

ASAM. National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. 2015. naabt.org

“Ceiling effect”

Naltrexone• Antagonist at mu opioid receptor – produces no dependence;

no addictive properties; tolerance does not develop

• Also approved for alcohol use disorder

• Prescribed in any setting by anyone licensed to Rx meds

• PO (daily) or IM (monthly)

• Displaces opioids from receptors; precipitates severe, acute withdrawal symptoms in persons who have not completely cleared opioids from their system

ASAM. National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. 2015.

Evidence – Show me the data!

Methadone

Mattick RP, et al. Cochrane Database of Systematic Reviews 2009.

Type Systematic review and meta analysis

Objective Evaluate the effects of methadone treatment vs. no opioidreplacement therapy for opioid dependence

PrimaryOutcomes

Retention in treatmentOpioid use (measured by UDS/hair and patient self report)Criminal activity Mortality

StudyCriteria

RCTs of methadone maintenance therapy vs. placebo maintenance therapy or other non-pharmacological therapy

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Methadone

Mattick RP, et al. Cochrane Database of Systematic Reviews 2009.

Studies 11 studies with a total of 1,969 participants

Results Methadone superior to drug free alternatives:• Treatment retention (RR 4.44, 95% CI: 3.26-6.04; I2=23%)• Suppression of heroin use based on urine/hair samples (RR 0.66, 95% CI: 0.56-0.78; I2=54%)

Greater reduction in criminal activity (RR 0.39, 95% CI: 0.12-1.25; I2=21%) and mortality (RR 0.48, 95% CI: 0.10-2.39; I2=25%) among methadone treated patients, however these differences were not statistically significant

Methadone, cont.

• Mortality – Prospective/retrospective cohort studies have found

that retention in methadone treatment is associated with statistically significant reductions in the risk for all cause and overdose mortality

• Reduction in HIV risk taking behavior (i.e. needle sharing); protection against HIV infection– From observational studies; no RCTs of methadone

that have included HIV status as an outcome

Sordo L, et al. BMJ 2017; Gowing L, et al. Cochrane 2011; Clausen T, et al. Drug Alcohol Depend 2008; Gibson, et al. Addiction 2008.

Buprenorphine

Mattick RP, et al. Cochrane Database of Systematic Reviews 2014.

Type Systematic review and meta analysis

Objective Evaluate buprenorphine maintenance compared to placebo and to methadone maintenance for opioid dependence

PrimaryOutcomes

Retention in treatmentIllicit drug use (measured via UDS/self report )Criminal activity Mortality

StudyCriteria

RCTs of buprenorphine maintenance vs. placebo or methadone maintenace in opioid dependent persons

Buprenorphine

Mattick RP, et al. Cochrane Database of Systematic Reviews 2014.

Studies 31 studies with a total of 5,430 participants

Results: Treatment Retention

Buprenorphine more effective vs. placebo:• Low dose (2-6 mg): RR 1.50, 95% CI 1.19-1.88• Medium dose (7-15 mg): RR 1.74, 95% CI 1.06-2.87• High dose (>16 mg): RR 1.82, 95% CI 1.15-2.90

Opioid use High dose (>16 mg) was more effective vs. placebo: • SMD -1.17, 95% CI -1.85 to -0.49

Low and medium dose were not more effective vs. placebo

Buprenorphine

Mattick RP, et al. Cochrane Database of Systematic Reviews 2014.

Results: Treatment Retention

Buprenorphine less effective vs. methadone:• Flexible dose: RR 0.83, 95% CI 0.73-0.95 • Fixed low dose (BP 2-6mg vs. methadone <40mg): RR 0.67, 95% CI 0.52-0.87

Buprenorphine vs. methadone: no difference • Fixed medium dose (BP 7-15mg vs. methadone 40-85mg)• Fixed high dose (BP >16mg vs. methadone >85mg)

Opioid Use Buprenorphine vs. methadone: no difference

Criminal Activity

Flexible dose: buprenorphine vs. methadone: no difference

Mortality Not well reported in studies; unable to assess

What we’ve covered thus far:

• Methadone and buprenorphine are effective for treatment retention (all BP dose thresholds) and in suppressing illicit opioid use (high dose BP only)

• Observational data has found treatment with methadone and buprenorphine effective in reducing all cause and overdose mortality and HIV risk taking behaviors

• Methadone is better able to retain participants than buprenorphine in flexible dosing approaches

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Naltrexone

Oral naltrexone:

• Medication compliance + retention in treatment is poor

• Studies supporting efficacy conducted in highly motivated pts who were legally mandated to receive treatment and/or taking medication under supervision

ASAM. National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. 2015.

Naltrexone ER (Vivitrol®)

• Effective vs. placebo/drug-free treatment for opioid use disorder

• Obvious drawbacks: need for complete opioid detoxification prior to use and lag time before treatment can begin; cost/insurance coverage

Krupitsky E, et al. Lancet 2011.

Naltrexone ER (Vivitrol®)

Study

Type Open-label, randomized, controlled, comparative effectiveness trial

Funding National Institute on Drug Abuse (NIDA)

Duration 24 weeks

Location United States

TreatmentGroups

XR-NTX (monthly IM inj) vs. BUP-NX (daily self administered SL film) following an acute inpatient detox

Primary Outcome

Relapse to regular opioid use (time to relapse event)

SecondaryOutcomes

Failure to initiate medication, opioid use during treatment, adverse events including ODs, opioid craving

Lee JD, et al. Lancet 2017.

Naltrexone ER (Vivitrol®)

Patients

Inclusion >18 yoEnglish speakingDiagnosis of opioid use disorderUsed non-Rx opioids in previous 30 days

Exclusion Other serious medical/psychiatric/SUDsLFTs >5x ULNSuicidal or homicidal Methadone maintenance treatmentChronic pain requiring opioids Legal status precluding study completion Pregnant/breastfeeding/planning conception/unwilling to use birth control

Lee JD, et al. Lancet 2017.

Naltrexone ER (Vivitrol®)

Results

Patients N=570; 283 XR-NTX vs. 287 BUP-NX

Characteristics

Most participants were:White men; 25-45 yoPrimary heroin use disorder (injection)Low-severity opioid useSingle; unemployedMedicaid insured

Baseline characteristics were well balanced between groups, with the exception of:Stimulant use (past 30 days): 47% XR-NTX vs. 57% BUP-NXSedative use (past 30 days): 25% XR-NTX vs. 32% BUP-NX

Lee JD, et al. Lancet 2017.

Naltrexone ER (Vivitrol®)

Outcome XR-NXT (n=283) BUP-NX (n-287) Treatment Effect

Inducted to study medication (ITT)

204 (72%) 270 (94%) OR 0.16, 0.09-0.28;P<0.0001

Relapse-freesurvival (weeks)

8.4 (3-23.4)

20.4 (5.4-23.4)

14.4 (5.1-23.4)

15.2 (5.7-23.4)

HR 1.36, 1.10-1.68; p=0.0040HR 0.92, 0.71-1.18, p=0.49

Opioid relapse, weeks 3-24

185 (65%)

106/204 (52%)

163 (57%)

150/270 (56%)

OR 1.44, 1.02-2.01; p=0.036OR 0.87, 0.60-1.25; p=0.44

Lee JD, et al. Lancet 2017.

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Naltrexone ER (Vivitrol®)

Outcome XR-NXT (n=283) BUP-NX (n-287)

Opioid craving (subjective)

Declined rapidly from BL in both grpsInitially less for the XR-NXT grp (wk 7); p=0.0012Converged by week 24; p=0.20

AEs + Serious AEs:Inj Site RxnGI

4634

N/A59

Overdose AllFatal

182

103

Lee JD, et al. Lancet 2017.

Conclusions from the data

• Methadone and buprenorphine are effective for treating opioid use disorder– Methadone use limited by OTP requirement– Buprenorphine use limited by DATA 2000 waiver

requirement

• Naltrexone ER is effective for treating opioid use disorder when patients are able to be successfully inducted – Induction failure a large barrier/issue– May be more successful in certain patient populations

Other ReferencesAlexander, BK ‘Addiction: The View from the Rat Park,” www.brucekalexander.com/articles-speeches/rat-park/148-addition-the-view-from-rat-park.

Centers for Disease Control and Prevention, National Center for Injury and Prevention Control, Division of Unintentional Injury Prevention. ”Opioid Overdose”

Childress AR et al. Prelude to Passion: Limbic Activation by “Unseen” Drug and Sexual Cues January 30, 2008 PLoS ONE 3(1): e1506.

Coffin PO et al. Nonrandomized Intervention Study of Naloxone Coprescription for Primary Care Patients Receiving Long-Term Opioid Therapy for Pain. Ann Intern Med 2016 Aug 16; 165(4): 245-52

Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep 2016;65(No. RR-1):1–49. DOI: http://dx.doi.org/10.15585/mmwr.rr6501e1

Koob GF, Volkow ND. Neurocircuitry of Addiction. Neuropsychopharmacology. 2010;35(1):217-238.

Lee JD et al. Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders NEJM 2016; 374:1232-1242

Lewis, M. The Biology of Desire: Why Addiction is Not A Disease Public Affairs: New York 2015.

Robins, LN et al. How Permanent Was Vietnam Drug Addiction? Am J Public Health. 1974 December; 64(12 Suppl): 38–43.

Szalavitz, M. Unbroken Brain: A Revolutionary New Way of Understanding Addiction St. Martin's Press (April 5, 2016)

Trafton, Jodi New Concepts in the Neurobiology of Pain and Addiction. Lecture at CSAM Addiction Medicine State of the Art Conference October 23, 2015 San Francisco