Opioids October 29, 2010 Addiction Medicine Review Course CSAM, Newport Beach, CA Daniel P. Alford, MD, MPH, FACP, FASAM Associate Professor of Medicine Boston University School of Medicine Boston Medical Center
Disclosure of Relevant Financial Relationships October 2010 Name Commercial Interests Relevant Financial Relationships : What Was Received Relevant Financial Relationships: For What Role No Relevant Financial Relationships with Any Commercial Interests Daniel P. Alford, MD X
Opiates and Opioids Opiates Present in opium from seedpod of Papaver somniferum Morphine, codeine, thebaine Opioids Are manufactured Semisynthetics (e.g. heroin, oxycodone) are derived from an opiate Synthetics (e.g. methadone, fentanyl) are synthesized to have function similar to natural opiates
Opioids Natural (opiates) & Semisynthetic Opiates Morphine Codeine Synthetic
Source: SAMHSA, OAS, NSDUH data, July 2007
SAMHSA NSDUH 2010
Issues of Concern Percent of 12th Graders Reporting Nonmedical Use of OxyContin and Vicodin in the Past Year Remained High 12 10.5 9.6 9.3 9.5 9.7 9.6 9.7 10 8 Percent 6 4 4 4.5 5 5.5 4.3 5.2 4.7 2 0 OxyContin Vicodin 2002 2003 2004 2005 2006 2007 2008 No year-to-year differences are statistically significant. SOURCE: University of Michigan, 2008 Monitoring the Future Study
Deaths per 100,000 related to unintentional overdose and annual sales of prescription opioids by year, 1990-2006 Source: Paulozzi, CDC, Congressional testimony, 2007 8 600 Crude rate per 100,000 7 6 5 4 3 2 1 500 400 300 200 100 0 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 Sales in mg/person Deaths per 100,000 Opioid sales (mg per person) 0
Overdose Epidemiology Injection heroin users, annual mortality rate 2% 6-20 X that of non-drug using peers Half attributable to overdose Late 20s to early 30s Use for 5-10 years, only 17% novice users Multiple drug use (70%) High risk periods First 12 months after addiction treatment and First 2 weeks after release from incarceration Darke S. Addiction 1996, Gossop M. BMJ 1996
The Reward Pathway
The Reward Pathway
Physical Dependence Neurobiological adaptation that occurs with chronic opioid exposure The onset of signs and symptoms of withdrawal if opioid administration is abruptly stopped an opioid antagonist is administered
Physical Dependence & Withdrawal
Physical Dependence & Withdrawal
Physical Dependence & Withdrawal
Physical Dependence & Withdrawal
Opioid Withdrawal Assessment Hours after use 4-6 6-8 8-12 12-72 Grade 0 1 2 3 4 Anxiety, Drug Craving Symptoms / Signs Yawning, Sweating, Runny nose, Tearing eyes, Restlessness Insomnia Dilated pupils, Gooseflesh, Muscle twitching & shaking, Muscle & Joint aches, Loss of appetite Nausea, extreme restlessness, elevated blood pressure, Heart rate > 100, Fever Vomiting / dehydration, Diarrhea, Abdominal cramps, Curled-up body position Clinical Opiate Withdrawal Scale (COWS): pulse, sweating, restlessness & anxiety, pupil size, aches, runny nose & tearing, GI sx, tremor, yawning, gooseflesh (score 5-12 mild, 13-24 mod, 25-36 mod sev, 36-48 severe)
Spontaneous Opioid Withdrawal Syndrome Develops spontaneously if a physically dependent person suddenly stops, or markedly decreases, the opioid use Severity is usually less with longer half-life drugs Duration depends on half-life of opioids person uses Onset Peak Duration Heroin 4-6 hours ~3 days 4-5 days Methadone 1-2 days ~7 days 12-14 days
Precipitated Opioid Withdrawal Syndrome Precipitated in a physically dependent person, by administration of either: an opioid antagonist drug (e.g. naloxone, naltrexone) or an opioid partial agonist drug (e.g. buprenorphine) Qualitatively similar to spontaneous withdrawal but faster onset Duration depends upon half-life of drug Onset Peak Duration Naloxone minutes minutes ~20 minutes Naltrexone minutes minutes 1-2 days Buprenorphine minutes minutes 1-2 days
Natural History of Opioid Dependence Withdrawal Normal Euphoria Acute use Tolerance & Physical Dependence Chronic use
DSM IV Criteria: Opioid Abuse 1 or more of the following in a year: Recurrent use resulting in failure to fulfill major role obligations Recurrent use in hazardous situations Recurrent drug-related legal problems Continued use despite social or interpersonal problems caused or exacerbated by drugs
DSM IV Criteria: Opioid Dependence 3 or more of the following in a year: Tolerance Withdrawal A great deal of time spent to obtain drugs, use them, or recover from their effects Important activities given up or reduced because of drugs Using more or longer than intended Persistent desire or unsuccessful efforts to cut down or control substance use Use continued despite knowledge of having a persistent or recurrent physical or psychological problem caused or exacerbated by drug use
Pharmacologic Treatment of Opioid Dependence Pharmacologic taper/medically supervised withdrawal Detoxification Opioid antagonist treatment Naltrexone Opioid agonist treatment Methadone Buprenorphine
Medically Supervised Withdrawal detox Methadone Hospitalized, or in addiction Rx program Buprenorphine Hospitalized, waivered MD or addiction Rx program Other Clonidine (hyperadrenergic state) + NSAIDS (muscle cramps and pain) + Benzodiazepines (insomnia) + Dicyclomine (abdominal cramps) + Bismuth subsalicylate (diarrhea)
Opioid Detoxification Outcomes Low rates of retention in treatment High rates of relapse post-treatment < 50% abstinent at 6 months < 15% abstinent at 12 months Increased rates of overdose due to decreased tolerance O Connor PG JAMA 2005 Mattick RP, Hall WD. Lancet 1996 Stimmel B et al. JAMA 1977
Reasons for Relapse Protracted abstinence syndrome Secondary to derangement of endogenous opioid receptor system Symptoms Generalized malaise, fatigue, insomnia Poor tolerance to stress and pain Opioid craving Conditioned cues (triggers) Priming with small dose of drug
Medication Assisted Recovery Goals Alleviate physical withdrawal Opioid blockade Alleviate drug craving Normalized deranged brain changes and physiology Some options Naltrexone Methadone Buprenorphine
Medication Assisted Therapy Withdrawal Normal Euphoria Acute use Tolerance & Physical Dependence Chronic use Medication Assisted Therapy
Pure opioid antagonist Oral naltrexone Well tolerated, safe Naltrexone Duration of action 24-48 hours FDA approved 1984 Injectable naltrexone (Vivitrol ) IM injection (w/ customized needle) once/month FDA approved Oct 12, 2010 patients must be opioid free for a minimum of 7-10 days before treatment
Opioid Potency 100 90 80 % Efficacy Opioid effect, sedation, respiratory depression 70 60 50 40 30 20 10 0 Full Antagonist (Naltrexone, Naloxone) -10-9 -8-7 -6-5 -4 Log Dose of Opioid
Oral Naltrexone 10 RCTs ~700 participants to naltrexone alone or with psychosocial therapy compared with psychosocial therapy alone or placebo No clear benefit in treatment retention or relapse at follow up Benefit in highly motivated patients Impaired physicians > 80% abstinence at 18 months Cochrane Database of Systematic Reviews 2006
Naltrexone Injectable, Sustained-Release RCT, DB 8 weeks 2 med ctrs 60 heroin dependent All 2x/wk counseling Comer SD et al. Arch Gen Psychiatry 2006
Naltrexone Oral versus Implant RCT, DB 6 month f/u 70 heroin dependent Outcome: return to regular heroin use >4d/wk Hulse GK et al. Arch Gen Psychiatry 2009
Methadone Hydrochloride Full opioid agonist available in tablets, oral solution, parenteral PO onset of action 30-60 minutes Duration of action 24-36 hours to prevent opioid withdrawal and craving and block effects of illicit opioid use 6-8 hours analgesia
Opioid Potency 100 90 80 Full Agonist (Heroin, Oxycodone, Methadone) % Efficacy Opioid effect, sedation, respiratory depression 70 60 50 40 30 20 10 0 Full Antagonist (Naltrexone, Naloxone) -10-9 -8-7 -6-5 -4 Log Dose of Opioid
Heroin vs Methadone
Dose Response
Effects of Psychosocial Services McLellan, AT et.al, JAMA 1993
Methadone Maintenance Improved Neurochemistry 140 p< 0.002 p< 0.002 130 p< 0.09 Short Term (35 weeks) Normalize d Value (% Control) 120 110 p< 0.09 Long Term (105 weeks) Control 100 90 80 %PME %PDE PME/PDE Kaufman MJ et al. Psychiatry Res 1999 Cerebral Phospholipid Metabolites
Safety of Methadone Maintenance Prospective study of 129 patients Retrospective study of 1435 patients Greater than 3 years of treatment Results No change in baseline LFTs Normal hematologic and endocrinologic studies 48% increased sweating 22% decreased libido 17% constipation Kreek MJ. JAMA. 1973
In a Comprehensive Rehabilitation Program JAMA 2005 Increases overall survival Increases treatment retention Decreases illicit opioid use Decreases hepatitis and HIV seroconversion Decreases criminal activity Increases employment Improves birth outcomes
Methadone Maintenance Treatment Opioid Treatment Programs (OTP) Highly regulated (Narcotic Addict Treatment Act of 1974) Highly structured Daily methadone dosing take home dose Daily nursing assessment Weekly individual and/or group counseling Random supervised toxicology screens Psychiatric services Medical services Acupuncture
Methadone Maintenance Limitations Separate system (Opioid Treatment Programs) Limited access Inconvenient Punitive Stable & unstable patients Lack of privacy No ability to graduate Stigma
Buprenorphine 2000: Drug Addiction Treatment Act of 2000 2002: FDA approved 2 medications for treating opioid dependence, DEA scheduled III narcotic Sublingual tablets Buprenorphine (Subutex ) Buprenorphine/naloxone (Suboxone ) Film (Suboxone ) Faster to dissolve, favorable taste Individually wrapped pouches that are child-resistant Implants (Ling W et al. JAMA 2010) To improve adherence and decrease diversion
Partial Agonist: Ceiling Effect 100 90 Full Agonist 80 % Efficacy Opioid effect, sedation, respiratory depression 70 60 50 40 30 20 10 0 Maximum opioid agonist effect is never achieved Partial Agonist (Buprenorphine) Increasing activity at increased doses Full Antagonist -10-9 -8-7 -6-5 -4 Log Dose of Opioid
Buprenorphine Efficacy Studies (RCT) show buprenorphine more effective than placebo and equally effective to moderate doses (80 mg) of methadone on primary outcomes of: Abstinence from illicit opioid use Retention in treatment Decreased opioid craving Johnson et al. NEJM 2000 Fudala PJ et al. NEJM 2003 Kakko J et al. Lancet 2003
Opioid Blockade MRI Bup 00 mg Binding Potential (Bmax/Kd) Bup 02 mg 4 - Bup 16 mg 0 - Bup 32 mg Slide Courtesy of Laura McNicholas, MD, PhD
Decreased Opioid Craving Fudala P et al. N Engl J Med 2003
Buprenorphine: More Favorable Withdrawal? Kosten, O Connor NEJM 2003
Buprenorphine Maintenance vs Detox Remaining in treatment (nr) 20 15 10 5 75% retention 75% UTS negative 20% mortality in placebo group Control Buprenorphine 0 0 50 100 150 200 250 300 350 Treatment duration (days) Kakko J et al. Lancet 2003
Summary Opioid overdose high risk period when tolerance is low Acute opioid administration stimulates the Reward Pathway Chronic opioid administration results in physical dependence and subsequent acute and chronic withdrawal Opioid dependence is a chronic relapsing medical condition Methadone maintenance, highly structured, with many years of proven efficacy, but w/ limitations Buprenorphine maintenance in office-based settings, less structured, as effective as moderate dose methadone w/ fewer limitations