substance abuse disorders trevison

8/3/2019 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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