David A. Gorelick, MD, PhD, DLFA PA
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There is no FDA-approved pharmacotherapy for stimulant dependence.
COCAINE USE DISORDER
Goals of Treatment
Currently available “off-label” medications are considered to act by one of three mechanisms:
1. Reducing or eliminating the positive reinforcement from taking a cocaine dose
2. Reducing or eliminating a subjective state (such as “craving”) that predisposes to taking cocaine
3. Reducing or eliminating negative reinforcement from taking a cocaine dose (as by reducing withdrawal-associated dysphoria)
Medication does not address these other mechanisms:
4. Making cocaine-taking aversive
5. Increasing the positive reinforcement obtained from non–cocaine-taking behaviors
Pharmacologic Mechanisms
Four pharmacologic approaches are potentially useful in the treatment of cocaine use disorder:
1. Substitution treatment with a cross-tolerant stimulant (analogous to methadone maintenance)
2. Treatment with an antagonist medication that blocks cocaine at its site of action
3. Treatment with a medication that functionally antagonizes the effects of cocaine (as by reducing the reinforcing effects of or craving for cocaine)
4. Alteration of cocaine pharmacokinetics so that less drug reaches or remains at its site(s) of action in the brain
No medication has met the scientifically rigorous standard of consistent, statistically significant efficacy in replicated, controlled clinical trials.
CHOICE OF OFF-LABEL MEDICATION
Heterocyclic Antidepressants
Tricyclic and other heterocyclic antidepressants are the most widely used and best-studied class of medications for the treatment of cocaine use disorder.
Their use is based on the clinical observation of frequent depressive symptoms among cocaine-dependent individuals seeking treatment and on their pharmacologic mechanism of increasing biogenic amine neurotransmitter activity in synapses. Desipramine is the best studied, but results in meta-analyses have not showed efficacy. Patients dually dependent on cocaine and opioids may do better on desipramine if their opioid dependence is treated with buprenorphine rather than methadone, or if they receive contingency management.
Experience with other heterocyclic antidepressants shows limited evidence for efficacy. No medically serious side effects have been reported in trials of heterocyclic antidepressants. However, patients who relapse to cocaine use while still on antidepressant medications could, in theory, be at increased risk of cardiovascular side effects as cocaine and the tricyclics have quinidine-like membrane effects that could lead to cardiac arrhythmias.
Selective Serotonin Reuptake Inhibitors
There is no evidence for the efficacy of selective serotonin reuptake inhibitors.
Monoamine Oxidase Inhibitors
The rationale for the use of monoamine oxidase inhibitors lies in their effect of increasing brain levels of biogenic amine neurotransmitters by inhibiting a major catabolic enzyme. Limited open-label experience with phenelzine suggests that this medication can reduce cocaine and other stimulant use. However, its clinical usefulness may be limited due to its potential to precipitate a hypertensive crisis with concurrent cocaine use.
Dopamine Agonists (Anti-Parkinson Agents)
Dopamine agonists, by stimulating synaptic dopamine activity, might ameliorate the effects of decreased dopamine activity caused by cessation of cocaine use. Bromocriptine, pergolide, and amantadine, all marketed for the treatment of parkinsonism (another dopamine deficiency condition), have not shown consistent efficacy in clinical trials. Disulfiram can be considered a functional dopamine agonist because it blocks the conversion of dopamine to norepinephrine by the enzyme dopamine-β-hydroxylase, thereby increasing dopamine concentrations. Studies to date have shown mixed results.
Stimulants
Several stimulants marketed for the treatment of attention deficit hyperactivity disorder have been used to implement the substitution approach. Two small controlled clinical trials of amphetamine found significant reductions in cocaine use with doses of 30 to 60 mg daily but no difference from placebo at lower doses. Several controlled clinical trials using immediate-release amphetamine or methylphenidate alone or combined with modafinil found them ineffective.
Antipsychotics
The older antipsychotics and newer “second-generation” antipsychotics also have not been confirmed to significantly reduce cocaine craving or use in clinical trials. Caution should be exercised when prescribing any antipsychotic to cocaine users because of their potential vulnerability to the neuroleptic malignant syndrome.
Anticonvulsants
Anticonvulsants have been evaluated for the treatment of cocaine dependence because they block the development of cocaine-induced “kindling” in animals. “Kindling,” increased neuronal sensitivity to a drug because of prior intermittent exposure, has been hypothesized as a neurophysiologic mediator of cocaine craving in humans.
Nutritional Supplements and Herbal Products
The use of amino acid mixtures, either alone or with other nutritional supplements, has been widely publicized in the drug abuse treatment field, but few have undergone controlled clinical evaluation.
Calcium Channel Blockers
There is no evidence for the efficacy of calcium channel blockers in the treatment of cocaine addiction.
Other Physical Treatments
Acupuncture of the outer ear (auricular) has enjoyed growing popularity as a treatment for drug withdrawal, but studies have not shown any benefit.
AMPHETAMINE USE DISORDER
Many of the medications evaluated for the treatment of cocaine use disorder have also been studied for the treatment of amphetamine use disorder for the same pharmacologic rationale. As with cocaine use disorder, most controlled clinical trials do not show efficacy.
SPECIAL TREATMENT SITUATIONS
Opioid Use Disorder
Concurrent opioid use disorder is a common clinical problem among patients with cocaine use disorder. Some individuals use cocaine and opioids simultaneously (as in the so-called “speedball”) to enhance the drugs’ subjective effects. Up to 20% or more of opioid-dependent patients in methadone maintenance treatment also use cocaine to replace the “high” no longer obtained from opioids, self-medication for the sedative effects of methadone, or attenuation of opioid withdrawal symptoms. Some studies in dually addicted patients suggest that cocaine use (as well as opioid use) is reduced at higher buprenorphine maintenance doses (16 to 32 mg/day).
Gender-Specific Issues
Women tend to be excluded from or underrepresented in many clinical trials of cocaine dependence pharmacotherapy, in part because of concern, embodied in former FDA regulations, over risk to the fetus and neonate should a female participant become pregnant.
In the absence of directly relevant and systematically collected data, caution should be used when prescribing medications to pregnant women with stimulant dependence and to those with pregnancy potential, keeping in mind both the risks of medication and the risks of continued stimulant use.
KEY POINTS
1. There are no FDA-approved medications for cocaine or methamphetamine use disorders.
2. A variety of agents have been postulated and tested, and many are used in an “off-label” capacity.
REVIEW QUESTIONS
1. Which of the following medications is FDA approved for the treatment of cocaine use disorder?
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