Transcript MSR for 07 12 12 no methadone

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]