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www.mghcme.org John A. Renner, Jr., MD Consultant, Department of Psychiatry Massachusetts General Hospital Professor of Psychiatry Boston University School of Medicine Treatment of Addictive Disorders Alcohol and Opiates October 2O, 2019

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Page 1: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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John A. Renner, Jr., MD Consultant, Department of Psychiatry Massachusetts General HospitalProfessor of Psychiatry Boston University School of Medicine

Treatment of Addictive DisordersAlcohol and Opiates

October 2O, 2019

Page 2: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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I have the following relevant financial relationship with a commercial interest to

disclose:

APA Publishing: royalties

Disclosures

Page 3: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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Dual Diagnosis Patient Management

• SOBRIETY is the primary goal

• Supportive care - BUILD DEFENSES

• MEDICATIONS for relapse; monitor compliance

• Treat co-morbid psychiatric disorders

• Learn to work with A.A. / N.A.

• CBT & relapse prevention counseling

• Anticipate lapses & relapses

• Active therapeutic stance

• For persistent insomnia: TRAZODONE

• Avoid prescription tranquilizers

Page 4: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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• Alcohol Use Disorder

– Drinking Trends

– SBIRT & Screening for Alcohol Related Problems

– DSM-5

– Alcohol Biomarkers

– Alcohol Withdrawal Medications

– Anticraving Medications

• Opiate Use Disorder

– Changes in Abuse Patterns

– Treating Opioid Overdose

– Opioid Withdrawal Protocols

– Opioid Agonist Therapy

– Opioid Antagonist Therapy

• Appendix – Managing Dual Diagnosis Patients

Agenda

Page 5: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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Over Part Month Substance Use

SAMHSA, NSDUH 2018

Page 6: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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Past Month Alcohol Use

SAMHSA, NSUDH, 2018

Page 7: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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Trends in DSM-IV alcohol use disorder in the past year

SAMHSA, NSDUH 2018, (AUD Diagnosis 2002-2018)

Page 8: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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SBIRT & SCREENING FOR PROBLEM DRINKING

Screening, Brief Intervention, Referral to Treatment (SBIRT):

Single Alcohol Screening Question (SASQ)“How many times in the past year have you had 5 or more

drinks in one day?” (4 drinks for women)Any positive response within the past year warrants

assessment for problem drinking. Review drinking during the last 28 days. Review DSM-5 criteria.

(Canagasby & Vinson, Alcohol Alcohol, May-June 2005)www.niaaa.nih.gov/guide

A large British study has questioned the effectiveness of screening and brief interventions in primary care settings

E Kaner, et al. BMJ 2013;346:e8501

Page 9: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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• The SBIRT approach is effective for individuals with heavy/at risk drinking

• There is little evidence of efficacy for individuals with an alcohol use disorder or a drug use disorder

• More intensive counseling or interventions are required for individuals with more serious problems

• None the less all patients should be screened to identify risky or problem drinking

R.Saitz JAMA 2014;312(5):502-513

RECOMMENDATIONS FOR SCREENING

Page 10: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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DSM-5 CHANGESCRITERIA FOR SUBSTANCE USE DISORDERS

1. USE IN LARGER AMOUNTS / LONGER PERIODS THAN INTENDED

2. UNSUCCESSFUL EFFORTS TO CUT DOWN 3. EXCESSIVE TIME SPENT TAKING DRUG4. FAILURE TO FULFILL MAJOR OBLIGATIONS5. CONTINUED USE DESPITE KNOWLEDGE OF PROBLEMS6. IMPORTANT ACTIVITIES GIVEN UP7. RECURRENT USE IN PHYSICALLY HAZARDOUS SITUATIONS8. CONTINUED USE DESPITE SOCIAL OR INTERPERSONAL PROBLEMS 9. TOLERANCE10. WITHDRAWAL11. CRAVING

SEVERITY:0 TO 1 CRITERIA: NO DIAGNOSIS2 TO 3 CRITERIA: MILD4 TO 5 CRITERIA: MODERATE6 OR MORE CRITERIA: SEVERE

Page 11: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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ALCOHOL BIOMAKERS

INDIRECT TESTS – all measure long-term drinking only

1. Carbohydrate-Deficient Transferrin (CDT): most sensitive indicator of relapse (serum) > 20 units/L in men > 26 units/L in women

2. GGT: > 65 units/L in men > 50 units/L in women

3. MCV> 95 microns/cubic ml. in males > 100 microns/cubic ml. in females

4. LFT’s: AST, ALT, & Alk. Phos.

5. CAMP in WBC are 3 x normal

Page 12: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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ALCOHOL BIOMARKERS

DIRECT TESTS – can detect recent relapse / drinking

1. Blood Alcohol Concentration (BAC)

2. Ethyl Glucuronide (EtG) is present for 5 days in urine, very sensitive and may have a high incidence of false positives. Use can be problematic in monitoring situations.

3. Phosphatidyl Ethanol (Peth): 2 drinks/day for 2 weeks (in RBCs) will track moderate drinking; is positive for 2-4 weeks

Page 13: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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NEUROBIOLOGY OF ALCOHOL:CHRONIC ALCOHOL USE

• UP-REGULATION OF NMDA RECEPTORS: EXCITATORY NEUROTRANSMISSION, PRIMARY CAUSE OF WITHDRAWAL SYMTPOMS

• DOWN-REGULATION OF INHIBITORY GABARECEPTORS

• DOWN-REGULATION OF EXCITATORY DOPAMINE D-2RECEPTORS

• INCREASED NOREPINEPHRINE ACTIVITY

Page 14: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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NEUROBIOLOGY OF ALCOHOL

EFFECTS OF ALCOHOL WITHDRAWAL:• CNS HYPERACTIVITY- NO OPPOSITION TO

ALCOHOL INDUCED EXCITATORY STATE(NMDA HYPERACTIVITY)

• RELEASE OF CRF

PREDICTORS OF RELAPSE:• DELAYED RECOVERY OF D-2 RECEPTOR

SENSITIVITY AFTER DETOX • ELEVATED ACTIVITY IN THE VENTROMEDIAL

PREFRONTAL CORTEX (vmPFC)

R. Sinha, JAMA Psychiatry 2013

Page 15: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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MEDICATIONS FOR ALCOHOL WITHDRAWAL

• Benzodiazepines remain the standard of care

• Anticonvulsants (carbamazine & valproic acid) are effective but have significant side effects (Myrick, 2003)

• Gabapentin may offer an alternative option for ambulatory withdrawal treatment:• 400 mg TID for 8-10 days• Effective control of withdrawal• As compared to lorazepam, less craving,

anxiety & sedation• Reduced probability of relapse in post-

withdrawal week (Myrick, Alcohol Clin Exp Res, 2009 33:1582-88)

• Can present abuse problems in some patients

Page 16: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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MEDICATIONS FOR ALCOHOL WITHDRAWAL

• Experimental Phenobarbital Protocol for treatment resistant alcohol withdrawal requiring high benzodiazepine doses• Barbiturates seen as efficacious and

safe• IV phenobarbital loading doses followed

by tapering oral or IM doses• May require intensive medical

monitoring and ICU level care• Protocol may reduce length of ICU stay

and need for ventilation• Phenobarbital will self-taper in

circumstances of premature discharge

• Nisavic M, et al. Psychosomatics 9/1/2019 (5):458-467

Page 17: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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• Professional Counseling:

– CBT

– Motivational Enhancement Therapy

– 12-Step Facilitation

• Medications for Addiction Treatment:

The New Standard of Care for all alcoholics

– Naltrexone

– Acamprosate

– Disulfiram

• Mutual Support Groups

EVIDENCE-BASED TREATMENTS

Page 18: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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• DISULFIRAM *

• NALTREXONE (PO* & IM* formulations)

• ACAMPROSATE *

• TOPIRAMATE

• ONDANSETRON

* FDA APPROVED

RELAPSE PREVENTION MEDICATIONS

LONG-TERM MANAGEMENT OF ALCOHOL USE DISORDER

Page 19: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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ORAL NALTREXONE (ReVia)

Opioid antagonist / oral formulation• Modulates the mesolimbic dopamine system in the VTA &

projections to the nucleus accumbens• Reduces alcohol craving and euphoric effects of alcohol• Dose: 50 to 100 MG QDaily with meals• Side effects

– GI: abdominal pain, decreased appetite, nausea– Sedation: daytime sleepiness, fatigue, insomnia, headache

• Works best with compliant patients (Zweben, 2008); requires counseling (CBT) or frequent MD monitoring visits (Project Combine, 2006)

• Efficacy questioned in women (O’Malley, 2007)

Page 20: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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EXTENDED-RELEASE NALTREXONE (Vivitrol)

• Long-acting injectible formulation: 380 mg IM q 28 days• Screen LFTs and renal function• More stable plasma concentrations compared to oral • Side effects: NAUSEA & HEADACHE; more sedation than

with the oral formulation• Injection site reactions possible• Best results in patients sober 1 week prior to starting

the medication• Efficacy shown in more severe alcoholics

– Reduction in heavy-drinking days (48.9% vs 30.9% on placebo)

– Pettinati HM, Alcohol Clin Exp Res, May 2011

Page 21: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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RECOMMENDATIONS FOR USE OF NALTREXONE

• Begin 50 mg ORAL Naltrexone after 2-5 days sobriety• If no response after 2 weeks, increase to 100 mg

• If no response or minimal response, add Gabapentin 12OO mg/Day

– Anton R. Am J Psychiatry, July 2011

• If no response, switch to XR-Naltrexone

– Pettinati HM. Alcohol Clin Exp Res, May 2011

– Improve adherence with increased counseling, rehab, and psychiatric services (Chang, 2018)

• If no response consider Acamprosate or Disulfiram

Page 22: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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DISULFIRAM (Antabuse)

• DOSE: 500 mg po qd x 10 days; then 250 mg po qd

• SIDE EFFECTS: drowsiness, headache, metallic taste, decreased libido/potency

• SUPPORTIVE COUNSELING NECESSARY

• SUPERVISED DOSING recommended

• Follow serial LIVER FUNCTION TESTS

– Monitor for ALCOHOL-INDUCED HEPATITIS

• Rx for Antabuse reaction: BENADRYL 50 mg IM or IV

Jergensen CH, Alcohol Clin Exp Res, Oct 2011

Page 23: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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ACAMPROSATE (Campral)

• Glutamate antagonist• Alters GABA & NMDA systems

– Restores balance between inhibitory & excitatory neurotransmission

– Attenuates acute & prolonged withdrawal– Reduces rewarding effects of alcohol

• Benefit sustained for 3 to 12 mos. after end of treatment (Cochrane Review – 10 RCTs; Rosner 2011)

• No tolerance, withdrawal or sedation• Minimal side effects (mild diarrhea)• Excreted through the kidneys• No drug-drug interactions• Dose: 666 mg PO TID

Page 24: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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PROJECT COMBINE

1383 patients randomized to varying combinations of oral Naltrexone, Acamprosate, combined behavioral intervention (CBI) and medical management (MM)

• ALL groups improved

• Naltrexone + MM had the best outcome

– Adding CBI did not improve results

– Adding Acamprosate did not improve results

• One-year outcome: no significant differences among the groups

JAMA. 2006;295:2003-2017.

Page 25: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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TOPIRAMATE (Topamax)

• Facilitates GABA and inhibits Glutamate

• Reduced drinking and craving:

– DBPC trial (Johnson. Lancet. 2003)

– 150 subjects

• Dose: 25 mg PO QD, then increase up to 100 mg TID over an 8 week period

• Side effects: fatigue & cognitive dulling; reduced over time

• Replicated in 371 subjects

– DBPC randomized trial (Johnson. JAMA. 2007)

• Changed to pregnancy CATEGORY D in 2011

Page 26: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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ONDANSETRON (Zofran)

• Anti-nausea drug; selective 5-HT3 blocker

• Reduced drinking in EARLY-ONSET Alcoholism (Type B)Dose: 4 microgm/kg po bid – equivalent dose not currently marketed

• DBPC 11-week trial; 321 patients

– Johnson BA. JAMA. Aug 23, 2000

• Less expensive generic version available since 2008

• Higher efficacy in individuals with the LL GENOTYPE of the 5-HTT gene

– Johnson BA. AM J PSYCHIATRY, Jan 2011

Page 27: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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• Varenicline: Reduced both smoking & drinking in males

– O’Malley S, et al. JAMA Psychiatry Dec 20, 2017

• Topiramate effective for co-occurring AUD & PTSD

– Batki S, et al. Alcohol Clin Exp Res 38:2169-77, 2014

• Increased evidence for efficacy of AA

– Followup on Project Match: Pagano ME, Kelly JF, et al. Substance Abuse 34:51-59, 2013

– Kelly JF. Addiction 112:929-935, 2017

• Levels of “safe drinking”

– 1 beer/day for men and women. The Lancet, April 14, 2018

• Marijuana: no pattern of benefit for AUD. Subbaraman MS, Alcohol Alcohol 2014, 49(3):292-298

EMERGING ISSUES

Page 28: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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• Alcohol Use Disorder

– Drinking Trends

– SBIRT & Screening for Alcohol Related Problems

– DSM-5

– Alcohol Biomarkers

– Alcohol Withdrawal Medications

– Anticraving Medications

• Opiate Use Disorder

– Changes in Abuse Patterns

– Treating Opioid Overdose

– Opioid Withdrawal Protocols

– Opioid Agonist Therapy

– Opioid Antagonist Therapy

• Appendix – Managing Dual Diagnosis Patients

Agenda

Page 29: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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Trends In Past Year Heroin Use

SAMHSA,NSDUH, 2018 (2012-2018)

Page 30: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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US Drug Overdose Deaths

72,000 Overdose deaths in 2017; CDC WONDER August 2018

Page 31: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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LETHAL DOSE COMPARISONS

Page 32: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

The Washington Post gained access to CDC & DEA’s Automation of Reports and Consolidated Orders System (ARCOS) data: reported July 21, 2019

Page 33: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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CDC

3/18/17

RISK FOR DEVELOPING OUD

Page 34: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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• Opioid Use Disorder/Overdoses are the epidemic of this era

• Effective treatment/medications are available

• Clinicians have a responsibility to provide care

• Medications for OUD:

– Naloxone

– Methadone

– Buprenorphine

– Naltrexone

• The unique role of psychiatry: 70% comorbidity

RESPONDING TO A PUBLIC HEALTH CRISIS

Page 35: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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The Treatment of Opioid Overdose

• Signs: Coma, pinpoint pupils, depressed pulse and respirations, hypothermia

• Treatment

– Naloxone (Narcan) 0.4 mg (1ml) iv, q.4 min., prn

– If no response, treat for sedative/hypnotic OD

–Monitor methadone overdose patients for 24- 48 hrs.

– Single naloxone dose lasts 1-4 hours

– Fentanyl may require multiple doses of naloxone to reverse

Major public health initiative with Naloxone Rescue formulations; new standard of care

Page 36: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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Neurobiology of Opioid Withdrawal

• Hyperactivity of nor-adrenergic neurons in the locus coeruleus causes:– Increased BP, HR, respirations– Increased sweating, diarrhea–Clonidine , lofexidine & opiates reverse these

effects

• Increased GABA effects; reduced dopamine in the nucleus accumbens cause: –Dysphoria, depression, craving–Only opiates (methadone & buprenorphine)

reverse these effects

Page 37: Treatment of Addictive Disorders Alcohol and Opiates October …PDFs… · NEUROBIOLOGY OF ALCOHOL EFFECTS OF ALCOHOL WITHDRAWAL: •CNS HYPERACTIVITY- NO OPPOSITION TO ALCOHOL INDUCED

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Inpatient Buprenorphine Withdrawal Rx

• Document withdrawal before giving 1ST dose

• DAY 1: BUP/NALOXONE 4/1 mg SL, may redose in 2 to 4 hrs, up to 8/2 mg SL

• DAY 2: 8/2 to 12/3 mg SL

• DAY 3: 6/1.5 mg SL, final dose; may also taper 2-3 days

• 7 day protocol may be more effective

• Addicts prefer buprenorphine over methadone or clonidineUmbricht, 2003

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Withdrawal Treatment - Methadone

• Initiate treatment only after documenting withdrawal• Do not exceed initial dose of 20 mg methadone (10 mg in

younger addicts)• May repeat dose in 2 hrs., if withdrawal increases • Inpatients rarely require over 40 mg / 24 hours• Titrate dose to avoid intoxication or withdrawal• Detox taper:

– cut by 10 mg / day down to 20 mg– then cut by 5 mg / day down to zero

• Adding Very Low Dose Naltrexone (0.125 or 0.250 mg q daily) may improve outcome and ease transition to post-detox care (Mannelli, Am J Addict 2009)

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Buprenorphine Partial Agonist Therapy

• High affinity partial MU-opioid agonist / “ceiling effect” for respiratory depression, with low overdose risk

• Extended release 28 day SQ injection (Sublocade, 2017)

• Weekly/monthly depot (CAM 2038) under FDA review

• Can treat patients age 16 and older

• Maintenance range: 12-24 mg daily

• No evidence of hepatoxicity (Bogneschutz, 2010)

• Best option for younger, motivated more patients

• Requires 8 hour training & DEA WAIVER

• Patient limit can be increased from 30 to 100 to 275

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• XR-BUP (Sublocade) – monthly SQ injection

• Approved for stable patients

• Minimum 7 days initial treatment with BUP/NX sublingual formulation

• LFTs – no moderate or severe hepatic impairment

• Dosing (all SC in abdomen):

– Month 1: 300 mg

– Month 2: 300 mg

– Month 3: 100 mg - maintenance dose

• Fatalities if injected IV

Extended-Release Buprenorphine

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Buprenorphine Induction

• Abstinence prior to first BUP/NX dose:

– 16 hrs for short-acting opioids (heroin)

– 24 hrs for sustained-release opioid medications

– 36 hrs for methadone (30mg x 2 weeks; 15mg x 1 day; no methadone x 1 day; then induce on BUP/NX)

• COWS score 8-10 before 1st dose (2 or 4 mg)

• Higher COWS score (13-15) recommended for patients using fentanyl

• Rapid escalation to 16mg, if needed, by end of day 1

Gunderson EW, et al. Am J Addiction Sept, 2011

• Home inductions effective for selected patients

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• Waiver is only required for outpatient scripts

• Any authorized provider can administer or dispense inpatient to maintain or detoxify a person if care is incidental to treatment of a medical/surgical condition (other than addiction treatment) or to treat pain.

• 3 Day Rule: meds can be dispensed to relieve withdrawal (1 day at a time) while making arrangements for referral for treatment

Title 21 CFR Section 1306.07

EXEMPTIONS TO DEA WAIVER

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The Role of Counseling

• Standard recommendations since 1965 have stressed the importance of ancillary counseling for success in opioid agonist therapy

• Benefits are well documented by research –Ball & Ross, 1991; McLellan,1993

• Four recent buprenorphine trials suggest that brief, frequent physician medication monitoring visits are equal to, if not more effective than more intensive drug counseling, for less impaired patients.Fiellin, 2006, 2013; Weiss, 2011, Ling 2013

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• Continue BUP; divided in 6 to 8 hour schedule as needed

• If needed, add short-acting opioid for analgesia, such as 1 to 2 mg IV hydromorphone or 10 to 15 mg oxycodone po

• Convert back to original buprenorphine dose before discharge

• Maximize multimodal analgesia in addition to opioids

Refs: https://www.uptodate.com/contents/management-of-acute-pain-in-the-patient-chronically-using-opioids? Also see TIP 63 (pages 3-100)

Options: (1) Reduce BUP to 4mg BID; add full agonists as needed MGH protocol (Acampora G., J Clin Psych accepted for publication Aug 2019)

(2) Reduce BUP to 12mg daily; add full agonists as needed STANFORD protocol (Lembke, Pain Medicine 2018)

Severe Acute Pain in Inpatient Settings

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BUPRENORPHINE IN PREGNANCY

The MOTHER Study:• 175 pregnant opioid dependent women• 8 international sites• DB, double-dummy, flexible-dosing, randomized, controlled

trial (methadone PO vs. buprenorphine SQ)• Both drugs safe and effective• Retention: 72% methadone vs. 67% buprenorphine*

– * Most BUP dropouts in first few days, or with first dose• Comparison of 131 neonates (favors BUP vs. Methadone)

– Morphine dose required for NAS: 1.1 vs. 10.4 mg morphine

– Duration NAS: 4.1 vs. 9.9 days– Duration hospital stay: 10.0 vs. 17.5 days

Jones HE, et al. N Eng J Med, Dec 2010

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BUPRENORPHINE – DIVERSION MANAGEMENT

Studies indicate 96% of diversion is for self-medication: Swingle, 2018

Recommendations for minimizing diversion & misuse:• Use BUP/NX for all patients except pregnant women• Whenever possible keep dose to 16/4 mgs or below• After initial stabilization, wait at least 5-7 days to assess benefit of

any dose increase• For patients on 16/4 mg or more, emphasize psychosocial techniques

to manage ongoing craving or use• Weekly physician visits until stable• Regular urine toxicology screens• Regular check of state Prescription Drug Monitoring Program• Call-backs for pill counts and tox screens, as needed• Gradual dose reductions to 8/2 mg for long-term stable patients• Encourage AA / NA

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Opioid Antagonist Therapy

XR-NALTREXONE (Vivitrol)

• Long-acting injectable formulation

– 380 mg IM every 28 days

• NIDA funded X:BOT Study demonstrated comparable efficacy with buprenorphine once patients were stabilized on both drugs (open-label, randomized controlled trial). BUT: 25% induction failures on XR-NTX.Lee JD, et al. Lancet, Nov 14, 2017

• RETENTION ISSUES: Methadone >Buprenorphine >XR-NTX. Better retention has been associated with psychiatric co-morbidity, close prescriber monitoring, white race, participation in counseling and NA/AA.

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Opioid Antagonist Therapy

XR-NALTREXONE (Vivitrol) – Clinical Questions

• Identification of appropriate patients

• Difficulty initiating treatment – risk of precipitated opioid withdrawal; patients must be opioid free for 3 days from short-acting opiates; 7 – 10 days from long-acting opioids

• Risk for accidental overdoses and death:

–Opioid use at end of 1 month dosing interval

–Opioid use after missing monthly injection

–Attempts to overcome opioid blockade

• Contraindicated in acute hepatitis / liver failure

• Managing need for acute analgesia has not been a problem

• Naltrexone blockade can be over-ridden in inpatient settings.

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NEW PHARMACOTHERAPIES

• Lofexidine for opioid withdrawal treatment –comparable to clonidine but fewer side effects and may have better efficacy. More comparative studies are needed. FDA approved May 2018

• NSS-2 Bridge neurostimulator approved in 2018 to treat opioid withdrawal (based on acupuncture)

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• Early Interventions

– Treatment referral after an overdose

– Emergency Department induction (Yale model)

– Bridge clinics (between inpt/ED and outpatient)

• Retention a problem in general practice

– Treat co-occurring psychiatric disorders

– Close prescriber monitoring

– Psychosocial Services; NA/AA

• Limited number of providers – expanded residency training

IMPROVING PRACTICE

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[email protected]

Questions ?

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Cost Containment Issues

• State efforts to limit funding for treatment of opioid use disorder

• Illinois has limited BUP/NX Medicare coverage to 1 year

• Ohio and other states have proposed dose limit of 16/4 mg BUP/NX

• Pending budget tsunami for new Hep C drugs: sofosbuvir (Solvaldi) from Gilead Sciences

– $1000 per pill or $84,000 to $100,000 for 12 week course of treatment ($ 2.27 Billion sales 1st quarter 2014)

– 90% efficacy

– 3 million US infected; 50% in public sector (Veterans Administration, Medicare, prison population) primarily IV drug users

– States fear out of control costs

• Buprenorphine plus counseling reduced total health care costs compared to untreated individuals (Lynch FL, Addiction Science & Clinical Practice 2014, 9:16)

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Treatment Costs Alcohol Dependent Patients

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Treatment Costs Opiate Dependent Patients

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COMPARING METHADONE & BUPRENORPHINE / NX

BUP/NX METHADONE

Setting Office-based Clinic-based

Diagnosis DSM-5 1 year proven history

Age > 16 > 18

Target dose 12 to 16 mg 80 to 120 mg

Safety (risk of OD) Ceiling effect No ceiling effect

Cardiac risks None Over 100 mg, QTc risk

Pregnancy Safe; less NAS Safe

Efficacy Comparable in multiple studies

Pain treatment Off-label FDA approved

Diversion risk Higher Low from clinics

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Alcoholism: Rank of Co-morbid Conditions

1. Abuse of a second substance

2. Antisocial personality disorder

3. Phobias (& other anxiety disorders)

4. Major depressive disorder:13% of women alcoholics3% of male alcoholics

5. Dysthymic disorder

NOTE: Co-Morbidity is the norm for most alcoholics seen in any clinical setting

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Depression in Alcoholics• 20% of SUD patients have a co-occurring mood or anxiety disorder

(NESARC, 2004)

• Prolonged dysphoria & depression - rule out substance-induced depression

• For alcoholics with an independent major depressive disorder or dysthymic disorder. Review of randomized, DBPC trials, 1980 to 2009:– Efficacy shown for tricyclics and nefazodone– SSRI’s data currently inadequate

Iovieno N, et al. J Clin Psychiatry, August 2011

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Failure to Respond to Antidepressant Meds

• Medication NON-COMPLIANCE

• Check for RELAPSE:

– CDT

– GGT

• Check plasma levels of TCAs

• Consider enforced therapy

• Consider adding NALTREXONE or ACAMPROSATE

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Bipolar Disorder and Co-Occurring Alcoholism

• Drinking typically follows onset of mania

• Patients rarely relapse when depressed or euthymic

• Alcoholism often remits after moods are stabilized

• Medication SUGGESTIONS (no adequate DBPC trials):

– BIPOLAR I LITHIUM

– BIPOLAR II VALPROIC ACID

ATYPICAL ANTISPYCHOTICS

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DIAGNOSIS:• Wait 4 to 6 weeks for withdrawal symptoms to clear• Positive family history• +/- Symptoms antedate alcohol use

TREATMENT RECOMMENDATIONS:• Generalized anxiety dis.: BUSPIRONE • Panic disorder: ANTIDEPRESSANTS

BEHAVIORAL THERAPY• Agoraphobia: ANTIDEPRESSANTS

BEHAVIORAL THERAPY• Social phobia: PROPRANOLOL

or CLONIDINE

Anxiety Disorders in Alcoholics

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Treating ADHD in at Risk Patients

20% to 25% incidence of ADHD with any psychoactive substance use disorder

TREATMENT PROTOCOL – Adults with SUD & co-occurring ADHD:

• CBT X 2 weeks without medication

• Then start meds if symptoms persist – medication choices ranked by risk potential

– Atomoxetine (Stratera) – has no abuse potential

– Bupropion

– Desipramine

– Extended–Release Stimulants:

• Methylphenidate ER – generic (Concerta) or

• Adderal XR (amphetamine/dextroamphetamine mixed salts)

T. Wilens, 2012

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Anxiety Disorders in Addicts

The Role of Benzodiazepines:

• Comprehensive literature review

• Efficacy demonstrated for:

GAD, panic disorder and agoraphobia

• Probable efficacy for:

Social phobia, alcohol induced anxiety disorders

• Little evidence of added risk for medication abuse or increased relapse

Posternak & Mueller. Am J Addict. 2001;10:48-68.