Drug Addiction Treatment - Reading - Master List

This page contains all the reading given as handouts for the course, as a single document.

 Cognitive Behavioral Treatments - Kathleen M. Carroll
 Biology of Reward Mechanisms - Eliot L. Gardner
 Contingency Management with Cocaine Dependent & Special Treatment Populations - Stephen T. Higgins
 Overview of Drug Addiction Treatment - Herbert D. Kleber
 Anti-Cocaine Catalytic Antibodies - Donald W. Landry
 Pharmacological Treatment of Drug Addiction - Frances R. Levin
 Treatment Outcome Research on Drug Addiction - A. Thomas Mclellan
 Brain Imaging & Substance Abuse Research - Nora D. Volkow

Cognitive Behavioral Treatments - Kathleen M. Carroll

I. Overview

Cognitive-Behavioral Therapies (CBT) are among the most frequently evaluated approaches to the treatment of substance use disorders and have been found to be effective in many clinical trials and with many different types of substance-dependent populations. This presentation will focus on the theoretical background of this approach, its goals, the fundamentals of implementing CBT with substance users, and a brief review of the evidence supporting its effectiveness with drug abusers.

II. What is CBT?

  1. CBT is based on social learning theories on the acquisition and maintenance of substance use disorders

  3. CBT assumes that substance use is functionally related to other problems in the individuals life,

  5. CBT emphasizes the development of coping skills as effective alternatives to using substances as overgeneralized means of coping with problems

  7. CBT emphasizes the initiation and mastery of skills through within session practice, role playing, and extra-session tasks.
III. Key concept in CBT=Functional analysis of drug use (exploration of substance use in relationship to its antecedents and consequences) IV. Recognize, avoid, cope

V. Key learning processes involved in acquisition/maintenance of substance abuse.

VI. Skills training in CBT: VIII. Evidence for CBT
  1. Does it work and for whom?

VIII. Strengths of CBT:
  1. CBT has a comparatively high level of empirical support

  3. It is grounded in social learning theory, which itself has strong support

  5. It's a very flexible approach, that can be implemented as group or individual therapy, inpatient or outpatient, and delivered as a short-term or long term treatment. Most importantly, it is a treatment that can be tailored to meet the needs of a wide range of substance abusers.

  7. CBT is compatible with a number of treatment approaches, including family therapy and pharmacotherapy


OVERVIEW: The goal of this lecture is to describe the neurobiological mechanisms underlying reward/reinforcement and the role of these mechanisms in drug addiction and its attendant phenomena - including craving, rebound dysphoria, and relapse. We will describe the neuroanatomy, neurophysiology, and neurochemistry of the brain's reward/reinforcement circuits. We will describe laboratory paradigms for studying the role of brain reward mechanisms in addiction - including intracranial drug self-administration in lab animals, electrical brain-stimulation reward, and in vivo brain microdialysis and microelectrochemistry. We will describe genetic variation in brain reward activation by addicting drugs, and the neurobiology of drug craving. We will note the implications of addictive drug action on brain reward mechanisms for the development of rational pharmacotherapies for drug addiction at the human level.


Using a self-administration paradigm in which a progressive-ratio schedule of reinforcement is utilized to assess the amount of work animals will expend for such self-administration, a hierarchy of appetitiveness amongst different classes of addictive drugs can be calculated (cocaine extremely appetitive; heroin highly appetitive; valium marginally appetitive).

Strikingly, this hierarchy correlates strongly with hierarchies of appetitiveness reported by human users of these same drugs. The facilitation of the functioning of the pleasure/reward/reinforcement circuitry of the brain by addicting drugs (e.g., Fig. 1) is significantly attenuated by opioid antagonists (e.g., Fig. 2), implicating endogenous opioid peptidergic circuitry in addictive drug action on brain pleasure/reward/reinforcement mechanisms.

Fig. 1. Enhanced brain pleasure/reward following acute systemic administration of a prototypical addictive drug (morphine). Enhancement of brain reward is measured as a decrease in electrical brain-stimulation reward threshold in the ventral tegmental area (dopaminergic nucleus A10). "p<.01" indicates a statistically significant difference at greater than the 0.01 level of probability. "N.S." ("not significant") indicates the lack of a statistically significant difference.

Fig. 2. Opioid antagonist (naloxone)-induced blockade of pentobarbital-enhanced brain pleasure/reward. "p <.001 " indicates a statistically significant difference at greater than the 0.001 level of probability. "p<.02" indicates a statistically significant difference at greater than the 0.02 level of probability. "N.S." ("not significant") indicates the lack of a statistically significant difference.

Figure 3. Schematic diagram of the brain-reward circuitry of the mammalian (laboratory rat) brain, with sites at which various abusable substances appear to act to enhance brain-reward and thus to induce drug-taking behavior and possibly drug-craving. ICSS, descending, myelinated, moderately-fast-conducting component of the brain-reward circuitry that is preferentially activated by electrical intracranial self-stimulation., DA subcomponent of the ascending mesolimbic dopaminergic system that appears preferentially activated by abusable substances: Raphé brain stem serotonergic raphé nuclei LC, locus coeruleus; VTA ventral tegmental area; Acc, nucleus accumbens; VP, ventral pallidum; ABN, anterior bed nuclei of the medial forebrain bundle; AMYG, amydala; FCX frontal cortex: 5HT, serotonergic (5-Hydroxytryptamine) fibers, which originate in the anterior raphé nuclei and project to both the cell body region (ventral tegmental area) and terminal projection field (nucleus accumbens) of the DA reward neurons; NE, noradrenergic fibers, which originate in the locus coeruleus and synapse into the general vicinity of the ventral mesencephalic DA cell fields of the ventral tegmental area; GABA, GABAerqic inhibitory fiber systems synapsing upon the locus coeruleus noradrenergic fibers, the ventral tegmental area, and the nucleus accumbens, as well as the GABAergic outflow from the nucleus accumbens; Opioid, endogenous opioid peptide neural systems synapsing into both the ventral tegmental DA cell fields and the nucleus accumbens DA terminal projection loci; ENK, enkephalinergic outflow from the nucleus accumbens; DYN, dynorphinergic outflow from the nucleus accumbens; GLU, glutamatergic neural systems originating in frontal cortex and synapsing in both the ventral tegmental area and the nucleus accumbens.

Fig. 4. Enhanced extracellular synaptic dopamine in nucleus accumbens pleasure/reward synapses produced by the addicting drug morphine.

Fig. 5. Enhanced extracellular synaptic dopamine in nucleus accumbens pleasure/reward synapses produced by D9-tetrahydrocannabinol (THC), the addicting constituent of marijuana and hashish, and attenuation of same by the opioid antagonist naloxone (NAL). "p<.001" indicates a statistically significant difference at greater than the 0.001 level of probability. "p<.01" indicates a statistically significant difference at greater than the 0.01 level of probability. "p<.05" indicates a statistically significant difference at greater than the 0.05 level of probability.

Fig. 6. Enhanced brain reward following acute systemic administration of D9-tetrahydrocannabinol ("THC," the addicting constituent of marijuana and hashish) (top panel), and diminished brain reward (dysphoria) during withdrawal from THC (bottom panel). Enhanced brain reward is measured as a left-shift, and diminished brain reward as a right-shift, in mean rate-frequency electrical brain stimulation reward functions in the medial forebrain bundle axons of the ventral tegmental area (dopaminergic nucleus A10). In the above figure, THC significantly shifts the reward function curve to the left (enhanced brain reward), while withdrawalfrom THC significantly shifts the reward function curve to the right (diminished brain reward).

Fig. 7. Tolerance to the euphorigenic effects of morphine with repeated administration. Enhancement of brain reward is measured as a decrease in electrical brain-stimulation reward threshold in the ventral tegmental area (dopaminergic nucleus A10). Inhibition of brain reward is measured as a increase in electrical brain-stimulation reward threshold in the ventral tegmental area (dopaminergic nucleus A10).

Fig. 8. Genetic variation in the enhanced brain reward seen following acute systemic administration of D9-tetrahydrocannabinol ("THC, " the addicting constituent of marijuana and hashish). Enhanced brain reward is measured as a left-shift in mean rate-frequency electrical brain stimulation reward functions in the medial forebrain bundle axons of the ventral tegmental area (dopaminergic nucleus A10). In addictive-drug-nonpreferring Fischer 344 rats, THC does not significantly affect the brain reward function curve. In addictive-drug-neutral Sprague-Dawley rats, THC enhances brain reward functions only modestly. In addictive-drug-preferring Lewis rats, THC robustly shifts the reward function curve to the left (enhanced brain reward).

Fig. 9. Genetic variation in the neurochemical substrates of the enhanced brain reward seen following acute systemic administration of D9-tetrahydrocannabinol ("D9-THC, " the addicting constituent of marijuana and hashish). In vivo brain microdialysis is used to measure dopamine release at pleasure/reward synapses in the nucleus accumbens. In addictive-drug-neutral Sprague-Dawley rats, D9-THC enhances synaptic dopamine in nucleus accumbens pleasure/reward synapses only modestly. In addictive-drug-preferring Lewis rats, D9-THC robustly enhances synaptic dopamine in nucleus accumbens pleasure/reward synapses. "x" indicates statistical significance of comparisons of individual samples with pre-injection dopamine levels (x = p < 0.05, xx = p < 0.01).

Vulnerability to drug addiction correlates with a hypo-dopaminergic dysfunctional state within the core pleasure/reward/reinforcement circuitry of the brain (see Fig. 10).

Figure 10.

 Schematic summary of similar biochemical manifestations of the 'drug-addicted' and 'drug-preferring' state. (A) (Normal state) depicts a control VTA neuron projecting to the NAcc. Shown in the VTA cell are tyrosine hydroxylase (TH), dopamine (DA), presynaptic dopamine receptors (D2 coupled to G-proteins (Gi), and neurofilaments (NFs). Shown in the NAcc are, in addition to TH and DA, dopamine receptors (D1 and D2), G-proteins (Gi and Gs), components of the intraceIlular cyclic AMP system (AC, adenylate cyclase; PKA, cAMP-dependent protein kinase; and possible substrates for the kinase-ion channels and the nuclear transcription factors, CREB, fos and jun), as well as major inputs and outputs of this region (VP, ventral pallidum; HP, hippocampus; AMYG, amygdala; OLF, olfactory cortex; CTX, other cortical regions). (B) (Drug-addicted, drug-preferring state) depicts a VTA neuron projecting to the NAcc after chronic morphine or cocaine, or from a Lewis (drug-preferring) rat versus Fischer (F344) rat. In the drug-addicted or drug-preferring animal, TH levels are increased in the VTA, and decreased in the NAcc (due to either decreased phosphorylation as for morphine and cocaine, or decreased enzyme levels as in Lewis versus Fischer rats). In addition, NF levels are decreased in the VTA in the drug-addicted and drug-preferring state. This decrease in NFs may be associated with alterations in neuronal structure, decreases in axonal caliber, and/or decreases in axonal transport rate in these cells, as indicated in the figure. Such a decrease in axonal transport, demonstrated for chronic morphine,27 could account for the lack of correspondingly increased levels of TH in dopaminergic terminals in the NAcc. Decreased TH implies decreased dopamine synthesis, and may result in lower dopaminergic transmission to the NAcc. In the NAcc of the drug-addicted or drug-preferring state, Gi is decreased, and adenylate cyclase and cAMP-dependent protein kinase activities are increased, changes that could account for the D1 receptor supersensitivity observed electrophysiologically. It should be noted that alterations in dopaminergic transmission probably influence many cell types within the NAcc, as well as other nerve terminals in the NAcc. Similarly, altered local dopaminergic transmission in the VTA could also influence other nerve terminals in this brain region. Thus, biochemical alterations in the mesolimbic dopamine system could potentially lead to altered neuronal function in many other brain regions as well.

Fig. 11. Effects of CTDP-30,640 - a slow-onset long-acting dopamine reuptake blocker being explored at AECOM as a potential anti-cocaine-addiction medication - on intravenous cocaine self-administration in laboratory rats.

Time spent in chambers (min)
Treatment pairings1 Paired Unpaired
Saline/Saline 7.4 ± 0.3 7.6 ± 0.4 
Saline/Cocaine 11.6 ± 0.5* 3.4 ± 0.4** 
150 mg/kg GVG2/Saline 7.8 ± 0.5 7.2 ± 0.5 
150 mg/kg GVG2/Cocaine 7.9 ± 0.8 7.1 ± 0.8 

1 Each value represents the mean number of minutes spent in each chamber ± S.E.M. (n = 8-10).
2 Animals received GVG or Saline 2.5 hours prior to receiving saline or cocaine (20 mg/kg). 
*Significantly greater than all treatment groups,p < 0.05, ANOVA and Newman-KeulsTest. 
**Significantly less than all treatment groups, p < 0.01, ANOVA and Newman-Keuls test.

Time spent in chambers (min)
Treatment pairings1 Drug given on test day Paired Unpaired
Saline/Saline Saline 7.2 ± 0.21 7.8 ± 0.2
Saline/Saline  GVG, 150mg/kg 7.7 ± 0.2 7.3 ± 1.1
Saline/Cocaine  Saline 11.1 ± 0.5* 3.9 ± 0.4**
Saline/Cocaine  GVG, 150 mg/kg 7.9 ± 0.3 7.1 ± 0.3

1 Each value represents the mean number of minutes spent in each chamber S.E.M. ± (n = 10). 
*Significantly greater than all other treatment pairings, p < 0.01, ANOVA and Student Newman-Keuls test. 
**Significantly less than all other treatment pairings, p < 0.01, ANOVA and Student Newman-Keuls test.

Fig. 12. Effects of g -vinyl-GABA - a GABA-transaminase inhibitor being explored at AECOM as a potential anti-cocaine-addiction medication - on acquisition (upper panel, Table 1) and on expression (lower panel, Table 2) of cocaine-seeking behavior in laboratory rats. The GABAergic strategy for development of anti-cocaine-addiction medications at AECOM is based on the important functional regulation of the brain's dopaminergic pleasure/reward circuits by the neurotransmitter GABA (g -amino-butyric acid) (see Fig. 3 above).

Contingency Management with Cocaine-Dependent & and Special Treatment Populations - Stephen T. Higgins

 The reading for Dr. Higgins' presentation is:

 1. Stephen T. Higgins, Alan J. Budney, Warren K. Bickel, Florian E. Foerg, Robert Donham, Gary Badger. Incentives Improve Outcome in Outpatient Behavioral Treatment of Cocaine Dependence. Archives of General Psychiatry, July 1994; 51: 568-576.

 2. Stephen T. Higgins. Some Potential Contributions of Reinforcement and Consumer-Demand Theory to Reducing Cocaine Use. Addictive Behaviors, Vol. 21, No. 6, pp. 803-816, 1996.

 3. Kenneth Silverman, Stephen T. Higgins, Robert K. Brooner, Ivan D. Montoya, Edward J. Cone, Charles R. Schuster, & Kenzie L. Preston. Sustained Cocaine Abstinence in Methadone Maintenance Patients Through Voucher-Based Reinforcment Therapy. Arch. Gen. Psychiatry May 1996; 53: 409-415.

 The full text of these papers will appear on this page later, after copyright permissions have been obtained.

Overview of Drug Addiction Treatment - Herbert D. Kleber, M.D.

I. Extent of Problem

A. Current Magnitude
Nicotine – approximately 50 million addicts
Alcohol – 12 to 18 million alcoholics/problem drinkers
Marijuana – greater than 5 million use at least weekly
Cocaine – over 2 million addicts (perhaps as many as 3½ million)
Heroin – 810,000 addicts, at least
B. Trends
Nicotine – adult use stable, adolescent use continues to rise
Alcohol - use stable with some increase in binge use
Marijuana – sharp decrease in adolescent use from ‘80-‘92’;
sharp increase ‘92-97. 1998 stable to declining.
Use about 2/3’s of where it was in 1980.
Cocaine – 50% decline in non-addictive use since 1985. New initiates to crack decreasing but number of addicts stable.
Heroin – rising use over past decade as purity sharply increases and price drops. Increase in non-injecting use (snorting, smoking)
II. Treatment Overview
A. Treatment is not a liberal or conservative approach but a cost effective one

B. Treatment Efficacy

FDA generally considers a 30% improvement in target symptoms sufficient for proving clinical efficacy of a pharmacotherapy

With addiction, however, both lay & professional persons often expect the “smallpox vaccine’ –lifetime immunity after a single dose

More realistic expectations after any one treatment episode
Reduced use of drugs/alcohol

Longer abstention periods

Decreased psychiatric symptoms

Improved health

Maintaining or getting employment

Improved family relations

Decreased criminal behavior

C. Why Treatment?
In addition to being good for the addict, it is good for the rest of society
Not providing treatment for addicts may punish them
But it punishes the non-addicted members of society even more
Addiction impacts on crime, health care, AIDS, welfare, and family and community disintegration
D. Skepticism About Treatment Effectiveness
Skepticism arises from misunderstandings about:
-improvement vs cure
-rehabilitation vs habilitation
-chronic relapsing nature of the condition
-the visibility of failures and the anonymity of successes
E. Voluntary vs Involuntary Treatment
A false dichotomy – not competing frameworks but complimentary ones
Involuntary treatment can be about as effective as voluntary
Treatment can be a cost-effective alternative to incarceration
Criminal justice system pressure can improve length of stay and treatment effectiveness
Family, employer and criminal justice system pressure are all ways of “raising the bottom” to bring about earlier treatment
F. There Is No One Effective Treatment
-Need patient-treatment matching
-Anyone who says they have the treatment for substance abuse is lying – either to you, to themselves or both
III. Role of Pharmacotherapy
“Cure” of withdrawal or overdose

To increase the holding power of outpatient treatment and thus reduce costs

To create a “window of opportunity” during which patients can receive psycho- social intervention to decrease the risk

To serve as long-term maintenance agents for patients who can’t function without them, but can lead productive lives with them.

IV. Types of Pharmacotherapy
Treatment of co-morbid disorders
V. Pharmacotherapy by Drug of Abuse
A. Opiate Addiction
Agonists: Methadone
Partial Agonists: Buprenorphine
Antagonists: Naltrexone
Anti-Withdrawal: Methadone; Buprenorphine;
Clonidine; rapid detox using buprenorphine, naltrexone and
Anti-Craving: Clonidine or lofexidine
B. Cocaine
Agonists – none yet
Antagonists - none yet
Antiwithdrawal – not a major problem
Anti-craving – none yet; over 30 drugs tried
Vaccine – none yet
Agents to reverse toxic reactions – none yet
C. Alcohol
Agonists – none yet
Antagonists – Disulfiram (Antabuse)
Anti-withdrawal –benzodiazepines
anti-convulsants (Carbamazepine
Valproic acid)
Anti-craving – Naltrexone (Revia)
D. Nicotine
Agonists – nicotine substitution (gum, patch, aerosol)
Antagonists – mecamylamine
Anti-withdrawal – nicotine substitution
Bupropion (Zyban)
Anti-craving – Bupropion
VI. Treatment of Co-Morbid Conditions, especially:
Unipolar depression
Bipolar disorders
Anxiety disorders
Treating Comorbid Psychiatric Disorders
Untreated depression and anxiety disorders are common causes of relapse

Withholding psychiatric treatment from a depressed, substance-abusing patient would be like withholding penicillin from a drug abuser with pneumonia

VII. Non-Pharmacologic Approaches
Type of Programs
By Setting
Residential Chemical Dependency Programs (RCD’s)
Residential Therapeutic Communities (T.C.’s)
Outpatient: Intensive, Non-intensive
By Approach
Behavioral (including Relapse Prevention Training)
VIII. Summary

Anti-Cocaine Catalytic Antibodies
Donald W. Landry

A clinically effective blocker of cocaine-induced reinforcement does not exist despite decades of effort. As an alternative to therapeutic approaches based on the pharmacology of the cocaine receptor, the delivery of cocaine to its receptor could be interrupted so that a dose of cocaine no longer had a reinforcing behavioral effect. Since there is no prospect for excluding cocaine from the circulation, this approach would require binding of cocaine by a circulating agent.

In the 1970's Schuster and colleagues investigated an immunologic approach1 to substance abuse based on this possibility of interference with CNS delivery. A rhesus monkey was allowed to self-administer heroin to dependence,and then was immunized to an opiate. Despite access to the heroin, the animal no longer self-administered it. The serum anti-opiate antibody titer greatly exceeded the cerebrospinal fluid titer and this localized the antibody effect to the serum. Thus, the association of heroin and circulating anti-heroin antibody must have been sufficiently rapid to block heroin's effect. However, the limitation of the approach was identified in that continued administration of very high doses of heroin exhausted the pool of circulating antibody and the animal resumed heroin self-administration. An antibody would ideally have the characteristics of an enzyme in order to avoid being stoichiometrically "depleted" itself as it depleted its target. The application of such a degradative enzyme to the problem of chroniccocaine abuse would be to deprive the abuser of the reinforcing effect of the drug and thus promote extinction of the addiction. Between binges cocaine addicts often to seek assistance but the relapse rate is > 50% and the proposed treatment could provide a window for appropriate psychosocial and relapse preventioninterventions. With the potential to promote cessation of use, prolong abstinenceand provide a treatment for acute overdose, the artificial enzyme approach comprehensively responds to the problem of cocaine.

Our approach relies on the creation of an artificial enzyme to degrade cocaine that is based on the exciting development of catalytic antibodies2,3.Catalytic antibodies not only bind but also act as artificial enzymes whichmetabolize their target thus freeing the antibody for further binding. The principles of this startling advance are illustrated by considering the hydrolysis of a carboxylic acid ester by an enzyme:

Hydrolysis of the planar ester commonly proceeds through a tetrahedral intermediate which decomposes to yield alcohol and planar carboxylic acid. The rate of the reaction varies with the magnitude of the activation barrier (DG)between the starting ester and the peak or transition-state structure. An enzyme'sactive site contains a pocket that complements the structure of the hydrolysis transition-state and through various binding interactions the enzyme stabilizes the transition-state relative to the starting material. This differential stabilization decreases DG and contributes to catalysis. The transition state corresponds to a particular configuration of atoms and is thought to resemble the definable species closest to it in energy, i.e. the tetrahedral intermediate in the case of ester hydrolysis. The transition state is unstable and evanescent but phosphonatemonoesters are stable compounds which resemble this species in geometry and distribution of charge and on this basis may serve as transition state analogs. An antibody elicited to such an analog will manifest binding interactions complementary to the hydrolysis transition state being modeled. This antibody, by binding to the modeled substrate, will stabilize the transition state relative to the starting state, lower the activation barrier and catalyze the hydrolysis. By binding and destroying its target the catalytic antibody is then freed to bind additional target.

Of all the commonly abused substances, cocaine is the best candidate for this approach. Attached to the ecgonine nucleus of cocaine is a benzoyl ester group which when hydrolyzed results in a virtually inactive product4 - this is one of the pathways of deactivating metabolism in humans. The transition state of that reaction resembles the tetrahedral intermediate of hydrolysis and can be mimicked by a suitably designed phosphonate ester:

A subpopulation of the antibodies elicited by this cocaine analog will function as esterases highly specific for cocaine. Thus, the principal impediment to the immunologic approach suggested two decades earlier - the exhaustibility of the circulating antibody - could be overcome. The anti-cocaine catalytic antibody generated in this fashion would destroy cocaine and be itself available for continued function. The application of such a reagent antibody to the problem of chronic cocaine abuse would be to deprive the abuser of the reinforcing effect of the drug, thereby providing a window of opportunity for appropriate psychosocial and relapse prevention interventions, and promoting extinction of the addiction.

Based on this analysis, we synthesized a transition-state analog of cocaine hydrolysis, immunized mice and prepared hybridomas. The hybridomas were initially selected based on anti-analog binding and then sub-selected with the capacity to degrade cocaine. In this manner, the first artificial cocaine esteraseswere identified5. Using several transition-state analogs with varying tether sitesthat exposed unique epitopes to the mouse immune system, we obtained a total of nine anti-cocaine catalytic antibodies6. We recently found that one of these antibodies (Mab 15A10) was sufficiently active to block cocaine-induced reinforcement and toxicity in animal models of addiction and overdose7. Present efforts are focused on improving the antibodies' activity through second generation analogs and through mutagenesis of our most potent catalytic antibody.


Why Provide Treatment?

Good for addicted individual
Good for society
Addiction impacts on health care, crime, AIDS

Role of Pharmacologic Treatment

"Cure" of withdrawal or overdose
Create "window of opportunity"
Long term maintenance agents

Treatment of Alcohol Dependence

Treatment of withdrawal: relief of symptoms; prevention of arrhythymias,
seizures; minimize dependence or risk of toxicity related to drug therapy
Antidipsotropic agents: disulfiram, naltrexone
Use of naltrexone: 50 mg each day, diminishes hedonic value of alcohol,
keep lapse from becoming a relapse, supervised intake preferable,
additional supportive/relapse prevention therapy
Treatment of comorbid disorders

Treatment of Opiate Dependence

Opiates: Rise in Use

Cost down, purity up
Why is heroin popular? Rapid onset, highly euphoric, rush is not as intense with slower routes, thus i.v. route is preferable

Heroin pharmacology

Average heroin dependent individual uses 2-4 per day
Tolerance develops within few weeks
Withdrawal begins within 12 hours, lasts 1-3 days, usually over within 5-7 days
Protracted withdrawal can last for months

Treatment of Opiate Withdrawal

Use the drug the individual is addicted to
Other drugs that produce cross tolerance
Medications for symptomatic relief
Drugs affecting mechanisms by which withdrawal is expressed

Pharmacologic Treatments for Opiate Withdrawal

Clonidine/Naltrexone-rapid detoxification.
Anesthesia-ultra rapid detoxification

Methadone Substitution

Requires special license
Completion rates ranges from less than 20% for outpatient, 70-80% inpatient
May have rebound withdrawal symptoms after last dose of methadone
Adjunctive use of benzodiazepines, NSAIDS, or clonidine


Alpha-2 adrenergic agonist
Doses range 0.3-2.0 mg/day, need to monitor blood pressure
Reduces autonomic withdrawal components but may not reduce craving,
insomnia, and muscle aches
Approximately 50% complete outpatient withdrawal
Use of benzodiazepines and NSAIDS

Clonidine/Naltrexone Rapid Detoxification
Day 1: 9:00 a.m.: Clonidine 0.2-0.4 mg/day orally

Oxazepam 30-60 mg
11:00: Naltrexone 12.5 mg orally
Clonidine 0. 1-0.2 mg every 4 hours up to 1.2 mg/day
Oxazepam 15-30 mg every 6 hours as needed
Patient in clinic until 5 p.m.

Day 2:
9:00 a.m.: Clonidine 0.1-0.2 mg orally and then every 4 hours up to 1.2 mg/day

Oxazepam 15-30 mg every 6 hours as needed
10:00 a.m.: Naltrexone 25 mg
Patient may leave 2 hours after naltrexone
Day 3
9:00 a.m.: Clonidine 0. 1-0.2 mg orally and then q4 hrs, tapering total dose by 0.2
Oxazepam 15-30 mg every 6 hours as needed
10:00 a.m.: Naltrexone 50 mg
Patient may leave 1 hour after naltrexone
Continue clonidine 0.1-0.2 mg every 4 hours as needed over next 2-3 days
Continue oxazepam 15-30 mg every 6 hours as needed over next 2-3 days
Adjunctive medication as needed; nonnarcotic analgesics, antiemetics
Continue naltrexone 50 mg/day

Anesthesia-Assisted Detoxification
            Why is it popular?

Magic bullet
Detoxification fear
Previous experience of discomfort
Shorten length of withdrawal for occupational or potential reasons
Difficulty in withdrawing from methadone

Anesthesia-Assisted Rapid Detoxification

Withdrawal precipitated by iv naloxone followed by NG naloxone
Withdrawal ameliorated by iv clonidine
Use of propofol anesthesia or midazolam

Opiate Detoxifications:Pros and Cons

Methadone taper:
Pros:Simple to use, few side effects but requires special license
Cons: Longest duration of withdrawal, rebound withdrawal
Clonidine substitution:
Pros: No special license, shortens withdrawal from Methadone but not heroin.
Cons: harder to use, more side effects, need to monitor blood pressure, not fully
relieve withdrawal symptoms
Ultra-rapid clonidine/naltrexone technique:
Pros: No special license, no rebound withdrawal, cuts withdrawal from methadone or
heroin to 2-3 days
Cons: more difficult to use, more side effects, first day need to be day or inpatient
Anesthesia-aided ultra-rapid antagonist detoxification:
Pros: Shortens time for withdrawal, useful for patients afraid of withdrawal discomfort,
use for withdrawal from high dose methadone.
Con: No adequate published studies, risk of anesthesia, aspiration if intubation not
used is possible, expensive

Treatment of Opiate Dependence: Maintenance Agents

Agonists: Methadone, Levo-alpha-acetyl-methadol (LAAM)
Partial agonists: buprenorphine
Antagonists: naltrexone

Characteristics of Ideal Maintenance Agent for Opiate Dependence

Low diversion potential
Long duration of action
Low potential for increasing concomitant use of other drugs
Low toxicity of overdose
Detoxification should be short, simple, and minimal rebound withdrawal
Facilitate abstinence from illicit opiates
Good acceptance by patients

Methadone Maintenance Programs

Best studied, but controversial
Methadone is orally effective, 24-hour opioid drug
110,000 slots nationwide
Patients maintained usually 1-3 years, minority may need long term
Relapse high when stop methadone
Increased services, better treatment outcome

LAAM- Levo alpha acetyl methadol

Slow onset, low reinforcement
Smooth onset, less abuse potential
Long duration, less withdrawal problems
Take home, compliance

Buprenophine- partial agonist

Reduced opiate agonist effect, less respiratory depression
Withdrawal easier
May be used as transition from methadone to naltrexone
Use for treating heroin addiction
May be used in office-based practice in the future
Buprenorphine-naloxone formulation
Naloxone 100x more potent intravenously compared to oral route
Small amount of oral naloxone will not antagonize buprenorphine
May limit street use
Naltrexone - opiate antagonist
50 mg daily or 100 mg/100 mg/150 mg taken 3x/week
Generally use for relapse prevention
High drop-out rate
Beneficial for patients who are motivated, family support, legitimate career
Treatment of Cocaine Dependence

What is the target?

Cocaine withdrawal symptoms
Prolonged cocaine craving
Block cocaine's effects but not dopamine
Rapidly inactivate cocaine's actions

Many pharmacologic treatments tried, none proven effective

Best studied medication is desipramine, although some trials negative
Must include appropriate psychosocial support
If successful, continue 3-6 months
Heterogeneity of population increases difficulty of determining what
Works. Targeting psychiatric subpopulations

Need for Treatment Medications

Effective behavioral interventions for some cocaine addicts have been
However, better approaches needed and an effective medication could
markedly improve treatment outcome
Both the human and financial cost of cocaine addiction suggest such a
medication would be cost-effective for the country
Some addicts will need habilitation regardless of a medication


Detoxification is simply the first step
Some patients benefit from pharmacologic interventions
No one treatment is universally effective given heterogeneity of population
Medications may provide "window of opportunity" such that other
nonpharmacologic interventions are enhanced
Treatment Outcome Research on Drug Addiction - A. Thomas Mclellan

 The reading for Dr. Mclellan's presentation is:

 1. A. Thomas Mclellan, George E. Woody, David Metzger, et. al., Evaluating the Effectiveness of Addiction Treatments: Reasonable Expectations, Appropriate Comparisons The Milbank Quarterly, Vol. 74, No. 1, 1996.

 2. Charles P. O'Brien & A. Thomas McLellan. Myths About the Treatment of Addiction, Lancet 347:236-240. (Reprinted as Chapter 2, in American Society of Addiction Medicine, Chapter 2

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Imaging the Effects of Psychostimulants in the Human Brain
Nora D. Volkow, Joanna S Fowler.

The ability of PET to measure the concentration of specific receptors,
transporters and/or enzymes in the human brain and to measure the concentration
of drugs of abuse, their pharmacokinetics and binding properties makes it a unique
tool for pharmacological research (Volkow et al 1996, Volkow et al., 1997a). We
have exploited this uniqueness to investigate the effects of psychostimulant drugs
like cocaine and methylphenidate (MP) in the human brain.

The reinforcing effects of cocaine, which is considered to be one of the most
reinforcing drugs of abuse, have been linked to cocaine's ability to block the
dopamine transporters (DAT) (Ritz et al., 1987; Madras et al., 1989). By blocking
DAT cocaine increases the concentration of DA in synapses including those in the
nucleus accumbens, which is a brain region considered to be crucial to the
reinforcing effects of most of the drugs of abuse (Koob and Bloom, 1988; Pontieri et
al., 1996). The paradox is that there are other drugs such as methylphenidate
(Ritalin) that are as effective as cocaine in blocking DAT and yet are abused much
less frequently. MP, which is a drug used widely in the treatment of attention deficit
hyperactivity disorder (ADHD) (Swanson et al., 1998) blocks DAT with an even
higher affinity than that of cocaine (Schweri et al., 1985). The abuse of MP by
humans is much less frequent than that for cocaine and when it is abused this is
done mainly via the intravenous route of administration (Parran and Jasinski, 1991).
We have used PET to compare the effects of MP and cocaine in the human brain to
determine if there are differences between these two drugs that could explain why
cocaine is more frequently abused than MP.

Brain Distribution and Pharmacokinetics of Cocaine and of Methylphenidate

The pharmacokinetics of MP and of cocaine in the human brain were
assessed using the C-11 labeled compounds. The high sensitivity of PET allowed
us to administer  [11C] cocaine and [11C]methylphenidate to human subjects at
concentrations that were devoid of pharmacological effects (tracer concentrations).
The distribution of these two drugs in the human brain showed an almost identical
distribution; for both of them the maximal concentration occurred in striatum, which
is the brain region with the highest concentration of DAT (Volkow et al., 1995).
Pretreatment with monoamine transporter blockers showed that these two drugs
were binding to the DAT and that they were binding to the same or closely adjacent
sites in the DAT since pretreatment with pharmacological doses of MP inhibited
binding of [11C]cocaine and pretreatment with pharmacological doses of cocaine
inhibited binding of [11C]methylphenidate. PET also allowed us to measure the
distribution of these two drugs as a function of time. The dynamic studies revealed
that cocaine and MP went into the brain very rapidly (peak uptake 4-6 minutes and
8-10 minutes respectively) and that cocaine also cleared very rapidly whereas MP
did not (half life 20 and 90 minutes respectively. Because the rapidity at which
psychostimulant drugs enter the brain is crucial for their reinforcing effects (Balster
and Shuster, 1973) the fast uptake of cocaine and MP in brain when they are
administered intravenously would favor their reinforcing effects. Though very little is
known about the role that the rate of clearance has on psychostimulant's reinforcing
effects we hypothesize that the slow clearance of MP may interfere with its frequent
administration since it would lead to DAT saturation while prolonging the duration of
its side effect (Volkow et al in press). Moreover, even though MP's half life in brain
is much longer than that of cocaine (90 versus 20 minutes) the "high" is of a similar
duration (Volkow et al 1995). This would indicate that it's the fast uptake of cocaine
or of MP in brain that accounts for the "high" but not its long lasting presence. Thus
it appears as if the "high" was associated with the perturbation in DA concentration
induced by the fast DAT blockade, which would indicate that cocaine's highly
reinforcing effects are not due to DAT blockade per se but to the dynamics of this
blockade. Cocaine's very fast uptake and clearance from brain are ideal to enable
its frequent repeated administration that is so characteristic of the "binge" pattern of
drug intake of the cocaine addicted subject (repeated injection of the drug every
20-30 minutes). On the other hand the slow clearance of MP would interfere with its
frequent administration since it would lead to DAT saturation.

DAT Blockade by Cocaine and by Methylphenidate

With PET and appropriate radiotracers, we showed that it was possible to measure
the levels of DAT occupancy achieved by drugs that block DAT in human subjects
reproducibly (Volkow et al., 1997b). We have used [11C]cocaine (Fowler et al.,
1998) and [11C]d threo-methylphenidate (Ding et al 1994) as DAT radiotracers to
measure DAT occupancies achieved by iv cocaine, iv MP and by oral MP. Both of
these radiotracers yield similar DAT occupancies measures and their fast kinetics
are well suited to estimate DAT occupancies achieved by cocaine and MP (Fowler
et al., 1998).

DAT occupancies after cocaine and MP were measured with PET using
[11C]cocaine as a DAT ligand. For the cocaine study we measured the occupancy
by different doses of intravenous cocaine (0.05, 0.1, 0.3, 0.6 mg/kg) in 19 active
cocaine abusers (Volkow et al., 1997b). This study showed that cocaine at the
doses commonly abused by cocaine abusers (0.3 mg/kg and 0.6 mg/kg) blocked
more than 60% of the DAT. Furthermore 0.05 mg/kg iv of cocaine, which is a dose
devoid of observable pharmacological effects blocked 40% of the DAT. This study
also showed that the higher the levels of DAT blockage the higher the intensity of
the high (r = 0.55, df 32, p < 0.001) and that for cocaine to induce a "high" it had to
block more than 60% of the DAT. For the MP study we measured the occupancy by
different doses of intravenous MP (0.025, 0.1, 0.25, 0.5,mg/kg) in 8 normal controls
(Volkow et al., 1999). This study showed that 0.1 mg/kg of iv MP blocked 60% of
the DAT and that the ED50 (dose required to block 50% of the DAT) was half that of
cocaine (MP = 0.075 mg/kg; Cocaine = 0.13 mg/kg). The differences in the ED50
between cocaine and MP are compatible with differences in their affinities for DAT
(Ki for inhibition of DA uptake correspond to 640 nM and 390 nM respectively) (Ritz
et al., 1987). As for cocaine, the magnitude of DAT occupancy induced by MP was
associated with the intensity of the "high" (r = 0.46 df 23, p < 0.05) corroborating the
importance of DAT blockade in the "high". However, there were subjects who
despite having DAT occupancies greater than 60% did not perceive the "high",
which suggests that there are additional variables involved in the "high".

The similar in vivo potency of cocaine and of MP was observed after their
intravenous administration, which is not the route of administration used in the
treatment of ADHD. Because routes of administration affect drug pharmacokinetics,
the results with intravenous MP cannot be extrapolated to oral MP. We therefore
conducted a separate study to measure the potency of oral MP (Volkow et al 1998).
The study was done in 7 control adult subjects who were tested 2 hours after one of
the following doses of oral MP (10, 20, 40 and 60 mg) (Volkow et al., 1998). The
levels of DAT blockade induced by oral MP were lower on a mg/kg basis than those
induced by iv cocaine or iv MP in the human brain (estimated ED50 of oral MP was
0.25 mg/kg; whereas for iv MP it was 0.075 mg/kg and for iv cocaine it was 0.13
mg/kg). As previously reported oral MP did not induce a "high" (Klein et al., 1997)
even when the higher doses led to DAT occupancies (60 mg 70-72%) equivalent to
those that induced a "high" with iv cocaine or with iv MP.

To assess the pharmacokinetics of oral MP we measured the kinetics of
[11C]methylphenidate when delivered via and orogastric tube in the baboon brain.
This study showed that [11C]methylphenidate did not reach peak concentration in
brain until 60 minutes after its administration. This contrasts markedly with the very
fast rate of brain uptake seen in the baboon brain after iv administration of MP (8-10
minutes) (Ding et al., 1994) or of iv cocaine (4-6 minutes). We postulate that the
reason why oral MP did not induce a "high" was due to its very slow uptake into the
brain that enables adaptation responses to occur before the drug reaches peak
concentrations in brain.

In summary, these PET studies have shown that the rate at which cocaine
and MP enter the brain and block the DAT is the variable associated with the "high"
rather than the presence per se of the drug in brain; they have also shown that
while the level of DAT blockade is important in predicting the intensity of the "high"
induced by these drugs (DAT blockade > 50% is required for these drugs to induce
a "high") the rate at which DAT are blocked determines whether the "high" is
perceived or not. This may explain why MP when given orally, which leads to very
slow uptake in brain, is not reinforcing.

Acknowledgments: This research was supported in part by the US. Department of
Energy under Contract DE-ACO2-76CH00016 and the Institute of Drug Abuse
under Grants No. DA06891, DA09490 and DA06278.