Pharmacologic Treatment of Addiction Dr Andrew Mallon
Your Brain on Drugs Today 1-2 Min 3-4 5-6 6-7 7-8 8-9 9-10 10-20 20-30 YELLOWshows places in brain where cocaine goes (striatum) Front of Brain Back of Brain Fowler et al., Synapse, 1989.
Addiction as a Brain Disease • Key brain pathways involve motivation, salience, memory, and reward • Prolonged drug use is associated with changes brain function • Changes are pervasive and persist after drug use stops • Brain changes demonstrated at molecular, cellular, structural and functional levels • These studies provide a rationale for medication-assisted treatment of addiction
Drug Addiction Treatment • Scientific studies demonstrate that the right mix of behavioural therapy, spiritual exploration, medication (when available), medical & social services can help addicted people navigate the road to recovery.
FDA Approved Treatments for Nicotine Addiction • Chantix™ (Varenicline) • Zyban • Nicotine Replacement Tobacco use is responsible for an estimated 5 million deaths worldwide each year http://www.drugabuse.gov/Infofacts/Tobacco.html
Chantix™ (Varenicline) • Non-nicotine aid for smoking cessation treatment + counseling • When smoke is inhaled, nicotine attaches to brain receptors & sends a message to a different part of the brain to release dopamine = pleasure feeling for a short time. • Chantix works by activating these receptors and blocking nicotine from attaching to them.
Chantix™ (Varenicline) Dual Mechanism of Action: • Partial agonist effect through selective receptor binding & stimulates brain receptor-mediated activity, but at significantly lower level than nicotine (agonist effect). • Blocks the ability of nicotine to activate the receptors & thus, to stimulate the central nervous mesolimbic dopamine sx, the neuronal mechanism underlying reinforcement and reward for smokers (antagonist effect). Use with caution in patients with hx psychosis
Two Trials Comparing Quit Rates* with Chantix, Zyban and Placebo Quit Rates = Continuous abstinence (not even one puff of a cigarette) during weeks 9-12 JAMA. 2006; 296:47-55 & JAMA. 2006; 296:56-63
Chantix (Varenicline) • Dose: 0.5 mg q day x 3 days, then 0.5 mg BID on days 4-7, then 1 mg BID x 12 weeks + • The most frequently reported adverse events (>10%) with CHANTIX were nausea, headache, insomnia and abnormal dreams. • Nausea was reported by approximately 30% of patients treated with CHANTIX 1 mg bid, with approximately a 3% discontinuation rate during 12 weeks of treatment.
FDA Approved Medications for Treatment of Alcoholism • Disulfiram (Antabuse) • Acamprosate (Campral) • Naltrexone NON-FDA Approved Medications • Topiramate (Topamax) • Modafinil • Prazosin (Minipress) - in clincial trials w/patients w/PTSD • …and many more!www.clinicaltrials.gov
Disulfiram (Antabuse) • Used to support the treatment of chronic alcohol abuse by producing an acute sensitivity to alcohol • Disulfiram should not be taken if alcohol has been consumed in the last 12 hours. • Initial dose is 500 mg for 1 to 2 weeks, followed by a maintenance dose of 250 mg (range 125 mg - 500 mg) per day. The total daily dosage should not exceed 500 mg • May cause liver toxicity so use w/caution in co-infected patients with chronic HBV and/or HCV • Alcohol may be a potent cue for cocaine use. Often concurrent use
Acamprosate (Campral) • Blocks release of glutamate, which is associated with alcohol withdrawal • Appears to be more helpful in preventing relapse than reducing drinking levels • Does not prevent withdrawal symptoms • Dose: .666 mg TID (can use 1/2 strength) • Side effects: diarrhea, gas, upset stomach, loss of appetite, dry mouth, dizziness, itching, weakness. Monitor for depression. No liver toxicity
Naltrexone • By blocking the µ-opioid receptors, naltrexone weakens the rewarding effects of alcohol and reduces dopamine release and the inhibitory GABAergic output. Blocks the “high” feeling • Appears to promote reduction in drinking level • Dose: 50 mg q day. Side effect nausea is transient and transaminitis rare • Extended-release naltrexone is the first once-a-month injection medication for alcohol dependence. May cause liver toxicity Noeline C Latt, Stephen Jurd, Jennie Houseman and Sonia E Wutzke. "Naltrexone in alcohol dependence: a randomised controlled trial of effectiveness in a standard clinical setting.". The Medical Journal of Australia176 (11): 530-534.
Recent Opioid Trends • Heroin related problems are stable • Major increases in problems related to prescription opioid use and abuse: • Non-medical use • Emergency department visits • Addiction treatment admissions • Prescription opioid-related death
New Non-medical Users of Pain Relievers Aged 12 or Older Source: Office of Applied Studies. (2003). Results from the 2002 National Survey on Drug Use and Health: National findings (DHHS Publication No. SMA 03–3836, NHSDA Series H–22). Rockville, MD: Substance Abuse and Mental Health Services Administration. Nonmedical Use of Prescription Pain Relievers May 21, 2004 Millions
Methadone Maintenance:Treatment Outcomes • Methadone: • Reduces overall and overdose deaths • Drug use • Criminal behavior • Spread of infectious diseases (HIV, TB) • Not a cure
Swedish Methadone StudyBefore Experimental Group(Methadone) Control Group(No Methadone) Gunne & Gronbladh, 1981
Swedish Methadone StudyAfter 2 Years Experimental Group(Methadone) Control Group(No Methadone) a b c d d d a Sepsisb Sepsis and Endocarditisc Leg Amputationd In Prison Gunne & Gronbladh, 1981
Frequency of Heroin Use & Methadone Dose Level Past month IV drug use (%) Adapted from V. Dole (1989) JAMA, 282, p. 1881
Reduction of Heroin Use By Duration of Methadone Treatment Pre- treatment Admission: < 6 months stay Average Stay: 6 to 54 months Long-term: > 54 months Adapted from: Ball & Ross, 1991.
Return to I.V. Drug Use Following Termination of Methadone Treatment % IV USERS Months Since Dropout Adapted from: Ball & Ross, 1991.
Methadone Maintenance:How Long? • Randomized trial of 179 patients • Maintenance versus 180-day psychosocially enriched detoxification • Maintenance resulted in greater treatment retention and less heroin use • No support for diverting resources from maintenance to long-term detoxification JAMA 2000;283:1303-10
Methadone Maintenance:Summary • Limitations • Highly structured program (6 days/week) • Limited clinical flexibility and minimal medical services • Expansion often opposed, stigma • For patients in Methadone Maintenance • Ask about urine tests and encourage adequate dose, take-home doses, and treatment retention
Buprenorphine:A New Office-Based Option • New medication for opioid dependence • Federal legislation (DATA 2000): • Allows trained MDs to prescribe Schedule III-V drugs approved for addiction treatment • Initially limited to 30 patients/group practice, but now each MD can treat up to 100 patients • Safer than methadone • With naloxone, reduced abuse potential
Full Agonist vs Partial Agonist 100 90 Full Agonist 80 70 Activity 60 Partial Agonist 50 40 30 20 Antagonist 10 0 -10 -9 -8 -7 -6 -5 -4 Log Dose of Opioid
Buprenorphine Maintenance versus Detoxification • Randomized trial of 40 Swedish patients ineligible for methadone but >1 year of dependence • Control group given buprenorphine taper (1 week) • Both groups given weekly Cognitive Behavioral Therapy, individual counseling and assistance with social services
Buprenorphine Maintenance/Withdrawal: Retention 20 15 Remaining in treatment (nr) 10 Control 5 Buprenorphine 0 0 50 100 150 200 250 300 350 (Kakko et al., 2003) Treatment duration (days)
Buprenorphine Maintenance/Withdrawal: Mortality (Kakko et al., 2003)
Maintenance Treatment Using Buprenorphine • Buprenorphine, methadone, LAAM comparison: • 17 week outpatient randomized, double-blind clinical trial, single site (n=220) • Four conditions with flexible dosing for three of the four: high dose methadone, LAAM (3x per week), buprenorphine (3x per week), and low dose methadone
Buprenorphine, Methadone, LAAM: Treatment Retention 100 73% Hi Meth 80 60 58% Bup Percent Retained 53% LAAM 40 20 20% Lo Meth 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Study Week (Johnson et al., 2000)
Buprenorphine, Methadone, LAAM:Opioid Urine Results 100 All Subjects 80 LAAM 49% 60 Bup 40% Hi Meth Mean % Negative 40 39% Lo Meth 20 19% 0 1 3 5 7 9 11 13 15 17 Study Week (Johnson et al., 2000)
Suboxone and HAART • Buprenorphine is metabolized through CYP3A4 • Protease Inhibitors: RTV, but not NFV or LPV/R, increases buprenorphine AUC, but no opioid excess seen • NNRTI: DLV increases and EFV decreases the buprenorphine AUC, but no clinically significant consequences • Naloxone has no CYP3A4 metabolism, so no HAART interactions expected
Buprenorphine Implementation • Major efforts by CSAT to train physicians, provide mentoring, help patients find help • Slow adoption by physicians • Difficulty integrating office-based treatment and psychosocial services • Insurance coverage inconsistent and generally not available for publicly funded patients
Buprenorphine: Who Gets It? • CSAT Waiver Evaluation Results: • 31% new to addiction treatment (60% new to medication assisted treatment) • 60% addicted to non-heroin opioid • No reduction in patients seeking methadone • Compared with a methadone treatment sample: • Younger, more white (92% vs 53%) • More employed (50% vs 29%) • More post-secondary education (56% vs 18%) • More non-heroin only users (40% vs 10%)
Buprenorphine in Washington State • Facilitate and evaluate the development and implementation of a pilot office-based buprenorphine program within the Washington State Medicaid program • Funded by the RWJ Substance Abuse Policy Research Program
WA State Buprenorphine Policy • Medicaid Eligibility Limitations • CNP/GAX coupons only (“dual eligible” and parents) • Not GAU, ADATSA (exception for special project) • Clinical Requirements • Patients must be enrolled in addiction program • Limited to 6 months with one 6-month extension • Limited to two-week supply of medication
Buprenorphine in WA State:Program Features • Physician Recruitment • HMC clinics (AMC, FMC, Madison, PSC) • Community clinics • Psychosocial Services • Evergreen Treatment Services • King County funding for CNP/GAX patients • Approximately 2 hours/month • RCKC for ADATSA patients
Buprenorphine in WA State:Limitations • Physician Issues • Many clinic directors not interested • Appointment scheduling difficult, especially induction • Psychosocial Treatment Issues • Off site services cumbersome • Patient Recruitment Issues • Many patients had wrong/no medical coupon • Access to methadone increased • Multiple steps prior to medication
HMC Addictions Program: Suboxone Track • Focus on HMC patients • Expedited access to assessment, induction • Still restricted to CNP/GAX patients • Centralized Induction Services • Devoted physician FTE • Refer to primary care physicians once stabilized • Collaborate with HMC Addictions Program • On site psychosocial services • Referrals: 744-9657 or call me
Summary • Buprenorphine has potential to expand treatment access and physician involvement in addiction treatment • Substantial limitations exist, especially regulatory restrictions and cost • Methadone maintenance remains an effective treatment option