Post on 25-Dec-2015
transcript
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 Motivation
• Ambivalence about initiating change
• Changes in level of motivation
o Environmental and social influences
• Exposure to substances or reminders of using
• Spending time with social group that continues to use
o Psychosocial stressors
• Everyday life problems (e.g., work, family, finances)
• Major life problems (e.g., medical conditions, homelessness)
o Psychological Disorders
• Comorbid anxiety, depression, PTSD
•What factors affect treatment and recovery efforts?
Mystery of Change
12 step involvement
co-dependency
coping skillsfamily dynamics
prolonged withdrawal
reward contingencies
problem severity
cognitive impairment
genetics
changes in brain chemistry
social support
Nutritional deficits should be treated
with dietary improvements and supplementation
Neurobiological dysregulation should
be treated with pharmacotherapy
Dysfunctional behavior should
be addressed with psychosocial
interventions
Substance Dependence
A Complex Disorder
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.
Age First Used Alcohol
14 or Younger 15 to 17 18 to 20 21 or Older0%
4%
8%
12%
16%
20%
16.5%
9.4%
4.4%2.5%
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
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.
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%)
0%
4%
8%
12%
16%
20%
12.6%
6.6%
2.1%
Age First Used Marijuana
14 or Younger 15 to 17 18 or Older
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
•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.
Dopamine and Reward
Image Credit: NIDA : “The Neurobiology of Drug Addiction”
NAc VTA
FCXAMYG
VP
ABN
Raphé
LC
GLU
GABA
ENK OPIOID
GABAGABA
GABA
DYN
5HT
5HT
5HT
NE
HIPP
PAG
RETIC
To dorsal horn
END
DA
GLU
AmphetamineCocaineOpioidsCannabinoidsPhencyclidine
Opioids
Ethanol
Barbiturates
Benzodiazepines
Nicotine
OPIOID
HYPOTHALLAT-TEG
BNST
NE
CRF
OFT
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
• People seek out experiences that feel good.
• These experiences are “natural reinforcers.”
• Natural reinforcers stimulate release of dopamine.
• 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.
•Dopamine transmission:•Natural reinforcer
• Dopamine transmission:• Substance-induced
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Natural Reward vs.Substance-Induced Reward
• Dopamine transmission:
• Natural reinforcer
•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.
•Dopamine transmission:
•Substance-induced•Dopamine transmission:
•Down-regulated
Down-Regulation of Dopamine
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
• MEDICATIONo INSUFFICIENT EVIDENCE REGARDING EFFICACYo CONTRADICTORY EVIDENCEo TOO EXPENSIVE
• NALTREXONE $2.50 - 4.43 PER DAYo CORRECT DOSE?o SIDE - EFFECTS
BARRIERS
• MEDICATIONo CANDIDATE SELECTION
• TOOLS NEED TO BE RESEARCHED - WHO WILL BENEFIT MOST?o POTENTIAL FOR ABUSEo POTENTIAL FOR DIVERSIONo “MAGIC BULLET THEORY”o DELIVERY SYSTEM
BARRIERS
• PATIENTo COMPLIANCEo SELECTIONo STIGMAo COST/INSURANCE COVERAGE
BARRIERS
• PHYSICIAN/NURSEo LACK OF AWARENESSo LACK OF TRAININGo LACK OF ONGOING TECHNICAL ASSISTANCEo DO NOT PROMOTE USEo MD’S NEEDED AT ALL PROGRAMSo EXTRA WORK
• OBSERVATION TIME
BARRIERS
• COUNSELORo LACK OF AWARENESSo LACK OF TRAININGo COUNSELORS IN RECOVERY
• “NOT THE WAY I DID IT”o MORE WORK
• AFTERCARE
BARRIERS
• PROGRAMo NEED PHYSICIAN SERVICESo NEED TO INCREASE COMMUNICATION BETWEEN PHYSICIANS
AND COUNSELORSo NEED LINKAGE TO MD AFTERCARE
• MONITOR DRUG LEVELS• MONITOR SIDE - EFFECTS• WRITE RX
o ENDANGERS PROGRAM INTEGRITY (THERAPEUTIC COMMUNITY)
BARRIERS
• SYSTEMo REGULATIONS NEED TO BE CHANGED
• WHO WILL PAY FOR MD SERVICESo NEED INCREASE IN EDUCATION AND T.A.o PRIVATE MD’S NEED TO BE ABLE TO LINK TO THE SYSTEMo NEED OUTCOME DATA
Does Treatment Work?Does Treatment Work? Medications +
psychosocial therapy bothbenefit brain function and recovery.
Each affects different partsof brain and inopposite ways.
PET scans adapted and retouched from Goldapple et al. 2004
Medications for Alcohol Dependence
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.
2006
1/month
VIVITROL® (naltrexone for extended-
release injectable suspension)4
1951
30 tabs/month*(1 tab/day)
Antabuse®
(disulfiram)1
1994
30 tabs/month*(1 tab/day)
ReVia® (naltrexone)2
2004
Campral® (acamprosate)3
180 tabs/month*(2 tabs, 3x/day)
Current PharmacotherapiesCurrent 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 EffectsNaltrexone: 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: ContraindicationsNaltrexone: Contraindicationspatients 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 High motivationo Failed agonist treatmento Successful agonist treatment but want a changeo Detox easily but relapse ofteno Early in diseaseo Positive family historyo 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 alcohol-related 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 6-month 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 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.o In the postindex period, naltrexone patients had a significantly smaller increase than alcohol controls in total
alcohol-related expenditures.o 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 alcohol-related and nonalcohol-related healthcare costs.
Vivitrol Studies
• 25% reduction in heavy drinking when compared to placebo group
o In 4 day lead in maintained abstinence was 32% in the treatment group vs 11% in the placebo group (all got behavioral treatment)
o Better abstinence rates with 7 day lead in
• Good adherence to medicationo 74% had 4 injectionso 64% had 6 injections
New Uses
• Nicotine dependence – men did better than womeno Women also don’t do as well with NRT: smoke for different
reasons than men??
• Cannabis dependenceo Actually increased the high and increased cravings
• Amphetamine/Stimulant dependenceo Decreased cravings and less depression and anxietyo 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®)Acamprosate (Campral®)
Modulator of neuronal excitatory processesApproved (FDA) in July 2004Evidence suggests that acamprosate increases abstinence and lowers the frequency of drinking in patients with alcohol use problems.
Acamprosate: Mechanism of ActionAcamprosate: Mechanism of Actionneuronal processes: excitatory (glutamate)
inhibitory (GABA)
acamprosate
Acamprosate: PharmacokineticsAcamprosate: PharmacokineticsMetabolismNone
EliminationKidney = 100% as unchanged acamprosate
Dose 333mg (2 tabs) TID
Acamprosate: Adverse EffectsAcamprosate: Adverse Effects
- well tolerated
-minor side effects: diarrhea, dizziness
Acamprosate: Drug InteractionsAcamprosate: Drug Interactions
None?
Acamprosate: ContraindicationsAcamprosate: Contraindicationspatients 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 PharmacotherapiesAnticraving Pharmacotherapies
CRAVING(irresistible desire to
drink)
conditioned cuesassociated with drinking
conditioned cuesassociated with withdrawal
naltrexone acamprosate
Alcohol - Deterrent TherapyAlcohol - Deterrent Therapy
+deterrenttherapy
Disulfiram (Antabuse®)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.
alcohol
acetaldehyde
acetate
carbondioxide
Disulfiram: Mechanism of ActionDisulfiram: Mechanism of Action
alcoholdehydrogenas
e
acetaldehydedehydrogenase
alcohol
acetaldehyde
disulfiram
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: EfficacyDisulfiram: Efficacy
?
Double-blinded studies are not possible with disulfiram.Disulfiram is usually only an adjunct therapy.
Disulfiram: Adverse EffectsDisulfiram: 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 EffectsDisulfiram: 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 InteractionsDisulfiram: 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 NO RESPIRATORY DEPRESSIONo NO INHIBITION OF LEARNING, UNLIKE BENZODIAZEPINESo NO ABUSE POTENTIALo 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 ORIGINALLY SYNTHESIZED AS ANTI-DIABETIC AGENTo APPROVED FOR PARTIAL ONSET AND PRIMARY GEN.
TONIC-CLONIC SEIZURES IN ADULTS AND CHILDREN
ANTICONVULSANTS
• TOPIRAMATE (TOPAMAX®)o I/2 LIFE 19-23 HOURSo 50-80% EXCRETED UNCHANGED IN THE URINEo NO THERAPEUTIC RANGE OR BLOOD LEVEL MONITORING
ANTICONVULSANTS
• TOPIRAMATE (TOPAMAX®)o FOUND TO BE MORE EFFECTIVE THAN CONTROLS AND
REDUCED THE NUMBER OF HEAVY DRINKING DAYS.o 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 EFFECTSo TRANSIENT PARESTHESIASo DECREASE COGNITION ( DECREASE IN CONCENTRATION AND
MEMORY)o SECONDARY ANGLE CLOSURE GLAUCOMA – RAREo KIDNEY STONES (1.5% OR 2-4 TIMES THE GENERAL
POPULATION)o WEIGHT LOSSo DECREASES ESTROGEN EFFECT OF BCPo INCREASED HALDOL LEVELo TEGRETOL AND DILANTIN WILL DECREASE TMX LEVEL
ANTICONVULSANTS
• TOPIRAMATE (TOPAMAX®) EVOLVING SPECTRUM OF USEo EPILEPSYo MIGRAINE PREVENTIONo ESSENTIAL TREMORo DIABETIC NEUROPATHIC PAINo MOOD DISORDERSo ALCOHOL DEPENDENCEo EATING DISORDERSo PTSDo TOURETTES SYNDROMEo OCDo OBESITYo TYPE 2 DIABETESo NICOTINE DEPENDENCEo 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 LICENSEDo BOARD CERTIFIED IN ADDICTION PSYCHIATRYo CERTIFIED IN ADDICTION MEDICINE BY ASAM OR AOAo INVESTIGATOR IN BUPRENORPHINE CLINICAL TRIALSo 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 DERIVATIVEo MAKES THIS LEGALLY CLASSIFIED AS AN OPIATE
• PARTIAL OPIOID AGONIST
• INITIALLY USED AS AN ANALGESIC
BUPRENORPHINE
• PARTIAL OPIOID AGONISTo VERY HIGH AFFINITY FOR MU RECEPTOR
• WILL DISPLACE MORPHINE, METHADONE
BUPRENORPHINE
• PARTIAL OPIOID AGONISTo 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 AGONISTo 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 USESo 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 USESo POOR ORAL BIOAVAILABILITY
• SUBLINGUAL WITH ABSORPTION THROUGH THE ORAL MUCOSAo SLOW DISSOCIATION RATE
• PROLONGED THERAPEUTIC EFFECT - SO CAN BE GIVEN EVERY OTHER OR EVERY THIRD DAY
BUPRENORPHINE
• PHARMACOLOGIC USESo TREATMENT OF ADDICTIONS*
• IN THE U.S.o 2 & 8 MG SUBLINGUAL TABLETS MADE BY RECKITT & COLMAN CALLED
SUBUTEX®o 2 & 8 MG SUBLINGUAL TABLETS WITH NALOXONE IN A 4:1 RATIO CALLED
SUBOXONE®
BUPRENORPHINE
• PHARMACOLOGIC USESo DOSES USED FOR OPIOID ADDICTION TREATMENT IS 1 -2
MG UP TO 16 - 32 MGo 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 IF TAKEN S.L. BUP>>>>>>NALONXONEo IF TAKEN I.V. NALOXONE>>>>>BUP
BUPRENORPHINE
• SAFETYo 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
o 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 EFFECTSo SIMILAR TO OTHER MU AGONISTS THOUGH LESS SO
• NAUSEA• VOMITING• CONSTIPATION
*NO DISRUPTION IN COGNITIVE AND PSYCHOMOTOR PERFORMANCE
BUPRENORPHINE
• TERATOGENESISo LIMITED REPORTS
• ONE STUDY FOUND NO SIGNS OF PHYSICAL DEPENDENCY IN NEONATES OF HEROIN ADDICTED MOTHERS TAKING BUPRENORPHINE
BUPRENORPHINE
• DRUG INTERACTIONSo SCANT STUDIESo DEATH CASE REPORT ASSOCIATED WITH IV BUPRENORPHINE
AND BENZODIAZEPINESo CANNOT GIVE WITH ReViao AVOID MEDICATIONS THAT ARE METABOLIZED BY THE
CYTOCHROME P450 3A4 SYSTEMo IF ACUTE PAIN TREATMENT IS NEEDED, MAY HAVE TO SWITCH
TO METHADONE
On the Horizon
• Implantable buprenorphine – Probuphineo 6 month durationo 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 patcho 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 SAFEo EFFECTIVE
SMOKING CESSATION
• 70 MILLION SMOKERS IN THE US
o 90% WOULD LIKE TO QUITo 60% HAVE TRIED TO QUITo 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
• UNASSISTEDo COLD TURKEYo 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
• ASSISTEDo SUPPORT GROUPSo COMMERCIAL PROGRAMSo ACUPUNCTUREo MD ASSISTED CESSATION
117
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).
118
Efficacy of Various Intensity Levels of Person-to-Person Contact (n = 43 studies)
Level of ContactLevel of Contact
No contact No contact (reference group)(reference group)
10.9%10.9%
22.1%22.1%
Minimal counselingMinimal counseling(< 3 minutes)(< 3 minutes)
Low intensity counselingLow intensity counseling(3-10 minutes)(3-10 minutes)
Higher intensity counselingHigher intensity counseling(> 10 minutes)(> 10 minutes)
13.4%13.4%
16.0%16.0%
Estimated Estimated Abstinence RateAbstinence Rate
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 SAFEo EFFECTIVE
NICOTINE REPLACEMENT THERAPIES (NRT)
• NICOTINE GUM (NICOTINE POLACRILEX, NICORETTE®
o FDA APPROVAL 1984o AVAILABLE IN 2MG AND 4MG
• .86 MG ABSORBED FROM THE 2MG PIECE
• 1.2 MG ABSORBED FROM THE 4 MG PIECE
o COMPOSED OF NICOTINE BOUND TO AN ION-EXCHANGE RESIN INCORPORATED INTO A GUM BASE
o “PARK AND CHEW” TECHNIQUEo AFFECTED BY CHEWING RATE
AND pH OF THE SALIVAo ADVERSE EFFECTS: JAW PAIN,
MOUTH SORENESS, DYSPEPSIA, HICCUPS
NICOTINE REPLACEMENT THERAPIES (NRT)
• NICOTINE TRANSDERMAL PATCHES (HABITOL®, NICODERM CQ ®, NICOTROL ® )
o APPROVED BY THE FDA IN 1991o OTC APPROVAL IN 1996o ALL 21 MG PATCHES DELIVER .9MG OF
NICOTINE PER HOURo TEMPERATURE AND CIRCULATION
AFFECT DELIVERYo ADVERSE EFFECTS: SLEEP
DISTURBANCE, SKIN REACTIONS
NICOTINE REPLACEMENT THERAPIES (NRT)
• NICOTINE INHALER (NICOTROL INHALER ® )
o FDA APPROVED IN 1998o CIGARETTE HOLDER SHAPE
WITH REPLACEABLE CARTRIDGES
• 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 DAYo AFFECTED BY PUFF RATE,
TEMPERATURE, SALIVA pHo 25% TAPER EVERY MONTH IN
NUMBER OF PUFFS
NICOTINE REPLACEMENT THERAPIES (NRT)
• NICOTINE SPRAY ( NICOTROL NS ® )o APPROVED BY THE FDA IN 1996o ONE INHALATION IN EACH
NOSTRIL = TOTAL DOSE OF 1MGo AVERAGE USE IS 13 - 20 DOSES
PER DAYo 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
o 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 GLAXO PACKAGES “TIME TO FIRST CIGARETTE” PROGRAM WITH LOZENGES - PROGRAM TO DECIDE IF PATIENT SHOULD START WITH A 2 OR 4 MG LOZENGE
127
Efficacy of Nicotine Gum
(n = 13 studies)
PharmacotherapPharmacotherapyy
Placebo Placebo (reference group)(reference group)
17.1%17.1%
Nicotine GumNicotine Gum23.7%23.7%
EstimatedEstimatedAbstinence Abstinence
Rate Rate
128
Efficacy of Nicotine Inhaler (n = 4 studies)
PharmacotherapyPharmacotherapy
Placebo Placebo (reference group)(reference group)
10.5%10.5%
Nicotine InhalerNicotine Inhaler22.8%22.8%
EstimatedEstimatedAbstinence Rate Abstinence Rate
129
Efficacy of Nicotine Nasal Spray (n = 3 studies)
PharmacotherapyPharmacotherapy
Placebo Placebo (reference group)(reference group)
13.9%13.9%
Nicotine NasalNicotine NasalSpraySpray
30.5%30.5%
EstimatedEstimatedAbstinence Rate Abstinence Rate
130
Efficacy of Nicotine Patch (n = 27 studies)
PharmacotherapyPharmacotherapy
Placebo Placebo (reference group)(reference group)
10.0%10.0%
Nicotine PatchNicotine Patch17.7%17.7%
EstimatedEstimatedAbstinence Rate Abstinence Rate
131
Efficacy of Combination NRT (n = 3 studies)
PharmacotherapyPharmacotherapy
One NRT One NRT (reference (reference group)group)
17.4%17.4%
Two NRTsTwo NRTs 28.6%28.6%
EstimatedEstimatedAbstinence Rate Abstinence Rate
NICOTINE REPLACEMENT THERAPIES (NRT)
• NICOWatero Illegal in NYSo Can easily be sold to minors
OTHER NICOTINE PRODUCTS
ONE DOSE IS EQUAL TO 1 MG NICOTINEFROM TOBACCO
NEW NICOTINE REPLACEMENT
• THE STRAW™o 8 MG – NICOTINE BITARTRATE
BEADSo 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 STIMULIo INCREASED COMPLIANCEo BEHAVIORAL COMPONENT
• RECOVERY PHARMACEUTICALSo 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 e-cigarette smoking makes dosing nonuniform over time and calls into question their usefulness as nicotine delivery devices.
o The vacuum required to smoke conventional cigarettes varied among the eight brands tested. Lights and ultra-light brands required stronger vacuums to smoke than unfiltered and regular filtered brands.
o Except for one brand, higher vacuums were required to smoke e-cigarettes than conventional brands.
o 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 ANTIDEPRESSANTo 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 EFFECTSo DRY MOUTHo INSOMNIAo 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 .5 mg and 1.0 mg twice daily titratedo .5 mg and 1.0 mg twice daily non-titrated.
• Weeks 9-12 continuous abstinence rates pooled by dose.o 1.0 mg twice daily doses = 50.6%o 0.5 mg twice daily doses = 45.1%o 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 – cystenineo Used in Tylenol ovedose, mucolytic agento Source of cysteine which can restore glutamate levels seen in
cocaine withdrawal
• Modafinilo Wake promoting agento Non-amphetamine stimulanto Increase levels of glutamate and decreased levels of GABAo Low abuse potential
• Topiramateo anticonvulsant
Cocaine Dependence
• Vigabatrin (Gamma – Vinyl- GABA)o Atypical seizure med
• Baclofeno GABA agonist
• Tiagabineo Anticonvulsant
• Antabuseo Inhibit Dopamine Beta-Hydroxylase so increased dopamine
levels
• Bupropiono Dopamine and NE reuptake inhibitor
Gambling
• Naltrexone and Nalmefineo Opiate antagonists which will block the high
• Have tried antidepressants and mood stabilizerso Paxil worked in one trial and not anothero 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 Acamprosate – anticravingo Antabuse - ???o Newest regimen:
• Naltrexone is first choice as decreases high and impulsivity
• If fail, add low dose Ondansetron to Naltrexoneo 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.