treatment of addictive disorders alcohol and opiates...
TRANSCRIPT
www.mghcme.org
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 21, 2018
www.mghcme.org
• 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
www.mghcme.org
Substances for Which Most Recent Treatment Was Received in the Past Year among Persons
Aged 12 or Older: 2012
4
www.mghcme.org
Alcohol Use Disorders
Epidemiology:
•Alcohol use accounts for 1 in 10 deaths in US adults age 20 to 64, approximately 88,000 deaths per year
•Drinkers lives are shortened by about 30 years
•Drinking costs US $224 billion a year due to lost productivity, including reduced wages and health care costs• Increased drinking among the elderlyCDC 2014 http://www.cdc.gov/alcohol/index.htm
www.mghcme.org
High School Binge Drinking
Monitoring The Future, 2015
www.mghcme.org
Binge Drinking in the US
CDC, 2015
www.mghcme.org
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
www.mghcme.org
• 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
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
ALCOHOL SUBTYPESNESARC study, adapted from Moss H, Drug Alc Depend, 2007
YOUNG ADULTS32%
LATE ONSET38%
EARLY ONSET30%
EPISODIC HEAVY BINGE DRINKING
MODERATE DRINKING SEVERE CHRONIC DRINKING
LITTLE PSYCHO-PATHOLOGY
MINIMAL PSYCHO-PATHOLOGY
SEVERE PSYCHO-PATHOLOGY
MINIMAL GENETIC RISK MODERATE GENETIC RISK SEVERE GENETIC RISK
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
MEDICATIONS FOR ALCOHOL WITHDRAWAL
• Experimental Phenobarbital Protocol for treatment resistant alcohol withdrawal requiring high benzodiazepine doses• Data suggests barbiturates are
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
Martin K, Katz A. Literature review, Psychosomatics 2016 57:341-347
www.mghcme.org
• Professional Counseling:
– CBT
– Motivational Enhancement Therapy
– 12-Step Facilitation
• Medications for Addiction Treatment:
– Naltrexone
– Acamprosate
– Disulfiram
• Mutual Support Groups
EVIDENCE-BASED TREATMENTS
www.mghcme.org
RELAPSE PREVENTION PHARMACOTHERAPY
ANTICRAVING MEDICATIONSas
THE NEW STANDARD OF CARE
Consider, immediately post-detoxification for ALLalcoholics
Efficacy requires counseling and/or frequent physician monitoring; med compliance is critical for success
Less than 9 % of individuals with AUD get MAT
www.mghcme.org
• DISULFIRAM *
• NALTREXONE (PO* & IM* formulations)
• ACAMPROSATE *
• TOPIRAMATE
• ONDANSETRON
• SSRIs
• CLOZAPINE
• QUETIAPINE
* FDA APPROVED
ADDICTION PHARMACOTHERAPY:MEDICATIONS IN THE LONG-TERM MANAGEMENT OF ALCOHOL USE DISORDER
www.mghcme.org
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)
www.mghcme.org
Naltrexone Outcome associated with variants of opioid receptor gene OPRM 1
Asp 40 Allel Asn 40 Allel
NALTREXONE 87%GOOD OUTCOME
55%GOOD OUTCOME
PLACEBO 49%GOOD OUTCOME
54%GOOD OUTCOME
Project Combine; Anton R. Arch Gen Psychiatry. 2008.In meta-analysis of 6 studies, patients carrying the G allele of A118G polymorphism of OPRM1 had lower relapse rates, but no difference in abstinence rates (Chamorro et al, 2012)
www.mghcme.org
EXTENDED-RELEASE NALTREXONE (Vivitrol)
• Long-acting injectible formulation: 380 mg IM q 28 days• Screen LFTs• More stable plasma concentrations compared to the oral
formulation• 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
www.mghcme.org
RECOMMENDATIONS FOR USE OF NALTREXONE
• Screening tests for hepatic/renal function• Begin 50 mg ORAL Naltrexone after 2-5 days sobriety
(post detox)• If no response after 2 weeks, go 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
• If no response consider Acamprosate or Disulfiram
www.mghcme.org
• Rarely offered to patients
• Poor adherence (average 2-3 months rx)
• Improving adherence:
– Increased psychosocial treatment
– Intensive rehabilitation when needed
– Psychiatric care and monitoring
Chang C. et al. Am J Addiction XX 1-7, 2018
ISSUES with XR-NALTREXONE
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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.
www.mghcme.org
TOPIRAMATE (Topamax)
• Facilitates GABA
• Inhibits Glutamate
• Reduced drinking and craving:
– DBPC trial (Johnson. Lancet. 2003)
– 150 subjects
• Dose: 25 mg PO QD, then increase dose 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
www.mghcme.org
ONDANSETRON (Zofran)
• Anti-nausea drug approved 1991
• 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
www.mghcme.org
QUETIAPINE (Seroquel)
• Atypicals target both DA & 5-HT Systems• Reduced substance use on clozapine• 12-week DBPC trial in 61 subjects• 11 of 61 achieved total abstinence:
– 9 were on quetiapine
– 2 were on placebo• TYPE B/Early Onset – marked quetiapine benefit• TYPE A/Late Onset – no difference from placebo
Kampman & Pettinati. J Clin Psychopharmacology. 2007
A large meta-analysis of 13 DB studies of antipsychotics failed to demonstrate efficacy for relapse prevention. Subjects were not categorized by subtypes. T. Kishi, J Clin Psych 2013
www.mghcme.org
SSRIs May Reduce Drinking in Some Alcohol Subtypes
• CITALOPRAM: Reduced drinking in non-depressed male alcoholics; no efficacy in non-depressed female alcoholics (Naranjo, 2000)
• SERTRALINE: Reduced drinking in Late Onset men; no efficacy, or made drinking worse in Late Onset women or Early Onset men or women (Pettinati, 2004)
www.mghcme.org
ALCOHOLISM PHARMACOTHERAPY SUGGESTIONS
ALCOHOLISM SUBTYPE INTERVENTION
Binge Drinking Young Adults Education
Motivational Enhancement Therapy
Naltrexone - oral
Early Onset; Severe
Psychiatric Co-morbidity
Ondansetron
Topiramate; Atypical Antipsychotics ?
Late Onset; Moderate Naltrexone – XR formulation
Topiramate
SSRIs in males
Late Onset; Severe
Psychiatric Co-morbidity
Naltrexone – XR formulation
Topiramate
Elderly Onset Naltrexone – XR formulation
www.mghcme.org
Treatment Costs Alcohol Dependent Patients
www.mghcme.org
• 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
www.mghcme.org
Patient Management Techniques
• 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.
• CBT & relapse prevention counseling
• Anticipate lapses & relapses
• Active therapeutic stance
• For persistent insomnia: TRAZODONE
• Avoid prescription tranquilizers
www.mghcme.org
US Drug Overdose Deaths
72,000 Overdose deaths in 2017; CDC WONDER August 2018
www.mghcme.org
• 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
www.mghcme.org
Heroin Use; Monitoring The Future, 1974- 2016
DROPS IN HEROIN USE (MTF, 2016)
www.mghcme.org
Narcotics use other than heroin, Monitoring the Future 1974 - 2016
DROPS IN OTHER NARCOTICS (MTF, 2016)
www.mghcme.org
CDC
3/18/17
RISK FOR DEVELOPING OUD
www.mghcme.org
www.mghcme.org
LETHAL DOSE COMPARISONS
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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)
www.mghcme.org
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
www.mghcme.org
Withdrawal Rx - Outcome Data Percent patients drug-free at 13 weeks,
MEDICATION INPATIENTDETOXIFICATION
OUTPATIENTDETOXIFICATION
BUPRENORPHINE / NALOXONE
77 % 29 %
CLONIDINE 22 % 5 %
W. Ling, 2005
www.mghcme.org
Opioid Agonist Therapy
BUPRENORPHINE:
• High affinity partial MU-opioid agonist / “ceiling effect” for respiratory depression
– Low overdose risk
• Kappa receptor antagonist
• Sublingual buprenorphine/naloxone tablet
–New film strip formulation in 2010
–Generic sublingual formulations 2013
• Extended release subdermal rods 2016
• Over 400,000 patients currently in active treatment
• Prescribing requires training & CSAT / DEA WAIVER waiverlimit can be increased from 30 to 100 to 275
www.mghcme.org
Opioid Agonist Therapy
BUPRENORPHINE:
• DSM-5 criteria for addiction (Opioid Use Disorder–Moderate)
• Can treat patients age 16 and older
• Rapid stabilization in 1-2 days
• Maintenance range: 12-24 mg
• Long half-life: 24 to 72 hr dosing
• No evidence of hepatoxicity (Bogneschutz, 2010)
• Best option for younger, motivated patients with shorter addiction histories and less sociopathy
• Not recommended in severe chronic pain syndromes
www.mghcme.org
Opioid Agonist Therapy
BUPRENORPHINE – OUTPATIENT INDUCTION RECOMMENDATIONS:
• 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)
• Rapid escalation to 16mg, if needed, by end of day 1
Gunderson EW, et al. Am J Addiction Sept, 2011
www.mghcme.org
• Waiver is only required for outpatient prescriptions
• 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
www.mghcme.org
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
www.mghcme.org
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 (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
www.mghcme.org
Jones et al, N Engl J Med, 2010
Neonatal Abstinence Syndrome
56
www.mghcme.org
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 patients• Encourage AA / NA
www.mghcme.org
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
www.mghcme.org
Opioid Antagonist Therapy
XR-NALTREXONE (Vivitrol)
• Long-acting injectable formulation
– 380 mg IM every 28 days
• FDA approved for opioid use disorder in 2010
• 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.
www.mghcme.org
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
• Acute pain control may be a problem. Naltrexone blockade can be over-ridden in inpatient settings.
www.mghcme.org
Opioid Antagonist Therapy
XR-NALTREXONE (Vivitrol) – Induction Protocol
• Non-opioid treatment for withdrawal will speed induction on to XR-NTX.
• Research protocols impractical in most settings
• Model withdrawal protocol leading to XR-NTX induction (A. Bisaga, Columbia group)– Days 1 to 5 *
• Clonazepam 1 mg tid
• Clonidine 0.1 to 0.2mg tid
• Trazodone 100mg QHS
– Day 6 • Naltrexone12.5mg oral (1/4 tablet); if tolerated:
• Wait 2 hours, then naloxone challenge test or XR-NXT first dose
* if patient has been using fentanyl or high doses of heroin, give bup/nx8mg /2mg on day 1, after documenting opioid withdrawal
www.mghcme.org
• XR-BUP (Sublocade) – monthly SQ BUP formulation; approved Nov 2017 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: 300mg
– Month 2: 300mg
– Month 3: 100mg - maintenance dose
• Fatalities if injected IV
Extended-Release Buprenorphine
www.mghcme.org
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
• Probuphine - extended release subdermal buprenorphine implant rods. (R. Rosenthal, W. Ling, et al. Addiction 8/2013)
• FDA approved 2016.
• Patients must be stabilized 1st on BUP/NX SL, 8mg/2mg or a lower dose
• Patients may require supplemental SL BUP/NX
• Improved medication compliance
• Option for stable long term patients; not appropriate for patients new to treatment or unstable patients
• NSS-2 Bridge neurostimulator approved in 2018 to treat opioid withdrawal (based on acupuncture)
• Generic BUP/NX film strips approved 2018
www.mghcme.org
• 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 training
IMPROVING PRACTICE
www.mghcme.org
Treatment Costs Opiate Dependent Patients
www.mghcme.org
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)
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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
www.mghcme.org
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.
www.mghcme.org
Opiate Agonist Therapy – Pain Management
• Opioid agonist maintained patients do experience pain and will have high tolerance to opioids
– Manage with non-opioids meds if possible
• For Methadone patients
– a full opioid agonist can be added as needed, or dispense methadone in divided doses
• For Buprenorphine patients
– add supplemental BUP dose or dispense in divided doses
– or add full agonists to daily buprenorphine dose
– switch to methadone or morphine
• For patients with chronic pain and addiction
– Buprenorphine/Naloxone in divided doses may be ideal for long term management