Management of Cocaine Dependence Flashcards
Management of Cocaine Dependence
Currently there is no FDA approved pharmacologic treatments for cocaine or methamphetamine dependence.
Medical Treatment of Crash Phase Symptoms
The crash phase is the period at the end of the binge session.
Often no treatment is needed.
Benzodiazepines are helpful in relieving agitation and promoting sleep; may be prescribed by an MD or used extemporaneously by cocaine users.
Opioids are seldom prescribed; commonly used extemporaneously by cocaine users.
Neuroleptics (antipsychotics) are ONLY for cocaine psychosis persisting into the crash period; always prescribed and never used extemporaneously.
Treatment Goals in Initiation of Abstinence and Prevention of Relapse
Complete and continue abstinence; this is not attainable for most users while the ones that follow are more realistic.
Reducing amount and frequency of use.
Reducing frequency and severity of relapses.
Decreasing morbidity associated with stimulant use.
Improving psychological and social functioning.
Impediments of Abstinence and Prevention of Relapse
Craving, depression, anhedonia, anergia; these frequently cause of relapse.
Environmental cues activates intense craving are strong with cocaine.
National Institute on Drug Abuse assessment
Evaluated the efficacy of a variety of non-pharmacologic treatment programs.
One year after termination of treatment… 23% patients known to use cocaine weekly, 15% were thought to be using weekly, 18% had returned to treatment, total failure rate was 56%- this is not bad considering the reinforcing power of cocaine.
Pharmacotherapy
At present time, pharmacotherapy is minimally successful- THERE ARE NO WIDELY EFFECTIVE MEDICATIONS FOR COCAINE DEPENDENCE.
Maintenance Therapy
Also called substitution therapy.
Patient might be eventually weaned off the drug or may take it indefinitely.
An attempt to relieve craving by providing dopaminergic stimulation, not at a level sufficient to cause high and does not foster abuse of the maintenance agent; increase dopamine in mesolimbic or pleasure pathway.
Candidate agents: dopamine releasing agents, dopamine transporter inhibitors, direct dopamine agonists, misc.
Mechanisms of Chronic Cocaine Use
Cocaine users show lower rates of glucose utilization as measured with fluorodeoxyglucose and PET scan.
Effects: decreased activation of prefrontal cortex areas called HYPOFRONTALITY.
Coupled with D2 receptor levels in the ventral striatum.
Basis of hypofrontality: Decreased DA synthesis, reduced endogenous DA levels, blunted stimulant-induced DA release, reduced D2/D3 receptor levels, not D1 levels.
Increased DAT, up-regulated NET, dysregulated GLU.
Medication Development for Cocaine Dependence
Medications that have shown positive results for treating cocaine dependence by primarily acting on DA, NE, and GLU neurotransmission.
Modafinil
Mechanism of action:
Increases histamine, DA, and NE levels.
Promotes GLU neurotransmission.
Suppresses GABA.
Activates the hypocretin-orexin system.
May stimulate DA D2 receptors; may play a role in its wake-promoting effects.
Drug Properties: not self administered by rodents (not something someone would desire to take); maintains self-administration only at very high doses in non-human primates.
Binds to the DAT but has low abuse liability like bupropion; increases DA by binding to the DAT in a unique manner (binds to different site on the transporter, increases DA in the synapse).
Clinical studies: low abuse potential, not self administered by cocaine dependent people; attenuates the positive subjective and reinforcing effects produced by cocaine and reduces cocaine use; mechanism unknown; inhibiting DAT may by key to its therapeutic actions.
Modafinil does not decrease cocaine use in cocaine dependent heavy alcohol users-reasons unclear.
Therapeutic usefulness: may be useful as a pharmacotherapeutic agent for cocaine dependence-improves cognition in several reports: healthy volunteers, adults with ADHD, meth-depdentn individuals.
NOT APPROVED BY FDA.
N-acetylcysteine
Medications that reverse changes in GLU (glutamate) transmission imposed by cocaine may be a therapeutic option for cocaine dependence.
BUT there is a lack of clinically available GLU receptor ligands and there is an innate complexity of this neurotransmitter system-slowed progress defining GLU’s role in the psychostimulant dependence.
Effects of cocaine on the glutamate system:
Cocaine down regulates the glial cysteine-glutamate antiporter in the nucleus accumbens, GLU levels are normally maintained by the glial antiporter.
GLU in the nucleus accumbens mediates re-instatement of cocaine self-administration in rodents.
Unknown whether GLU neurotransmission is definitively compromised in cocaine-depdnent people.
N-acetylcysteine blocks cocaine reinstatement and re-engages mGluR2/3 auto receptors that control pre-synaptic GLU release; reverses cocaine induced neuroplasticity important in relapse.
Clinical studies: Generally support N-acetylcysteine’s efficacy for cocaine dependence.
N-acetylcysteine effects: blocks some of cocaine’s subjective effects, attenuates reactivity to drug cues that elicit the craving.
Disulfiram
Shown potential as a treatment for cocaine dependence regardless of alcohol use.
Disulfiram and its metabolite diethyldithiocarbamate chelate copper; copper sequestration, in turn, compromises many copper dependent enzymes including DbetaH, which catalyzes the conversion of DA to NE.
Mechanism of action: inhibition of DbetaH, which increases DA and decreases NE synthesis, which is likely responsible for its therapeutic effects in cocaine dependence,
Inhibits carboxylesterase and cholinesterase enzymes, which metabolize cocaine; leads to increased plasma levels and potentiation of its cardiovascular effects.
Clinical studies are contradictory on subjective effects: reported to decrease the positive subjective effects of cocaine, reported to increase its negative effects, reported to produce no changes.
Clinical trials for therapeutic efficacy for cocaine dependence appear complex; studies have found disulfiram treatment decreases cocaine use, produces no change in cocaine use (lack of efficacy may be due to non-compliance); higher doses of disulfiram reduced cocaine use in clinical trials, lower doses of disulfiram increased cocaine use.
Therapeutic uses: more specific inhibitors of DbetaH may be of value: do not interact with alcohol, do not block peripheral metabolism of cocaine.
Not really used in a clinical setting.
Prazosin/Doxazosin
Mechanism of action: alpha 1 adrenergic receptor antangonists; doxazosin is longer acting.
Useful in PTSD; hypersensitive noradrenergic system with increased NE release and receptor sensitivity.
Clinical studies: systemic prazosin does not reduce maintenance of cocaine self-administration, blocks drug induced reinstatement of cocaine-seeking behavior.
Doxazosin decreased cocaine’s positive subjective effects for non-treatment seeking cocaine-dependent individuals.
Therapeutic uses: suggests alpha 1 receptor antagonism can decrease the positive subjective effects; doxazosin may be a viable treatment for cocaine dependence.
Sustained release AMPH/METH
DA antagonists have not been shown to decrease cocaine use in humans and they increase cocaine self administration in rodents.
DA agonists and indirect agonists decrease cocaine self administration in rodents and monkeys.
Mechanism of action: could be related to ability of these compounds to correct deficiencies; monoaminergic neurotransmission.
Use in treatment of ADHD, refractive obesity, and narcolepsy; increase DA synthesis and neurotransmitter release, increase activity in cortical brain areas, improve working memory and impulse control.
SR-AMPH and SR-METH alter the DAT and induce DA efflux; possibly corrects central hypodopaminergic tone (characteristic in cocaine-dependent individuals).
Efficacy for reducing cocaine use may be noradrenergic neurotransmission; NE modulates reinstatement of cocaine-seeking in animal models of relapse and SR-AMPH and SR-METH are more potent releasers of NE than DA.
Chronic treatment with stimulants produces tolerance; subsequent cocaine challenges may be reduced; preclinical data demonstrates AMPH-induced tolerance to cocaine.
Issue of abuse liability: the speed at which stimulants cross the BBB contributes to their reinforcing effects and abuse liability.
Slow-release preparations lower abuse liability compared to immediate release preparations: reduce the subjective effects and cocaine use in dependent individuals.
Clinical studies: SR, but not IR formulations of stimulant medications use is supported and have shown some promise in reducing cocaine use.
Chronic AMPH/METH decreases cocaines reinforcing effects; produce tolerance, not substitution for cocaine; increases DA which is low in cocaine dependent individuals.
Methylphenidate
Mechanism of action: increases synaptic levels of NE and increases DA in the nucleus accumbens.
Evidence it can be used safely and appear efficacious.
May involve increased D2/D3 receptor levels and DA neurotransmission in the orbitofrontal cortex.
May decrease hypofrontality.
Clinical studies:
Cocaine-dependent adults with ADHD; IR and SR methylphenidate: decreased cocaine use and improved ADHD symptoms.
Non-treatment seeking cocaine-dependent individuals without ADHD: decreased positive subjective effects of IV cocaine.
Another study in cocaine-dependent individuals without ADHD: no benefit of IR-methylphenidate.
SR methylphenidate is safe and effective in reducing ADHD symptoms in cocaine-dependent individuals with ADHD; appears a better choice then IR methylphenidate.
Osmotic-release methylphenidate (OROS); associated with negligible positive subjective effects, low abuse liability, clinical trials have yet to be completed testing.
SR= drug present, but not in huge amounts, like methadone, long half life, available at lower concentrations for longer time.
