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MEDICATION SUPPORTED RECOVERY Steven Kipnis MD, FACP, FASAM Medical Director, NYS OASAS WHAT IS THE MOST COMMONLY USED PSYCHOACTIVE SUBSTANCE IN THE WORLD? WHAT IS THE MOST COMMONLY USED PSYCHOACTIVE SUBSTANCE IN THE WORLD? WHAT IS THE FIRST SPORT TO TEST FOR DRUGS? WHAT IS THE FIRST SPORT TO TEST FOR DRUGS? Mystery of Change • Why do people who seem to want to stop using alcohol and drugs continue to use? o o o o Motivation • Ambivalence about initiating change • Changes in level of motivation Environmental and social influences • Exposure to substances or reminders of using • Spending time with social group that continues to use Psychosocial stressors • Everyday life problems (e.g., work, family, finances) • Major life problems (e.g., medical conditions, homelessness) Psychological Disorders • Comorbid anxiety, depression, PTSD Mystery of Change •What factors affect treatment and recovery efforts? family dynamics cognitive impairment 12 step involvement co-dependency coping skills prolonged withdrawal reward contingencies problem severity changes in brain chemistry genetics social support A Complex Disorder Neurobiological dysregulation should be treated with pharmacotherapy Nutritional deficits should be treated with dietary improvements and supplementation Substance Dependence Dysfunctional behavior should be addressed with psychosocial interventions Changes in Brain Chemistry • Drugs of abuse produce their effects by altering brain chemistry and structure. • Neurotransmitters and associated receptors responsible for everyday functions are altered by the consumption of drugs. • Rats give THC as adolescents • Rats exposed to heroin as adults o THC+ rats used heroin at a higher rate than THC – exposed rats • Same is true for nicotine • Protein changes on autopsy Adults Who Initiate Alcohol Use Before Age 21 More Likely to Abuse or Become Dependent on Alcohol • • • Early onset of alcohol use is associated with a greater likelihood of developing alcohol abuse or dependence at a later age, according to data from the National Survey on Drug Use and Health (NSDUH). Those who first used alcohol at or before the age of 14 were nearly four times more likely to meet the criteria for past year alcohol abuse or dependence than those who started using alcohol between the ages of 18 and 20 (16.5% vs. 4.4%) and more than six times more likely than those who started using alcohol at or after age 21 (16.5% vs. 2.5%). These findings illustrate the need for alcohol education and prevention efforts as early as middle school. Percentage of Adults (Ages 21 or Older) Who Abused or Were Dependent on Alcohol in the Past Year, by Age of First Alcohol Use, 2009 20% 16.5% 16% 12% 9.4% 8% 4.4% 4% 0% 2.5% 14 or Younger 15 to 17 18 to 20 Age First Used Alcohol SOURCE: Adapted by CESAR from Substance Abuse and Mental Health Services Administration, Results from the 2009 National Survey on Drug Use and Health: Detailed Tables, 2010. Available online at http://oas.samhsa.gov/WebOnly.htm#NSDUHtabs. 21 or Older Early Marijuana Use Related to Later Illicit Drug Abuse and Dependence • Adults who first started using marijuana at or before the age of 14 are most likely to have abused or been dependent on illicit drugs in the past year, according to data from the National Survey on Drug Use and Health (NSDUH). Adults who first used marijuana at age 14 or younger were six times more likely to meet the criteria for past year illicit drug abuse or dependence than those who first used marijuana when they were 18 or older (12.6% vs. 2.1%) Percentage of Adults (Ages 18 or Older) Who Abused or Were Dependent on Illicit Drugs in the Past Year, by Age of First Marijuana Use, 2009 20% 16% 12.6% 12% 8% 6.6% 4% 2.1% 0% 14 or Younger 15 to 17 Age First Used Marijuana 18 or Older Dopamine and Reward •Dopamine is one of the primary neurotransmitters in the experience of pleasure and the maintenance of addiction. Many drugs of abuse stimulate neurons in the ventral tegmental area, releasing dopamine in the nucleus accumbens and prefrontal cortex. Nearly all drugs of abuse increase dopamine in the nucleus accumbens, which appears to be the primary reinforcement center of the brain. Image Credit: NIDA : “The Neurobiology of Drug Addiction” NAc VTA GLU FCX Amphetamine Cocaine Opioids Cannabinoids Phencyclidine HIPP AMYG CRF GLU 5HT GABA OPIOID OPIOID GABA GABA DYN 5HT ENK VP OFT BNST DA GABA NE LC ABN HYPOTHAL Opioids Ethanol Barbiturates Benzodiazepines Nicotine NE LAT-TEG PAG END To 5HT dorsal Raphé horn RETIC REWARD CIRCUIT Initial Pleasure Craving Generalizes to other Substances Binge Behavior Decreased Inhibitions Impaired Motor Control Loss of Control Family Problems Poor Performance at Work Neglecting Hygiene Major Loss of Focus Turn Loss of Focus into Financial Opportunity Regrets Medication Supported Recovery – Homer on a Diet - Eating a Rice Cake Natural Reward vs. Substance-Induced Reward QuickTime™ and a H.264 decompressor are needed to see this picture. QuickTime™ and a H.264 decompressor are needed to see this picture. •Dopamine transmission: •Natural reinforcer • People seek out experiences that feel good. • These experiences are “natural reinforcers.” • Natural reinforcers stimulate release of dopamine. • • • • Dopamine transmission: Substance-induced Nearly all drugs of abuse also increase dopamine availability. Dopamine release in the nucleus accumbens is 3-5 times greater for substances than natural reinforcers. Down-Regulation of Dopamine •Dopamine transmission: •Dopamine transmission: •Dopamine transmission: •Natural reinforcer •Substance-induced •Down-regulated •Continual activation of the dopamine pathway alters the availability of dopamine. •The reduction or down-regulation in dopamine availability has a blunting effect on the natural reward circuit. IT IS NOT ABOUT THE BRAIN BEING ADDICTED TO A SUBSTANCE, IT’S ABOUT THE BRAIN BEING ADDICTED TO ITS OWN CHEMISTRY Neurotransmitters, Medications and the Receptor Site AGONIST PARTIAL AGONIST ANTAGONIST ADDICTION MEDICINES • • • • • • • ACAMPROSATE ANTABUSE ANTICONVULSANTS BACLOFEN BUPRENORPHINE CLONIDINE METHADONE/LAAM • • • • • • • NALTREXONE NALOXONE NEURONTIN NICOTINE REPLACEMENT THERAPIES SSRI’S ZYBAN VACCINES BARRIERS • • • • • • MEDICATION PATIENT PHYSICIAN/NURSE COUNSELOR PROGRAM SYSTEM BARRIERS • MEDICATION o o o INSUFFICIENT EVIDENCE REGARDING EFFICACY CONTRADICTORY EVIDENCE TOO EXPENSIVE • NALTREXONE $2.50 - 4.43 PER DAY o o CORRECT DOSE? SIDE - EFFECTS BARRIERS • MEDICATION o CANDIDATE SELECTION • TOOLS NEED TO BE RESEARCHED - WHO WILL BENEFIT MOST? o o o o POTENTIAL FOR ABUSE POTENTIAL FOR DIVERSION “MAGIC BULLET THEORY” DELIVERY SYSTEM BARRIERS • PATIENT o o o o COMPLIANCE SELECTION STIGMA COST/INSURANCE COVERAGE BARRIERS • PHYSICIAN/NURSE o o o o o o LACK OF AWARENESS LACK OF TRAINING LACK OF ONGOING TECHNICAL ASSISTANCE DO NOT PROMOTE USE MD’S NEEDED AT ALL PROGRAMS EXTRA WORK • OBSERVATION TIME BARRIERS • COUNSELOR o o o LACK OF AWARENESS LACK OF TRAINING COUNSELORS IN RECOVERY • “NOT THE WAY I DID IT” o MORE WORK • AFTERCARE BARRIERS • PROGRAM o o o NEED PHYSICIAN SERVICES NEED TO INCREASE COMMUNICATION BETWEEN PHYSICIANS AND COUNSELORS NEED LINKAGE TO MD AFTERCARE • MONITOR DRUG LEVELS • MONITOR SIDE - EFFECTS • WRITE RX o ENDANGERS PROGRAM INTEGRITY (THERAPEUTIC COMMUNITY) BARRIERS • SYSTEM o REGULATIONS NEED TO BE CHANGED • WHO WILL PAY FOR MD SERVICES o o o NEED INCREASE IN EDUCATION AND T.A. PRIVATE MD’S NEED TO BE ABLE TO LINK TO THE SYSTEM NEED OUTCOME DATA Does Treatment Work? Medications + psychosocial therapy both benefit brain function and recovery. Each affects different parts of brain and in opposite ways. PET scans adapted and retouched from Goldapple et al. 2004 Medications for Alcohol Dependence Antabuse® ReVia® Campral® VIVITROL® (disulfiram)1 (naltrexone)2 (acamprosate)3 (naltrexone for extendedrelease injectable suspension)4 30 tabs/month* (1 tab/day) 30 tabs/month* (1 tab/day) 180 tabs/month* (2 tabs, 3x/day) 1/month 1951 1994 2004 2006 1. Antabuse full Prescribing Information. Odyssey Pharmaceuticals, Inc. 2. ReVia full Prescribing Information. Duramed Pharmaceuticals, Inc. 3. Campral full Prescribing Information. Merck Santé s.a.s. 4. VIVITROL full Prescribing Information. Alkermes, Inc. Current Pharmacotherapies 2 general categories: - anticraving (naltrexone, acamprosate) - alcohol-aversion (dilsufiram) Pharmacotherapies should be used in combination with psychosocial treatment. Opioid Receptors and Alcohol Dependence 1. Gianoulakis C. Alcohol Health Res World. 1998;22:202-210. 2. Woodward JJ. Principles of Addiction Medicine. 3rd ed. 2003:101-118. Naltrexone: Adverse Effects - generally well tolerated -minor side effects in 10% patients: nausea, dizziness and headache -Start with lower dose 12.5 – 25 mg and build up to 50mg Naltrexone: Contraindications patients receiving long-term opioids - therapy for chronic pain - methadone/buprenorphine maintenance therapy - heroin dependence patients with acute hepatitis or hepatic failure - hepatotoxicity shown with high doses patients with renal impairment - use caution FDA pregnancy C category - no complete human studies done patients with allergy to naltrexone Candidates for Naltrexone • Good candidate: o o o o o o o High motivation Failed agonist treatment Successful agonist treatment but want a change Detox easily but relapse often Early in disease Positive family history Very high craving level • Bad candidate: • History of overdose • When patient is opiate free do not feel normal Vivitrol • • • • Depot naltrexone Approved for alcohol and opiate dependence 380mg/month Cost is a factor – but it improves compliance Effects of Naltrexone Treatment for Alcohol-Related Disorders on Healthcare Costs in an Insured Population • Henry R. Kranzler et al Alcoholism Clinical and Experimental Research June 2010 • Objective: To determine the impact of treatment with oral naltrexone on healthcare costs in patients with alcohol-related disorders. Methods: Using data from the MarketScan Commercial Claims and Encounters Database for 2000–2004, we identified a naltrexone group (with an alcohol-related diagnosis and at least one pharmacy claim for oral naltrexone) and two control groups. Alcohol controls had an alcoholrelated diagnosis and were not prescribed an alcoholism treatment medication. Nonalcohol controls had no alcohol-related diagnosis and no prescription for an alcoholism treatment medication. The control groups were matched three to one to the naltrexone group on demographic and other relevant measures. Healthcare expenditures were calculated for the 6month periods before and after the index naltrexone drug claim (or matched date for controls). Univariate and multivariate analyses were used to compare the groups on key characteristics and on healthcare costs. Results: • • o o o • Naltrexone patients (n = 1,138; 62% men; mean age 45 ± 11 years) had significantly higher total healthcare expenditures in the pre-index period than either of the control groups. In the postindex period, naltrexone patients had a significantly smaller increase than alcohol controls in total alcohol-related expenditures. Total nonalcohol-related expenditures also increased significantly less for the naltrexone group than for the alcohol control group. Conclusions: Although prior to treatment patients with alcohol-related disorders had higher healthcare costs, treatment with oral naltrexone was associated with reductions both in alcoholrelated and nonalcohol-related healthcare costs. Vivitrol Studies • 25% reduction in heavy drinking when compared to placebo group o o In 4 day lead in maintained abstinence was 32% in the treatment group vs 11% in the placebo group (all got behavioral treatment) Better abstinence rates with 7 day lead in • Good adherence to medication o o 74% had 4 injections 64% had 6 injections New Uses • Nicotine dependence – men did better than women o Women also don’t do as well with NRT: smoke for different reasons than men?? • Cannabis dependence o Actually increased the high and increased cravings • Amphetamine/Stimulant dependence o o Decreased cravings and less depression and anxiety Decreased cocaine use if also used opiates • Low dose naltrexone when coming off agonists • Too long a period after off agonists and start of vivitrol (can be 10days before naltrexone and 15 daysbefore vivitrol with methadone tapers) Acamprosate (Campral®) Modulator of neuronal excitatory processes Approved (FDA) in July 2004 Evidence suggests that acamprosate increases abstinence and lowers the frequency of drinking in patients with alcohol use problems. Acamprosate: Mechanism of Action neuronal processes: excitatory (glutamate) inhibitory (GABA) acamprosate Acamprosate: Pharmacokinetics Metabolism None Elimination Kidney = 100% as unchanged acamprosate Dose 333mg (2 tabs) TID Acamprosate: Adverse Effects - well tolerated -minor side effects: diarrhea, dizziness Acamprosate: Drug Interactions None? Acamprosate: Contraindications patients with severe renal impairment or renal failure - reduced dosage for moderate renal impairment patients with sulfite hypersensitivity FDA pregnancy C category - teratogenic in animals patients breastfeeding patients with suicidal ideation - caution Anticraving Pharmacotherapies CRAVING (irresistible desire to drink) naltrexone conditioned cues associated with drinking acamprosate conditioned cues associated with withdrawal Alcohol - Deterrent Therapy deterrent therapy + Disulfiram (Antabuse®) Interferes with the hepatic oxidation of acetyladehyde Approved (FDA) in 1951 after discovery by Danish scientists in the 1930’s as an antihelminthic (flatworms) Early evidence suggested that disulfiram can help patients to remain sober if taken under supervision. Disulfiram: Mechanism of Action alcohol acetaldehyde alcohol dehydrogenase acetaldehyde dehydrogenase alcohol acetaldehyde acetate disulfiram carbon dioxide Dosing • • • • Rapidly absorbed Peak plasma levels in 9 hours Usual dose is 250 mg qd The patient should be alcohol abstinent for a minimum of 48 hours before starting disulfiram Disulfiram: Efficacy ? Double-blinded studies are not possible with disulfiram. Disulfiram is usually only an adjunct therapy. Disulfiram: Adverse Effects Severe reaction after alcohol ingestion: problems breathing, severe fall in blood pressure, heart attack, acute congestive heart failure, unconsciousness, seizure, and death Sides effects even in the absence of alcohol: skin rash, drowsiness, headache, a metallic or garlic aftertaste, and psychotic reactions (confusion, extreme fear, or hallucinations) Rare hepatotoxicity – occurs 1/25,000 patient years of treatment (mechanism unknown) Disulfiram: Adverse Effects Psychosis and Hallucinations due to interference with dopamine hydroxylase (dopamine can’t be metabolized into NE) so more dopamine = psychotic reactions Disulfiram: Drug Interactions Anything that contains alcohol: - aftershaves, cologne, antiperspirants, hair dyes/rinses, mouthwashes - cough and cold medicines, some vitamin preparations - vinegar, cakes Use in Cocaine Dependence • FDA approved for alcohol dependence • 80% of cocaine dependent patients have alcohol dependence – can decrease in alcohol use decrease cocaine use? • Inhibits dopamine – B – hydroxylase, an enzyme which catalyzes the rate limiting step in conversion of dopamine to norepinephrine (increase dopamine which may be needed in the depleted cocaine patient) • In the human laboratory model, disulfiram elevates cocaine plasma levels through an unknown mechanism ANTICONVULSANTS • USED IN PAIN MANAGEMENT AND WITHDRAWAL TREATMENT o CARBAMAZEPINE (TEGRETOL®) • IN 3 TRIALS, AS EFFECTIVE AS BENZODIAZEPINES FOR MILD TO MODERATE ALCOHOL WITHDRAWAL • ? IF IT REDUCED DRINKING BEHAVIOR IMMEDIATELY POST WITHDRAWAL TREATMENT • ? IF REDUCED COCAINE CRAVING 5 STUDIES POSITIVE AND 5 WERE NEGATIVE (200-1000MG/D) ANTICONVULSANTS • CARBAMAZEPINE (TEGRETOL®) o o o o NO RESPIRATORY DEPRESSION NO INHIBITION OF LEARNING, UNLIKE BENZODIAZEPINES NO ABUSE POTENTIAL ANTICONVULSANT PROPERTIES ANTICONVULSANTS • CARBAMAZEPINE (TEGRETOL®) o ADVERSE EFFECTS • NEUTROPENIA • THROMBOCYTOPENIA • HYPONATREMIA ANTICONVULSANTS • CARBAMAZEPINE (TEGRETOL®) o ALCOHOL WITHDRAWAL PROTOCOLS • 600 - 800 MG PER DAY IN DIVIDED DOSES • CONTINUE FOR 2 DAYS THEN DECREASE BY 200 MG PER DAY ANTICONVULSANTS • TOPIRAMATE (TOPAMAX®) o o ORIGINALLY SYNTHESIZED AS ANTI-DIABETIC AGENT APPROVED FOR PARTIAL ONSET AND PRIMARY GEN. TONIC-CLONIC SEIZURES IN ADULTS AND CHILDREN ANTICONVULSANTS • TOPIRAMATE (TOPAMAX®) o o o I/2 LIFE 19-23 HOURS 50-80% EXCRETED UNCHANGED IN THE URINE NO THERAPEUTIC RANGE OR BLOOD LEVEL MONITORING ANTICONVULSANTS • TOPIRAMATE (TOPAMAX®) o o FOUND TO BE MORE EFFECTIVE THAN CONTROLS AND REDUCED THE NUMBER OF HEAVY DRINKING DAYS. STUDY MEASURED ABSTINENCE INITIATION NOT PERSISTENCE • PERHAPS DIFFERENT PHARMACOTHERPIES COULD BE USED FOR INITIATION, MAINTENANCE AND PROLONGED ABSTINENCE • WORK BY B.JOHNSON IN LANCET 2003;361;1677-1685. ANTICONVULSANTS • TOPIRAMATE (TOPAMAX®) ADVERSE EFFECTS o o o o o o o o TRANSIENT PARESTHESIAS DECREASE COGNITION ( DECREASE IN CONCENTRATION AND MEMORY) SECONDARY ANGLE CLOSURE GLAUCOMA – RARE KIDNEY STONES (1.5% OR 2-4 TIMES THE GENERAL POPULATION) WEIGHT LOSS DECREASES ESTROGEN EFFECT OF BCP INCREASED HALDOL LEVEL TEGRETOL AND DILANTIN WILL DECREASE TMX LEVEL ANTICONVULSANTS • TOPIRAMATE (TOPAMAX®) EVOLVING SPECTRUM OF USE o o o o o o o o o o o o o o EPILEPSY MIGRAINE PREVENTION ESSENTIAL TREMOR DIABETIC NEUROPATHIC PAIN MOOD DISORDERS ALCOHOL DEPENDENCE EATING DISORDERS PTSD TOURETTES SYNDROME OCD OBESITY TYPE 2 DIABETES NICOTINE DEPENDENCE COCAINE DEPENDENCE BUPRENORPHINE • OVERVIEW OF THE DRUG ADDICTION TREATMENT ACT OF 2000 - AN AMENDMENT TO THE CONTROLLED SUBSTANCES ACT (10/17/01) o REVISION IN LEGISLATION ALLOWS PRACTITIONER TO PRESCRIBE NARCOTIC DRUGS IN SCHEDULE III, IV, V, OR COMBINATIONS OF SUCH DRUGS, FOR THE TREATMENT OF OPIOID DEPENDENCE BUPRENORPHINE • OVERVIEW OF THE DRUG ADDICTION TREATMENT ACT OF 2000 - AN AMENDMENT TO THE CONTROLLED SUBSTANCES ACT (10/17/01) o PRACTITIONER REQUIREMENTS • “QUALIFYING PHYSICIAN” o o o o o LICENSED BOARD CERTIFIED IN ADDICTION PSYCHIATRY CERTIFIED IN ADDICTION MEDICINE BY ASAM OR AOA INVESTIGATOR IN BUPRENORPHINE CLINICAL TRIALS 8 HOURS OF DESIGNATED TRAINING • HAS CAPACITY TO REFER PATIENTS FOR APPROPRIATE COUNSELING AND ANCILLARY SERVICES • NO MORE THAN 30 PATIENTS (INDIVIDUAL OR GROUP) INITIALLY, CAN GO TO 100 AFTER ONE YEAR (MUST APPLY) • METHADONE CLINICS CAN HAVE UNLIMITED NUMBERS BUPRENORPHINE • THEBAINE DERIVATIVE o • • MAKES THIS LEGALLY CLASSIFIED AS AN OPIATE PARTIAL OPIOID AGONIST INITIALLY USED AS AN ANALGESIC BUPRENORPHINE • PARTIAL OPIOID AGONIST o VERY HIGH AFFINITY FOR MU RECEPTOR • WILL DISPLACE MORPHINE, METHADONE BUPRENORPHINE • PARTIAL OPIOID AGONIST o DESIRABLE PROPERTIES • • • • LOW ABUSE POTENTIAL LOWER LEVEL OF PHYSICAL DEPENDENCE SAFETY IF INGESTED IN OVERDOSE QUANTITIES WEAK OPIOID EFFECT AS COMPARED TO METHADONE BUPRENORPHINE • PARTIAL OPIOID AGONIST o IF GIVEN TO A PATIENT MAINTAINED ON A FULL AGONIST, IT CAN PRECIPITATE AN ABSTINENCE SYNDROME DUE TO LOW EFFICACY AND DUE TO HIGH AFFINITY TO THE MU RECEPTOR • CANNOT EASILY OVERCOME THE BUPRENORPHINE EFFECT NOR CAN AN ANTAGONIST OVERCOME ITS EFFECT. BUPRENORPHINE • PHARMACOLOGIC USES o POTENT ANALGESIC • AVAILABLE IN MANY COUNTRIES AS A SUBLINGUAL TABLET (0.3 - 0.4 MG) CALLED TEMGESIC® • AVAILABLE IN THE U.S. AS AN PARENTERAL FORM CALLED BUPRENEX® • LOW DOSES FOR PAIN TREATMENT AS COMPARED TO ADDICTION TREATMENT ( 0.3 - 0.6 MG IM OR IV Q 6 HOURS) BUPRENORPHINE • PHARMACOLOGIC USES o POOR ORAL BIOAVAILABILITY • SUBLINGUAL WITH ABSORPTION THROUGH THE ORAL MUCOSA o SLOW DISSOCIATION RATE • PROLONGED THERAPEUTIC EFFECT - SO CAN BE GIVEN EVERY OTHER OR EVERY THIRD DAY BUPRENORPHINE • PHARMACOLOGIC USES o TREATMENT OF ADDICTIONS* • IN THE U.S. o o 2 & 8 MG SUBLINGUAL TABLETS MADE BY RECKITT & COLMAN CALLED SUBUTEX® 2 & 8 MG SUBLINGUAL TABLETS WITH NALOXONE IN A 4:1 RATIO CALLED SUBOXONE® BUPRENORPHINE • PHARMACOLOGIC USES o o DOSES USED FOR OPIOID ADDICTION TREATMENT IS 1 -2 MG UP TO 16 - 32 MG DURATION IS A FEW WEEKS TO YEARS? • SHORT-TERM TREATMENT IN ADOLESCENTS? o JAMA article by G. Woody et al, (2008) adolescents aged 15 to 21 did better with long term Suboxone than a short (2 week) detox protocol using Suboxone o TO REDUCE POTENTIAL FOR ABUSE THE COMBINATION TABLET WAS MADE • WORKS ON PRINCIPLE THAT NALOXONE IS 100 TIMES MORE POTENT BY INJECTION THAN BY THE SUBLINGUAL ROUTE o o IF TAKEN S.L. BUP>>>>>>NALONXONE IF TAKEN I.V. NALOXONE>>>>>BUP BUPRENORPHINE • SAFETY o o IF SWALLOWED ACCIDENTIALLY BY A NON- PHYSICALLY DEPENDENT PERSON DUE TO POOR ORAL BIOAVAILABILITY THERE IS VIRTUALLY NO OPIOID EFFECT IN ADULT – PEDIATRIC CASES OF OVERDOSE REPORT OF 53 CASES OF HEPATITIS IN FRANCE SINCE 1996. ALL INVOLVED IV BUPRENORPHINE WHICH LEAD TO HEPATITIS • PERHAPS DUE TO INCREASE BIOAVAILABILITY IF TAKEN IV BUPRENORPHINE • SIDE EFFECTS o SIMILAR TO OTHER MU AGONISTS THOUGH LESS SO • NAUSEA • VOMITING • CONSTIPATION *NO DISRUPTION IN COGNITIVE AND PSYCHOMOTOR PERFORMANCE BUPRENORPHINE • TERATOGENESIS o LIMITED REPORTS • ONE STUDY FOUND NO SIGNS OF PHYSICAL DEPENDENCY IN NEONATES OF HEROIN ADDICTED MOTHERS TAKING BUPRENORPHINE BUPRENORPHINE • DRUG INTERACTIONS o o o o o SCANT STUDIES DEATH CASE REPORT ASSOCIATED WITH IV BUPRENORPHINE AND BENZODIAZEPINES CANNOT GIVE WITH ReVia AVOID MEDICATIONS THAT ARE METABOLIZED BY THE CYTOCHROME P450 3A4 SYSTEM IF ACUTE PAIN TREATMENT IS NEEDED, MAY HAVE TO SWITCH TO METHADONE On the Horizon • Implantable buprenorphine – Probuphine o o 6 month duration Being studied by Dr. Walter Ling at UCLA • 108 patients and 55 placebo patients • 40% in bup group and 28% in placebo group tested negative for illegal drugs at 16 weeks. • At 24 weeks 66% of treatment group compared to 31% in placebo group were still in treatment • Buprenorphine patch o For pain and not addiction – much different dosing NALOXONE (NARCAN) • Opioid antagonist which reverses opioid overdoses • Pushes most other opioids off the receptors, then sits on the receptor preventing it from being activated for 30-90 minutes • Analogy - getting the wrong key stuck in a lock NALOXONE IN ACTION • Reverses sedation and respiratory depression • Causes sudden withdrawal in the opioid dependent person • No psychoactive effects • Over the counter in some countries, but not the US • Routinely used by EMS ADMINISTRATION • Inject into muscle but subcutaneous and intravenous are fine also • Acts in 2-8 minutes • If no response in 2-5 minutes repeat- and if 911 has not been called do it now!! • Do not repeat naloxone more than twice • Lasts 30-90 minutes http://www.health.state.ny.us/diseases/aids/harm_reduction/opioidprevention/index.htm NICOTINE REPLACEMENT THERAPIES (NRT) • CORNERSTONE OF TOBACCO DEPENDENCE TREATMENT o o SAFE EFFECTIVE SMOKING CESSATION • 70 MILLION SMOKERS IN THE US o o o 90% WOULD LIKE TO QUIT 60% HAVE TRIED TO QUIT 66% HAVE HEALTH CONCERNS HIGH MOTIVATION BUT LIMITED SUCCESS 1634 RUSSIA: CZAR ALEXIS CREATES PENALTIES FOR SMOKING: 1ST OFFENSE IS WHIPPING, A SLIT NOSE, AND TRASPORTATION TO SIBERIA. • 1634 RUSSIA: 2ND OFFENSE IS EXECUTION SMOKING CESSATION METHODS • UNASSISTED o o COLD TURKEY WARM CHICKEN • INTAKE LIMITED • BRAND CHANGING o NONPRESCRIPT. AIDS • NICO BLOC NicoBloc • • • • • A completely natural product viscous liquid you apply directly to your cigarette filter. o The main ingredients of consist of: water, a sugar compound, citric acid, food coloring and preservatives. o Approved by FDA • $49.97 - In each pack there is one bottle of NicoBloc which contains approximately 700 drops. In the first week of using NicoBloc, you apply ONE drop of NicoBloc to the filter of EACH cigarette you smoke. This reduces the amount of tar and nicotine you inhale by up to 33%. In week two you use TWO drops of NicoBloc on the filter of EACH cigarette you smoke. This reduces the amount of tar and nicotine you inhale by up to 66%. Week three onwards, you apply THREE drops of NicoBloc to EACH cigarette you smoke. SMOKING CESSATION METHODS • ASSISTED o o o o SUPPORT GROUPS COMMERCIAL PROGRAMS ACUPUNCTURE MD ASSISTED CESSATION Findings and Recommendations of US Public Health Service Clinical Practice Guidelines (June 2000) 5. There is a strong dose-response relation between the intensity of tobacco dependence counseling and its effectiveness. Treatments involving person-to-person contact (via individual, group, or proactive telephone counseling) are consistently effective, and their effectiveness increases with treatment intensity (e.g., minutes of contact). 117 Efficacy of Various Intensity Levels of Person-to-Person Contact (n = 43 studies) Level of Contact No contact (reference group) Minimal counseling (< 3 minutes) Low intensity counseling (3-10 minutes) Higher intensity counseling (> 10 minutes) Estimated Abstinence Rate 10.9% 13.4% 16.0% 22.1% 118 MD SUPPORTED TREATMENT National Cancer Institute MD SUPPORTED TREATMENT • AVERSIVE CONDITIONING • NICOTINE ANTAGONIST?? o MECAMYLAMINE NICOTINE REPLACEMENT THERAPIES (NRT) • DEVELOPED IN SWEDEN DURING THE 1970”S AS A MEANS TO ASSIST SUBMARINERS • CORNERSTONE OF TOBACCO DEPENDENCE TREATMENT o o SAFE EFFECTIVE NICOTINE REPLACEMENT THERAPIES (NRT) • NICOTINE GUM (NICOTINE POLACRILEX, NICORETTE® o FDA APPROVAL 1984 o AVAILABLE IN 2MG AND 4MG • • o o o o .86 MG ABSORBED FROM THE 2MG PIECE 1.2 MG ABSORBED FROM THE 4 MG PIECE COMPOSED OF NICOTINE BOUND TO AN ION-EXCHANGE RESIN INCORPORATED INTO A GUM BASE “PARK AND CHEW” TECHNIQUE AFFECTED BY CHEWING RATE AND pH OF THE SALIVA ADVERSE EFFECTS: JAW PAIN, MOUTH SORENESS, DYSPEPSIA, HICCUPS NICOTINE REPLACEMENT THERAPIES (NRT) • NICOTINE TRANSDERMAL PATCHES (HABITOL®, NICODERM CQ ®, NICOTROL ® ) o o o o o APPROVED BY THE FDA IN 1991 OTC APPROVAL IN 1996 ALL 21 MG PATCHES DELIVER .9MG OF NICOTINE PER HOUR TEMPERATURE AND CIRCULATION AFFECT DELIVERY ADVERSE EFFECTS: SLEEP DISTURBANCE, SKIN REACTIONS NICOTINE REPLACEMENT THERAPIES (NRT) • NICOTINE INHALER (NICOTROL INHALER ® ) o o FDA APPROVED IN 1998 CIGARETTE HOLDER SHAPE WITH REPLACEABLE CARTRIDGES • • • • o o EACH CONTAINS 10 MG NICOTINE AND 1 MG MENTHOL 400 PUFFS PER CARTRIDGE DELIVERING 13 UG PER PUFF 80 PUFFS EQUAL ONE CIGARETTE USE 4 - 6 INHALERS PER DAY AFFECTED BY PUFF RATE, TEMPERATURE, SALIVA pH 25% TAPER EVERY MONTH IN NUMBER OF PUFFS NICOTINE REPLACEMENT THERAPIES (NRT) • NICOTINE SPRAY ( NICOTROL NS ® ) o APPROVED BY THE FDA IN 1996 o ONE INHALATION IN EACH NOSTRIL = TOTAL DOSE OF 1MG o AVERAGE USE IS 13 - 20 DOSES PER DAY o ADVERSE EFFECTS: RUNNING NOSE, NASAL IRRITATION, THROAT IRRITATION, WATERY EYES, SNEEZING • ALL BUT THROAT IRRITATION DECREASE IN 1 - 7 DAYS NICOTINE REPLACEMENT THERAPIES (NRT) • NICOTINE LOZENGE (COMMIT ® ) o APPROVED BY THE FDA IN 2002, THOUGH DESCRIBED AS EARLY AS THE 1960’S o 2MG AND 4 MG DOSES o MAXIMUM NUMBER IS 20 LOZENGES PER DAY • Dosage • • • 2 mg-for those smoking >30 min after waking o 4 mg-for those smoking <30 min after waking First 6 weeks 1 lozenge every 1-2 hrs Weeks 7-10 1 lozenge every 2-4 hrs Weeks 11-12 1 lozenge every 4-8 hrs o o GLAXO PACKAGES “TIME TO FIRST CIGARETTE” PROGRAM WITH LOZENGES - PROGRAM TO DECIDE IF PATIENT SHOULD START WITH A 2 OR 4 MG LOZENGE Efficacy of Nicotine Gum (n = 13 studies) Pharmacotherapy Placebo (reference group) Nicotine Gum Estimated Abstinence Rate 17.1% 23.7% 127 Efficacy of Nicotine Inhaler (n = 4 studies) Pharmacotherapy Placebo (reference group) Nicotine Inhaler Estimated Abstinence Rate 10.5% 22.8% 128 Efficacy of Nicotine Nasal Spray (n = 3 studies) Pharmacotherapy Estimated Abstinence Rate Placebo (reference group) 13.9% Nicotine Nasal Spray 30.5% 129 Efficacy of Nicotine Patch (n = 27 studies) Pharmacotherapy Placebo (reference group) Nicotine Patch Estimated Abstinence Rate 10.0% 17.7% 130 Efficacy of Combination NRT (n = 3 studies) Pharmacotherapy One NRT (reference group) Two NRTs Estimated Abstinence Rate 17.4% 28.6% 131 NICOTINE REPLACEMENT THERAPIES (NRT) • NICOWater o o Illegal in NYS Can easily be sold to minors OTHER NICOTINE PRODUCTS ONE DOSE IS EQUAL TO 1 MG NICOTINE FROM TOBACCO NEW NICOTINE REPLACEMENT • THE STRAW™ o 8 MG – NICOTINE BITARTRATE BEADS o ORAL DELIVERY • AN INDIVIDUAL SIPS ANY BEVERAGE THROUGH THE STRAW™ AND SWALLOWS THE NICOTINE BEADS • THE ENTIRE DOSE OF NICOTINE IS DELIVERED IN THE FIRST SIP o MANUAL STIMULI o INCREASED COMPLIANCE o BEHAVIORAL COMPONENT • RECOVERY PHARMACEUTICALS o PHASE 1 & 2 COMPLETED o PHASE 3 - UNDERWAY A new type of tobacco free, nicotine delivery system – E Cigarettes • • Generally, e-cigarettes required stronger vacuums (suction) to smoke than conventional brands, and the effects of this on human health could be adverse. The amount of aerosol produced by e-cigarettes decreased during smoking, which necessitated increasing puff strength to produce aerosol. The decreased efficiency of aerosol production during ecigarette smoking makes dosing nonuniform over time and calls into question their usefulness as nicotine delivery devices. o o o • The vacuum required to smoke conventional cigarettes varied among the eight brands tested. Lights and ultralight brands required stronger vacuums to smoke than unfiltered and regular filtered brands. Except for one brand, higher vacuums were required to smoke e-cigarettes than conventional brands. Smoke/aerosol density was stable for conventional brands and for e-cigarettes over the first 10 puffs; however, aerosol density of e-cigarettes dropped during subsequent smoking, and higher vacuums were required to produce aerosol as the puff number increased. While conventional cigarettes were uniform in their smoking behavior within brands, vacuum and density varied within brands of e-cigarettes. ATrtchounian et al, Nicotine and Tobacco Research July 2010 USB powered E Cigarette ZYBAN® • • GENERIC FORM= BUPROPION HYDROCHLORIDE MARKETED FIRST AS AN ANTIDEPRESSANT o • • WELLBUTRIN® & WELLBUTRIN SR ® FIRST NON-NICOTINE MEDICATION APPROVED FOR SMOKING CESSATION 150 MG BID ZYBAN® • • • APPEARS TO WORK THRU THE DOPAMINE AND NOREPINEPHRINE PATHWAYS TO REDUCE CRAVING THOUGH NEWER WORK POINTS TO IT ALSO BEING A NICOTINE RECEPTOR ANTAGONIST CAN BE USED ALONE OR IN COMBINATION WITH NICOTINE REPLACEMENT MEDICATIONS SIDE EFFECTS o o o DRY MOUTH INSOMNIA NEJM 2002 – SEIZURE INDUCED BY INSUFFLATION OF BUPROPION – CASE REPORT OF ADOLESCENT WHO CRUSHED SIX 150MG TABLETS AND SNORTED THEM VARENICLINE • Varenicline is a drug which stimulates nicotine receptors in the brain without itself being addictive. • Developed by Pfizer Pharmaceuticals, varenicline is a nicotine partial receptor agonist which comes in pill form to prevent withdrawal symptoms in people attempting to quit smoking. • Warnings about suicidal ideations and increased cardiac events if smoker has a cardiac problem Results of 12-week phase 2 varenicline dosing trial (n = 627) • 4 doses evaluated: o o • .5 mg and 1.0 mg twice daily titrated .5 mg and 1.0 mg twice daily non-titrated. Weeks 9-12 continuous abstinence rates pooled by dose. o o o 1.0 mg twice daily doses = 50.6% 0.5 mg twice daily doses = 45.1% Placebo = 12.4% 1Oncken C, et al. (2005). Presented at the 2005 Meeting of the Society for Research on Nicotine and Tobacco. Prague, Czech Republic. Special Populations Cannabis Dependence • Numerous studies indicate that cannabis use among methadone maintenance patients does not lead to worse outcomes. • No specific medications to treat Cannabis Dependence • CBT effective for patients who want to quit • Use Motivational Interviewing for patients who do not want to quit • Gabapentin seems to show some progress Benzodiazepine Dependence • Gradual taper of primary sedative drug with more rapid taper for first 50% of dose and more slowly for each successive 25% • Clonazepam (Klonopin)taper for short acting benzodiazepines • Carbamazepine 200 – 800 mg daily or valproic acid 250 mg tid along with benzodiazepine for first 1 – 2 weeks, then taper benzo over 4 weeks; continue anticonvulsant alone for 2 – 4 weeks o Buprenorphine may have a drug – drug interaction with carbamazepine • Cognitive behavioral therapy significantly increases success rate Cocaine Dependence • • • • Need more randomized studies Need agents that can increase dopamine and NE Need to affect the glutamate system No medications approved as yet Cocaine Dependence • N-acetyl – cystenine o o Used in Tylenol ovedose, mucolytic agent Source of cysteine which can restore glutamate levels seen in cocaine withdrawal • Modafinil o o o o Wake promoting agent Non-amphetamine stimulant Increase levels of glutamate and decreased levels of GABA Low abuse potential • Topiramate o anticonvulsant Cocaine Dependence • Vigabatrin (Gamma – Vinyl- GABA) o Atypical seizure med • Baclofen o GABA agonist • Tiagabine o Anticonvulsant • Antabuse o Inhibit Dopamine Beta-Hydroxylase so increased dopamine levels • Bupropion o Dopamine and NE reuptake inhibitor Gambling • Naltrexone and Nalmefine o Opiate antagonists which will block the high • Have tried antidepressants and mood stabilizers o o Paxil worked in one trial and not another If bipolar, then mood stabilizers may work Binge Drinking • 5/4 rule: 5 drinks in men, 4 in women in a short period of time or one sitting o o o Acamprosate – anticraving Antabuse - ??? Newest regimen: • Naltrexone is first choice as decreases high and impulsivity • If fail, add low dose Ondansetron to Naltrexone o 8 ug/Kg is much lower than dosing for anti-emetic effect and is not available yet • • NICVAX ™ (NICOTINE CONJUGATE VACCINE) A NOVEL AND PROPRIETARY INVESTIGATIONAL VACCINE TO PREVENT AND TREAT NICOTINE ADDICTION AND AS AN AID TO SMOKING CESSATION. IN AUGUST 2003, NABI BIOPHARMACEUTICALS INITIATED A PHASE II CLINICAL TRIAL OF NICVAX IN THE U.S. THIS DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY IN 63 SMOKERS o NICVAX IS DESIGNED TO CAUSE THE IMMUNE SYSTEM TO PRODUCE ANTIBODIES THAT BIND TO NICOTINE AND PREVENT IT FROM ENTERING THE BRAIN. • • • The Hebrew University researchers, led by Dr. Rami Yaka of the university's Institute of Drug Research, were seemingly able to erase the drug-linked memories of rats that had been deliberately administered cocaine over two weeks' time. The researchers injected a small protein a peptide called ZIP - directly into an area of the addicted rats' basal forebrain called the nucleus accumbens, which controls pleasure and reward and which has been demonstrated to be connected to drug addiction. Afterward, the rats were returned to their pens to check their reactions. Rather than seeking out the place where they had been getting their "fixes" of cocaine, the rats ignored it, indicating that memories linked to their addiction had been erased. LASER TREATMENT FOR SMOKING • A company called Advanced Laser Therapy claims to be able to get smokers to quit in 30 minutes through the use of laser treatment • The laser stimulates endorphins and fools the body into thinking the patient is smoking. o The laser is used at various points of the body -- ears, wrist, and leg, among others -- to flush nicotine from the system. The flushing process continues over several days as patients drink copious amounts of water to clean out their system. o The laser treatment, which costs $275, is currently in clinical trials as the company seeks FDA approval. 09/2005 ADDICTION MEDICATIONS ARE FOR THE BRAIN, 12 STEP IS FOR THE SOUL. [email protected]