substance abuse disorders trevison
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Pharmacotherapy of Substance
Abuse Disorders
Louis A. Trevisan, M.D.Louis A. Trevisan, M.D.
Assistant Clinical Professor of Psychiatry, Yale University School of MedicineAssistant Clinical Professor of Psychiatry, Yale University School of Medicine
Associate Chief of PsychiatryAssociate Chief of Psychiatry
VA Connecticut Healthcare System, West Haven, CTVA Connecticut Healthcare System, West Haven, CT
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Topics Diagnosis of Substance Use Disorder
The Addicted Brain
Opioids Nicotine
Others-Stimulants,cocaine and prescribedmedications
Conclusion
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Diagnostic criteria for Substance
Dependence Tolerance
Withdrawal
Substance taken in larger amounts Desire or unsuccessful attempts to cut down
Great deal of time is spent obtaining the substance
social, occupational or recreational activities aregiven up or reduced
Substance is continued despite persistent orrecurring physical problem
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Biological Determinants of
Addiction Preclinical evidence
Human evidence
Mesolimbic Dopamine system
VTA,NAc,hippocampus,amygdala,cortex
CREB/delta FosB/glutamate
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Preclinical Evidence rats, mice and non human primates
self administer same substance as humans
within days they become addicted
readily administering substance such as
cocaine, amphetamines, opioids and
alcohol
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Preclinical Evidence Research animals prefer substances and
learn behaviors of addiction at the expense of
normal activity eating
sleeping
self administer until they die of exhaustion
prefer environment associated with the drug
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Cues and Abstinence Drug seeking behavior is extinguished
The pleasure of the drug is NOT forgotten
Even after months of abstinence-
animals return to bar pressing behavior when
given just a small taste of cocaine or,
if they are placed in a cage that is associated with
cocaine or a drug high.
Increasing stress = back to drug
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Cues/Craving and Relapse These same types of stimuli
exposure to low doses of drug
drug associated cues
places where the addict has used drugs
Bars/parties
stress Trigger Craving and relapse in Human
Addicts
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Brain Regions Regions associated with drug addiction
VTA (ventral tegmental area)
Nac (nucleus accumbens)
hippocampus
amygdala
cortex (frontal)
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Developed by R. Anton, Med. Univ. SC. USADeveloped by R. Anton, Med. Univ. SC. USA
Thalamus
Attention
VTA
BasalGanglia
Amygdala
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Reward Pathway/Center VTA-------Nac
dopaminergic pathway
evolutionarily ancient
Rheostat tells the other brain centers how rewarding an
activity is.
increasing reward = increasing likelihood theorganism will remember the activity and repeatit.
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Mammals VTA - Nac pathway is integrated with the
amygdala
amygdala = pleasure vs aversive hippocampus = recording of memories of an
experience including when, where and with whom
the activity occurred.
frontal cortex = coordinates and processes theinformation
determines ultimately whether a behavior occurs
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Brain Imaging fMRI (functional Magnetic Resonance
Imaging)
PET (Positron Emission Tomagraphy) Drug Addicts NAc lights up when:
they are offered cocaine,
see white lines of a substance on a mirror watch someone else use cocaine
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Mechanisms of Action of
Addicting Substances Dopamine
Cocaine: disables dopamine transporter in VTA
this causes increased VTA dopamine in the synapse Opiates bind to Mu opioid receptor in NAc
causes similar cascade to that of dopamine in the NAc
Alcohol enhances dopamine release by quieting neurons
that would otherwise inhibit dopamine secreting neurons in
VTA
Nicotine induces VTA cells to release dopamine into the
NAc
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Addiction is Born Tolerance
increasing amounts to get same high
promotes escalation of drug use
Dependence
leads to painful emotional and, at times,
physical reactions if drug is cut off withdrawal
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Why use Medications at all?
Agents to treat withdrawal
Agents to reduce consumption andcraving
Agents to treat psychiatricproblems (either disorder or symptoms)
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Principles of Pharmacotherapy:
Opioids
Agents to treat opioid withdrawalAgents to treat opioid withdrawal
Agents to reduce opioid consumptionAgents to reduce opioid consumptionand cravingand craving
Agents to treat psychiatric problemsAgents to treat psychiatric problems
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Opioids
MuMu--opioid receptor agonist medicationsopioid receptor agonist medications Create physical dependence (usually 3Create physical dependence (usually 3
weeks or more of daily use)weeks or more of daily use) Nature/severity of w/d related to:Nature/severity of w/d related to:
Drug used (metabolism)
Amount use
Duration/ pattern of use
Psychological factors
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Usual frequency of use in established habits and
first appearance of withdrawal
DrugUsual
frequency ofuse (hours)
Appearance ofnonpurposeive
withdrawalsymptoms (hours)
Peak(hours)
Meperidine 2-3 4-6 8-12
Dilaudid 3 4-5
Heroin 4 8-12 48-72
Morphine 5-6 14-20
Codeine 3 24
Methadone 8-12 36-72 72-96
HeroinMajority symptoms
5-10 days
Methadone Majority symptoms14-21 days
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Evaluation and DiagnosisEvaluation and Diagnosis
Drug History
Name of drug used (current, past use)Name of drug used (current, past use) Length of time used & frequency of useLength of time used & frequency of use
Date or time of last useDate or time of last use Route, Amount, CostRoute, Amount, Cost Purpose (e.g. to sleep, for energy, get high or: relievePurpose (e.g. to sleep, for energy, get high or: relieve
depression, sidedepression, side--effects of other drugs or boredom)effects of other drugs or boredom)
For drugs previously used: name, age started, length ofFor drugs previously used: name, age started, length oftime used, adverse effectstime used, adverse effects
Prescription drugs currently used: name, reason forPrescription drugs currently used: name, reason foruse, amount, frequency and duration of use, last doseuse, amount, frequency and duration of use, last dose
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Opioid Intoxication
Opioids:Opioids:
Bind to mu, kappa, deltaBind to mu, kappa, delta--opioid receptoropioid receptorMu receptors most important:Euphoria, pain control, respiratory
depression
Block activation of locus ceruleusBlock activation of locus ceruleus
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Opiate Withdrawal
AssessmentAssessment
ManagementManagement Substitution Treatment of Symptoms
Rapid Detoxification
Alternatives
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Symptoms
Anorexia Hot/Cold FlashAnxiety Irritability
Nausea Muscle Aches
Craving Broken Sleep
Dysphoria PerspirationFatigue Restlessness
Headache Yawning
Abdominal Cramps
Signs and Symptoms of
Opioid Withdrawal
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Signs and Symptoms of Opioid
WithdrawalSigns
Diarrhea Increased B.P.Elevated Pulse Lacrimation
Vomiting Rhinorrhea
Low grade fever Piloerection
Mydriasis(with dilated fixed pupils at the peak)
Muscle spasm(hence the term kicking the habit)
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Treatment of Opioid W/D
SubstitutionSubstitution Methadone
Buprenorphine
Treatment of Underlying NeurobiologyTreatment of Underlying Neurobiology Clonidine
Rapid DetoxificationRapid Detoxification Clonidine + Naltrexone UltraUltra--rapid detoxificationrapid detoxification
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Substitution with Methadone
MethadoneMethadone Substitute long acting agent for short acting agent
Individuals addicted to short acting opioidsIndividuals addicted to short acting opioids Stabilize on methadone/taper 20%/day for inpatients
5%/day for outpatients
Methadone maintained individualsMethadone maintained individuals 3%/week
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Methadone InteractionsAnti-retroviral Agents
Increased clearance/decreased plasma levelsMethadone:
Abacavir, amprenvir, efvirenz, ritonavir
Methadone increased AUC of Zidovudine
Methadone decreased AUC of Didanosine and
Stavudine
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Methadone Interactions
CYP3A4 inducers:
Rifampin
Phenytoin
St Johns Wort
PhenobarbitalCarbamazepine
May induce withdrawal symptoms
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Pregnancy: MethadoneMay require higher doses
Should only be used in pregnancy when benefitsoutweigh the risks
Nursing mothers: nursing infant receives 2-3%
of the maternal dose
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Clonidine Detoxification
AlphaAlpha--2 adrenergic agonist2 adrenergic agonist Eliminates symptoms associated with OWSEliminates symptoms associated with OWS
(lacrimation/rhinorrhea/restlessness/muscle pain/joint pain)
Protocol: 10-13 days
0.1mg clonidine q4-6 hours
Increase by 0.1 to 0.2 mg to symptoms(max=1.2mg)
Taper by 0.1 or 0.2 mg/day
Augment by using benzodiazepinesAugment by using benzodiazepines
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Clonidine and Naltrexone
Detoxification Shorten durationShorten duration Successfully gets patients on opioid blockingSuccessfully gets patients on opioid blocking
medicationmedication
Protocol:Protocol: 4 day protocol
Clonidine 0.1 to 0.3 mg TID x 3 days
Day #2, initiate low dose naltrexone 12.5 mg
Increase naltrexone to 25mg, then 50 mg, then 100mg
Clonidine 0.1 mg TID for day #4
Augment by using benzodiazepinesAugment by using benzodiazepines
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Buprenorphine Detoxification
BuprenorphineBuprenorphine Partial mu-opioid agonist
Not yet approved by FDA for this use Milder withdrawal symptoms Safer
Reduced danger of OD ?reduced abuse liability
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Buprenorphine hydrochloride has the molecular formula,
C29H41NO4HCl, and the following chemical structure:
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Sublingual Technique for Using SuboxonSublingual Technique for Using Suboxon
Sublingual Technique for Using
Suboxone and Subutex.
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Ultrarapid Detoxification
Shorten duration to 1 day Successfully gets patients on opioid
blocking medication Protocol: General anesthesia
Initiate naltrexone treatment
Long term results not yet knowLong term results not yet know Confers risks of general anesthesiaConfers risks of general anesthesia
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Methadone Maintenance
Orally effective opioid agonistOrally effective opioid agonist
Suppress narcotic w/d for 24Suppress narcotic w/d for 24--36 hours36 hours
In steady state, not sedating, intoxicatingIn steady state, not sedating, intoxicatingor effective for pain controlor effective for pain control
Federally regulatedFederally regulated 1-year hx of dependence
Current dependence (exceptions noted)
Over 18 years of age
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Buprenorphine(Suboxone)
Partial -agonist Opioid effects are limited
Less likely to cause overdose Sub lingual (under the tongue) Combination w/naloxone-prevents diversion
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Suboxone:
buprenorphine/naloxoneCombination medication
Dosage and Administration: (4-32mg daily) ceiling effect
titrate to 12-16 mg dailysublingually (increased bioavailability)
Induction with buprenorphine or buprenorphine/naloxone
Wait until the patient displays clear signs of withdrawal
Gradual induction over several days4 mg daily to range of from 4-24mg daily
suppress opioid withdrawal effects
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Suboxone Side Effects4 week study (16mg daily)
Constipation
Nausea
Headache4 month study (16 mg daily)
Pain
Withdrawal Syndrome
Insomnia
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Suboxone: Drug InteractionsMetabolized via CYP3A4CYP3A4 inhibitors:
ketoconazole
macrolide antibiotics (erythromycin)
HIV protease inhibitors
ritonavir
indinavir
saquinavir
May need to adjust dose
Benzodiazepines: Only known overdoses withBuprenorphine-in combination with benzodiazepines
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Naltrexone
Oral opioid antagonistOral opioid antagonist Prevent relapse,Prevent relapse,
Patients not always compliantPatients not always compliant Target populations:Target populations: (Health care(Health careprofessionals, employed, work releaseprofessionals, employed, work release
program, family involvement)program, family involvement)
Side effects: nausea, GI distress,Side effects: nausea, GI distress,headachesheadaches
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Psychosocial Treatment
All FDA-approved medications for alcohol only approvedwith use ofadequate psychosocial treatment
For opioids, naltrexone not effective without psychosocialtreatment (usually behavior contracting)
Methadone maintenance particularly regulated Buprenorphine approve for primary care MDs use, but
MDs must undergo additional training and provide
psychosocial treatment
Medications should always be thought of as adjunctivetreatment
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Nicotine Dependence Biological Treatments:
Nicotine Replacement Therapy (NRT)
Patch Inhaler
Gum
Spray
Medications
Buproprion Varenicline
Cost considerations
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Nicotine Replacement Therapy.
Form Advantages Disadvantages
Transdermal PatchProvides steady level of nicotine;
easy to use; unobtrusive;
available without prescription
User cannot adjust dose if craving
occurs; nicotine released more slowly
than in other products
Nicotine Polacrilex gumUser controls dose; oral
substitute for cigarettes;
available without prescription
Proper chewing technique needed to
avoid side effects and achieve efficacy;
user cannot eat or drink while chewing
the gum; can damage dental work;
difficult for denture wearers to use
Vapor inhalerUser controls dose; hand to-
mouth substitute for cigarettes
Frequent puffing needed; device
visible when used
Nasal spray
User controls dose; offers
most rapid delivery of
nicotine and the highest
nicotine levels of all nicotine-
replacement products
Most irritating nicotine replacement
product to use, device visible when
used.
Modified from: Rigotti, N., Clinical practice. Treatment of tobacco use and dependence.
New England Journal of Medicine, The, 2002. 346(7): p. 506-512.
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Nicotine Replacement
Therapy
Patch
Gum
Spray
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Treatment of Nicotine Dependence.
Rigotti, N., Clinical practice. Treatment of tobacco use and dependence. New England
Journal of Medicine, 2002. 346(7): p. 506-512.
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Medications Varenicline
Oral administered Alpha4-Beta2 nicotinic ACHreceptor partial agonist
Antagonizes nicotine response No dose adjustment in older adults
Buproprion SR Antidepressant- Weak inhibitor of dopamine
uptake
Well-tolerated, Advanced age in one study wasreported as a positive predictive factor
Zhao, Q., Schwam, E., Fuller, T., OGorman, M., Burstein, A.H. (2011). Pharmacokintics, Safety and Tolerability Following Multiple Oral Doses ofVarenicline Under Various Titrations Schedules in Elderly Nonsmokers. Journal of Clinicial Pharmacology51:492-501.
Elhassan, A, and Chow, R, D. (2007). Smoking Cessation in the Elderly. Clinical Geriatrics 15(2):38-45.
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Varenicline
Days How to take it
1 to 3 0.5mg daily
4 to 7 0.5mg BID
8 on 1mg BID
0.5mg 1mg
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Bupropion
Days How to take it
1 to 3 150MG daily
4 on 150MG BID
Continue for 7-12 weeks or up to 6 months to
maintain abstinence.
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Nicotine Dependence
Psychotherapeutic/Behavioral
Cognitive-Behavioral Therapy(CBT)
Motivational Interviewing
Brief Intervention (F.R.A.M.E.S.)Substance Abuse Among Older Adults Physicians Guide, (2000) Treat Improvement Protocol (TIP) 26, DHHS PublicationNo.(SMA) 00-3394. Rockville, MD: Substance Abuse and Mental Health Services Administration.
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Nicotine Dependence
F.R.A.M.E.S:
Feedback from the assessmentPersonal Responsibility for change
Advice to change
Menu of change options
Empathic counseling styleEnhanced client Self-efficacy/ongoing follow-up.
.
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Cannabis
Biological Treatments
No current empirical support Psychosocial
Brief interventions/Motivational Interviewing
CBT
Groups
Vandrey, R; (2009) Margaret Haney, Pharmacotherapy for Cannabis Dependence: How Close Are We?CNS Drugs.23(7): 543553.
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Prescription Misuse
Opiates
Benzodiazepines
Stimulants
Muscle Relaxants
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Prescription Misuse
Optimizing medical treatment
Pain
Regular urine toxicology screens
Medication
Slow taper for benzodiazepines
Management of withdrawal symptoms
Kalapatapu, R. K. ; Sullivan M. A. (2010). Prescription Use Disorders in Older Adults. American Journal on
Addictions, 19:515-522.
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Prescription Misuse
Psychosocial treatment plan Brief Interventions
Patient education
Self-help groups, AA
Family education and involvement
Long-term care facilities
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Cocaine/Stimulants
Cocaine/Stimulants
No evidence based support formedication
Supportive detoxification
Psychosocial focus
Future treatment: Vaccination?Martell, B.A. et al, (2009). Cocaine Vaccine for the Treatment of Cocaine Dependence in Methadone MaintainedPatients: A Randomized Double-Blind Placebo-Controlled Efficacy Trial Arch Gen Psychiatry.; 66(10): 1116
1123.
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Summary
Treatments should be tailored to theindividual/group
Brief intervention plus medicationspecifically for nicotine and alcohol
Psychosocial treatments
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References
Atkinson, R, ; Tolson, R.; Turner, J. , (1993). Factors Affecting Outpatient Treatment Compliance of Older Male ProblemDrinkers" Journal of Studies on Alcohol 54:102-106
Blow, F. C., & Barry, K. L. (2002). Use and misuse of alcohol among older women. Alcohol Research and Health, 26,
308, 315.
Culberson, J. W. (2006b). Alcohol use in the elderly: Beyond the CAGE. Part 2 of 2: Screening instruments and treatmentstrategies. Geriatrics, 61, 20-26.
Darchangelo, E., (1993) Substance Abuse in Later Life. Canadian Family Physician 39: 1986-1993. Dupree, L, Schonfeld, L, Dearborn-Harshman, K, & Lynn, N. (2008). A relapse prevention model for older
alcohol abusers. In G. Thompson, A. Steffen & L. W. Thompson (Eds.), Handbook of behavioral and cognitivetherapies with older adults (pp. 61-75). Berlin, Heidelberg: Springer-Verlag Publications.
Kofoed, L.; Tolson, R.; Atkinson, R.; Toth, R.; and Turner, J. , (1987) Treatment compliance of older alcoholics: An elder-
specific approach is superior to "mainstreaming." Journal of Studies on Alcohol 48:47-51
Magill, M; Ray, L. (1993 ) Cognitive-Behavioral Treatments with Adult Alcohol and Illicit Drug Users: A Meta-Analysis ofRandomized Controlled Trials Journal of Studies on Alcohol 54:102-106
http://www.icap.org/PolicyTools/ICAPBlueBook/BlueBookModules/23AlcoholandtheElderly/tabid/181/Default.aspx#3
http://pubs.niaaa.nih.gov/publications/aa02.htm
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2379910/pdf/canfamphys00115-0134.pdf http://www.psychiatryonline.com/pracGuide/PracticePDFs/SUD2ePG_04-28-06.pdf
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