Correspondence

Flupentixol-Induced Aversion to Crack Cocaine

N Engl J Med 1996; 334:1340-1341May 16, 1996

Article

To the Editor:

Disulfiram causes an aversive response to alcohol that is used therapeutically to foster abstinence. There is no similarly effective and safe aversive treatment for cocaine abuse. We report here that flupentixol decanoate can cause transient, severely distressing, involuntary muscular restlessness and movement (akathisia) after crack-cocaine smoking that is associated with the subsequent cessation of crack use. Flupentixol is a neuroleptic at high plasma concentrations but has nonneuroleptic, antidepressant activity at low concentrations,1 a characteristic that provides the basis for its use in treating cocaine craving and abuse. In injectable depot form, it has a duration of action of approximately 14 days.

In a clinical trial of the antidepressant effects of low-dose flupentixol among 40 patients dependent on crack cocaine,1,2 6 male patients 25 to 46 years old who received a mean dose of 12 mg of flupentixol had extreme akathisia after smoking cocaine. In five the akathisia occurred three to nine days after the first dose of flupentixol, and in one it occurred after the second dose. The akathisia immediately followed the first crack binge (>1 g of cocaine) after the injection as the crack high dissipated into the crash.3 The patients felt extreme motor restlessness, which they described as the worst somatic sensation they had ever experienced except for severe pain. Four had other extrapyramidal symptoms, including dysarthria, myalgia, and sporadic muscle contractions. Four patients sought emergency medical care and had rapid responses to intramuscular benztropine, diphenhydramine, or diazepam; their extrapyramidal symptoms were observed directly by medical personnel. In the others, the symptoms remitted in parallel with the remission of the crash dysphoria. None of the patients smoked cocaine again during the second week after the injection of the drug (they had used an average of 4.3 g the week before flupentixol was administered). No patient had akathisia as a result of using flupentixol alone, without smoking crack; the patients who reported crack smoking but had no akathisia had low one-week plasma flupentixol concentrations (mean value in these patients, 0.53 ng per milliliter, vs. 0.99 ng per milliliter in the patients with akathisia). Akathisia has not been reported as being induced by cocaine alone. Flupentixol itself was well tolerated. In animals the dopamine-blocking effects of flupentixol are potentiated in the short term by cocaine.4 This effect, combined with the hypodopaminergic state following cocaine use, explains the brief, intense akathisia.

We describe only accidental interactions, not intentional aversive therapy. Because flupentixol may combine well-tolerated treatment with extremely aversive, yet safe and reversible, interactions with cocaine, and given the inefficacy of current treatments for users of crack cocaine, the assessment of intentional aversion with flupentixol is warranted.

Frank H. Gawin, M.D.
Mood and Addiction Neuroscience Foundation, Los Angeles, CA 90025

M. Elena Khalsa-Denison, M.D., Ph.D.
University of California, Los Angeles, Los Angeles, CA 90073

Peter Jatlow, M.D
Yale University School of Medicine, New Haven, CT 06504

4 References

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Citing Articles (8)

Citing Articles

1. 1

   Simon Zhornitsky, Élie Rizkallah, Tania Pampoulova, Jean-Pierre Chiasson, Emmanuel Stip, Pierre-Paul Rompré, Stéphane Potvin. (2010) Antipsychotic Agents for the Treatment of Substance Use Disorders in Patients With and Without Comorbid Psychosis. Journal of Clinical Psychopharmacology 30:4, 417-424
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   Rasmon Kalayasiri, Atapol Sughondhabirom, Ralitza Gueorguieva, Vladimir Coric, Wendy J. Lynch, Peter T. Morgan, Joseph F. Cubells, Robert T. Malison. (2006) Self-reported paranoia during laboratory “binge” cocaine self-administration in humans. Pharmacology Biochemistry and Behavior 83:2, 249-256
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   Kyle M Kampman, Helen Pettinati, Kevin G Lynch, Thorne Sparkman, Charles P O'Brien. (2003) A pilot trial of olanzapine for the treatment of cocaine dependence. Drug and Alcohol Dependence 70:3, 265-273
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   St??phane Potvin, Emmanuel Stip, Jean-Yves Roy. (2003) Clozapine, quetiapine and olanzapine among addicted schizophrenic patients: towards testable hypotheses. International Clinical Psychopharmacology 18:3, 121-132
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   Stéphane Potvin, Emmanuel Stip, Jean-Yves Roy. (2003) Clozapine, quetiapine and olanzapine among addicted schizophrenic patients. International Clinical Psychopharmacology 18:3, 121-132
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6. 6

   Suzette M Evans, Sharon L Walsh, Frances R Levin, Richard W Foltin, Marian W Fischman, George E Bigelow. (2001) Effect of flupenthixol on subjective and cardiovascular responses to intravenous cocaine in humans. Drug and Alcohol Dependence 64:3, 271-283
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7. 7

   Michael Soyka, Jean De Vry. (2000) Flupenthixol as a potential pharmacotreatment of alcohol and cocaine abuse/dependence. European Neuropsychopharmacology 10:5, 325-332
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8. 8

   Frances Rudnick Levin, Suzette M. Evans, Siobhan Coomaraswammy, Eric D. Collins, Nicole Regent, Herbert D. Kleber. (1998) Flupenthixol Treatment for Cocaine Abusers with Schizophrenia: A Pilot Study. The American Journal of Drug and Alcohol Abuse 24:3, 343-360
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