Opiate Substitution Therapy for Opiate Dependence Alan Shein, M.D. OH #1-1 STATISTICS Prevalence of Specific Drug Abuse and Vulnerability to Develop Addictions National Household Survey and Related Surveys 1996 1999 Alcohol Use ever ~ 177 million Alcoholism ~ 15 million Cocaine Use ever ~ 26 million Cocaine Addiction ~ 1 to 2 million Heroin Use ever ~ 2.5 to 3 million Heroin Addiction ~ 0.5 to 1 million Development of Addiction After Self Exposure Alcoholism ~ 1 in 10 to 1 in 20 Cocaine Addiction ~ 1 in 10 to 1 in 20 Heroin Addiction ~ 1 in 3 to 1 in 5 NIDA, SAMHSA Reports 1
Prescription Opiates Prescription opiate use has escalated dramatically in the past decade Estimated 33 million people reported using prescription opiates for NONMEDICAL purposes at least once (2007) Estimated 4-5 million currently abusing or dependent on prescription opiates OH #1-4 DATA FROM 2004 NSDUH OH #1-5 HISTORY OF OPIATE ADDICTION 2
The Changing Face of Opioid Addiction Opioid addiction became a serious problem during and after the Civil War. By the late 19 th century, doctors became more cautious about prescribing opioids. Heroin introduced in 1898 as a cough suppressant By 1900, an estimated 300,000 people were opioid addicted in the United States. Hypodermic technique of drug administration (1910-1920) The Changing Face of Opioid Addiction In the early 20 th century, the size and composition of the opioid-addicted population changed. Addiction caused increasing concern as tolerance for people with addictions waned. By late 1990s, an estimated 898,000 Americans used heroin. HISTORY OF OPIATE ADDICTION TREATMENT OH #1-9 3
Early Treatment Efforts The Treasury closes opioid treatment clinics in the 1920s. The U.S. Public Health Service introduces two prison-like treatment facilities in 1929. In 1958, ABA and AMA recommend outpatient treatment to address opioid addiction. In the early 1960s, research begins on opioid maintenance treatment. Dole and Nyswander Dole and Nyswander: Rockefeller University NYC At the time, an estimated 50% of the active heroin addicts in the US lived in New York City Theorized that relapse was related to persistent or recurrent drug craving Any approach to treatment must first address craving factor Control drug craving through medically supervised opiate replacement Opiate Substitution Therapy Morphine initially used as opiate substitute to treat opiate dependence Problems: 1. Social functioning impaired due to marked sedation 2. Short half life required multiple doses per day (at least 4) 3. Needed to be administrated parenterally (IV, IM) oral administration preferred 4. Tolerance Developed Higher and higher doses needed with continued treatment to control cravings OH #1-12 4
Demonstrated Methadone: When taken daily at adequate does: 1. Effective orally administrated only once daily 2. Eliminated withdrawal symptoms 3. Eliminated drug cravings 4. Opiate euphoria absent 5. Blocked euphoric, tranquilizing effect of other opiates 6. Ability to function in daily life activities and goal is restored 7. Minimal side effects 8. No change in tolerance over time OH #1-13 Methadone Maintenance: From Research to Public Health Program In 1965, the initial research project on methadone safety and efficacy transferred to Manhattan General Hospital in NYC. Dr. Frances Rowe Gearing Columbia University Patients social functioning improved with time. Patients were stabilized on 80-120 mg/day. Patients who remained in treatment typically eliminated illicit-opioid use. Dr. Jerome Jaffe led a major public health initiative to treat opioid addiction. Mod 1 12 Development of Naltrexone Only pure opioid antagonist. Approved for opioid addiction treatment in 1984. Most useful for motivated patients who have undergone detoxification and need support to avoid relapse. Helps some patients in beginning stages of opioid use and addiction. Some patients demonstrate poor compliance with long-term naltrexone therapy. Mod 1 14 5
Development of Buprenorphine In 2002, DEA classified buprenorphine as a Schedule III drug. Buprenorphine is the first drug approved for treatment of opioid addiction in physicians offices. Mod 1 13 TREATMENT APPROACH OH #1-17 Two Views of Opioid Dependence View 1 Opioid addiction is a disease. Treatment requires long-term medical maintenance. View 2 Opioid addiction is caused by weak will, moral failing, or other psychodynamic factors or is predetermined. Treatment is criminalization of use and distribution and promotion of abstinence. 6
Opioid Dependence Diagnostic Criteria (DSM-IV-TR Definition) (3 or more within 12-month period) Tolerance Withdrawal (Abstinence Syndrome) Large amounts/longer period than intended Inability/persistent desire to cut down or control Increase amount of time spent in activities necessary to obtain opioids Social, occupational, and recreational activities sacrificed Continued use despite adverse consequences OH #1-19 Promoting Comprehensive Treatment NIDA Principles of Effective Drug Addiction Treatment: A Research-Based Guide Effective treatment attends to multiple needs of individual. Counseling and other behavioral therapies are critical components of effective treatment. Medications, especially combined with behavioral therapies, are an important element of treatment for many patients. Mod 1 28 Steps in Patient-Treatment Matching: Patient Assessment Comprehensive assessment should include patient s: Extent, nature, and duration of substance use Treatment history Medical, psychiatric, and psychosocial needs Functional status Gender, culture, ethnicity, and language Motivation to comply with treatment Recovery support Mod 5#2 7
Phased-Treatment Approach The phased-treatment approach comprises five or six patient-centered phases for planning and providing MAT services and evaluating treatment outcomes in an OTP: Acute Phase Rehabilitative Phase Supportive-Care Phase Medical Maintenance Phase Tapering Phase (optional) Continuing-Care Phase Mod 6 #2 1 Treatment Phases Acute 2 Rehabilitative 3 Supportive Care 4 Medical Maintenance Tapering and MSW 5 6 Continuing Care Mod 6 #5 PHARMACOLOGY OF OPIATES OH #1-24 8
Commonly Abused Opioids Diacetylmorphine (Heroin) Hydromorphone (Dilaudid) Oxycodone (OxyContin, Percodan, Percocet, Tylox) Meperidine (Demerol) Hydrocodone (Lortab, Vicodin) OH #1-25 Commonly Abused Opioids (continued) Morphine (MS Contin, Oramorph) Fentanyl (Sublimaze) Propoxyphene (Darvon) Methadone (Dolophine) Codeine Opium OH #1-26 Opioid Receptors Mu (MOR) Subtypes: μ1, μ2 Kappa (KOR) Subtypes: K 1, K 2, K 3 Delta (DOR) Subtypes: δ 1,δ 2 OH #1-27 9
Opiate Receptor Mediated Action Mu 1 Supraspinal analgesia Mu 2 Respiratory Depression Gastrointestinal stasis Urinary retention Bradycardia Pruritis Euphoria Physical dependence Kappa Supraspinal analgesia Spinal analgesia Sedation Miosis Hyperalgesia OH #1-28 Opioid Pharmacology FULL AGONISTS PARTIAL AGONISTS ANTAGONISTS OH #1-29 Opioid Pharmacology FULL AGONISTS Bind to the receptor and activate the receptor Increasing the amount or dose of the drug produces increasing receptor-specific effects with a maximum effect (Ex Heroin, Morphine, Methadone) OH #1-30 10
Opioid Pharmacology PARTIAL AGONISTS Bind to the receptor, But do not fully activate the receptor as a full agonists Increasing the amount or dose of the drug does not produce as great an effect as increasing that of a full agonists There is less of a maximal effect (Ex Buprenorphine) OH #1-31 Opioid Pharmacology ANTAGONISTS Bind to the receptor Do not activate the receptor Block the receptor from activation by a full or partial agonists (Ex Naloxone, Naltrexone) OH #1-32 OH #1-33 11
Opioid Pharmacology Effects of Opiates 1. Analgesia 2. Relaxation 3. Sense of well being 4. Euphoria 5. Sedation OH #1-34 Concerns 1. Tolerance develops rapidly 2. Physiologic dependence 3. Abrupt cessation results in myriad of withdrawal symptoms OH #1-35 Withdrawal Signs / Symptoms SIGNS Mydriasis Piloerection Diaphoresis Rhinorrhea Lacrimation Yawning Sneezing Restlessness/irritability Level of consciousness SYMPTOMS Sweats / chills Joint pain Muscle pain Leg cramps / jerks Stomach cramps Nausea / vomiting Diarrhea Insomnia Anxiousness Craving/Drug seeking OH #1-36 12
OPIOID PHARMACOLOGY Withdrawal Syndrome Time Course Onset = 6-12 hours Peak = 36-72 hours Duration = 5-10 days For Longer acting agents: Slower onset of symptoms Less severe symptomatology Longer duration OH #1-37 Treatment Options Opiate Substitution Methadone Buprenorphine Pharmacotherapy with assessment, psychosocial intervention, and support services Medically supervised withdrawal treatment Naltrexone Mod 1 24 TIP 43 PG 31 13
Stages of Pharmacotherapy Induction: Initial treatment process of adjusting maintenance medication dosage levels until a patient attains stabilization Stabilization: Process of providing immediate assistance to eliminate withdrawal symptoms and drug craving Maintenance: Dispensing an opioid addiction medication at stable dosage levels for a period in excess of 21 days Mod 4 #4 Voluntary Tapering and Dose Reduction Patients attempt reduction or cessation of maintenance for many reasons; there is a high relapse rate. Withdrawal should be tried when strongly desired by a stable patient, but sometimes dose tapering is necessary for administrative reasons. Many treatment providers can t improve outcomes for patients who undertake planned withdrawal, so withdrawal should be undertaken conservatively. Mod 4 #5 MSW After Detoxification Methadone or buprenorphine can be used for detoxification (controlled withdrawal from opioids) and then can be tapered gradually (MSW). Regulations specify two kinds of detoxification with methadone: Short-term treatment of fewer than 30 days Long-term treatment of 30 to 180 days. Dosing decisions in MSW are related to the intended steepness of tapering. Mod 4 #8 14
PHARMACOTHERAPY METHADONE OH #1-43 Methadone, LAAM Only long acting full opioid agonists approved for opioid pharmacotherapy Methadone 1. Long half life 24-36 hours 2. Extensive bioavailability 80% orally bio-available 3. Steady state achieved in 5 7.5 days ( 4-5 half lives) 4. Sustained activity and MV opiate receptors Eliminates cravings, withdrawal symptoms Blocks euphoric effect of heroin and other opiates 5. Serum methadone level 150 600 ng/ml Necessary to suppress cravings 6. Slow onset of action and gradual enhancement of its effect over time OH #1-44 Pharmacokinetics Methadone undergoes biotransformation to inactive metabolites in the liver Methadone and metabolites are eliminated in the urine and feces Metabolic clearance of methadone is generally not affected by liver disease requiring dose adjustment Except in ESRF it is not required to adjust the methadone dose because of renal insufficiency OH #1-45 15
GOALS FOR MEDICATION ASSISTED TREATMENT WITH METHADONE Prevention or reduction of withdrawal symptoms Prevention or reduction of drug craving Prevention of relapse to use of addictive drug Restoration to or toward normalcy of any physiological function disrupted by drug abuse Source: MJ Kreek, Rationale for Maintenance Pharmacotherapy of Opiate Dependence, 1992 OH #1-46 PROFILE FOR POTENTIAL PSYCHOTHERAPEUTIC AGENT Effective after oral administration Long biological half-life (>24 hours) Minimal side effects during chronic administration Safe, no true toxic or serious adverse effects Efficacious for a substantial % of persons with the disorder Source: MJ Kreek, Rationale for Maintenance Pharmacotherapy of Opiate Dependence, 1992 OH #1-47 GOALS: METHADONE DOSE TITRATION Titrate dose to achieve steady-state with methadone levels (clinically determined) in the comfort-zone throughout and beyond the dosing interval. Avoid over-medication / methadone toxicity. Ensure individualized and adequate dose Allow for methadone accumulation before increasing dose Allow time to react to a dose increase (3-5 days) Avoid overly aggressive titration OH #1-48 16
Methadone Simulated 24 Hr. Dose/Response At steady-state in tolerant patient J. Thomas Payte MD OH #1-49 METHADONE INITIAL DOSE COWS (Clinical Opiate Withdrawal Scale) Score Maximum Initial Dose (0-<5)* No withdrawal 0 mg, withhold dose pending onset of objective withdrawal (5-12) Mild withdrawal up to 15 mg (13-24) Moderate withdrawal up to 20 mg (25-36) Moderately severe withdrawal up to 25 mg (>36) Severe Withdrawal up to 30 mg * If withdrawal does not follow, methadone treatment cannot be initiated ( currently addicted to an opioid drug ) CFR 42 OH #1-50 Initial Dose* Estimated Tolerance Low or Non-Tolerant Unknown Tolerance & Oral Rx opioids Dose Range 10 mg +/- 5 20 mg +/- 5 Known Substantial Tolerance up to 30 mg* * clinical assessment based on H&P, in event COWS is not done J. Thomas Payte, MD OH #1-51 17
METHADONE TITRATION: DOSING Each day s dose is based on the response to the previous dose during peak levels of methadone. Considerations for continued titration Methadone half-life 15-55 hours (30 for example) Steady-state reached about 5 half-lives (about 5-7 days) Hence it takes 5-7 days to get full effect of a dose change Maximum effect occurs at peak levels, at about 3-4 hours after dose This is the optimum time for assessment of the recent dose Ideally based on direct observation at 3-4 hours after observed dose May have to rely on patient response to how were you feeling 3-4 hours after your dose? Is the information compatible with presentation at the window? OH #1-52 CONTINUED TITRATION AND STABILIZATION Considerations for continued titration after initial relief at peaks During this time dose should not be increased more than 5-10mg every 3-5 days. (Why 3-5 days?) Dose increases are still based on condition at peak while daily assessment monitors increasing time in the comfort zone (the dose holds longer) Continue daily assessment for signs of over or undermedication. Even slight over-medication today may lead to toxicity or overdose as accumulation continues This level of care (titration) continues until steady-state has been achieved evidenced by about 7 days stability at constant dose. Stabilization process may continue 1 or more months OH #1-53 Build-up peak SMLs days 1,2, & 3 v. days 4,5, & 6. Dose remains at 30 mg per 24 hours OH #1-54 18