#
2002 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2002 Volume 6 Pages 217 ± 219
217
A zolpidem and cocaine abuse case report 1
1
IA LIAPPAS , PN MALITAS , 2 3 NP DIMOPOULOS , OE GITSA , 4 1 AI LIAPPAS , CH K NIKOLAOU 1 AND GN CHRISTODOULOU
Int J Psych Clin Pract Downloaded from informahealthcare.com by Nyu Medical Center on 06/04/15 For personal use only.
1
Department of Psychiatry, Eginition 2 Hospital, Athens; Department of Neurology, 3 Evangelismos Hospital, Athens; Department of Pathophysiology, Laiko Hospital, Athens 4 and School of Biological Sciences, University of Central Lancashire, UK Correspondence Address Dr IA Liappas, Eginition Hospital, Department of Psychiatry, University of Athens, 72-74 Vas. Sophias Ave., GR - 11528 Athens, Greece Tel: +301 07757692 Fax: +301 07753240 E-mail: [email protected] Received 12 June 2002; revised 25 July 2002; accepted for publication 4 September 2002
A case is presented of a 30-year-old man, prescribed zolpidem for insomnia arising from cocaine abuse, who sought to use this hypnotic to reduce his craving for cocaine. However, after taking cocaine and up to 300 mg/day zolpidem, he became euphoric and hyperactive. It is suggested that at high doses, zolpidem, like cocaine, has a stimulatory effect on the brain dopaminergic reward pathway. (Int J Psych Clin Pract 2002; 6: 217 ± 219)
Keywords cocaine abuse
INTRODUCTION
T
he recent escalation of cocaine abuse, mainly in the western world, has captured the attention of health officials and policymakers because of its devastating social, financial and public health consequences. Cocaine has long been recognized as a potent central nervous system (CNS) stimulant and one of the most addictive substances known.1 Additional psychiatric diagnoses are quite common among cocaine abusers, who frequently use other drugs such as sedatives and opioids to modulate the 2 stimulation and toxic effects of cocaine. We present a patient who was taking zolpidem and cocaine during the same period of time. Zolpidem is a short-acting, non-benzodiazepine hypnotic agent. It is an agonist at the gamma aminobutyric acid type A (GABAA ) receptor and it has been suggested that it is strongly sedative in action with only minor anxiolytic, myorelaxant 3 ,4 and anticonvulsant properties. Nevertheless, as described below, our patient used zolpidem not for sedation, but to induce euphoria and stimulation.
CASE REPORT A 30-year-old, single, independently-wealthy man presented to the Drug Free Outpatient Drug Addiction
zolpidem case report
Department of Athens University Psychiatric Clinic (ATHENA) with a history of abuse of, and dependence on, cocaine. He had no other major health problems and he had been smoking tobacco cigarettes since the age of 18. His history of cocaine abuse started with the use of cocaine when he was 20 years old. From that time until the age of 25, he used the drug socially at parties, always by inhalation. Five years ago his mother developed cancer and after a short time she died. At that time, the patient manifested symptoms which fulfilled the criteria for the diagnosis of dysthymic disorder. His use of cocaine became systematic (intensified abuser) and within the next 2 months he inhaled up to 5 g daily. Bcause of the intense craving that followed the substance use, the patient started to ingest zolpidem tablets (dose 10 mg) in order to calm down. Zolpidem was prescribed by his general practitioner for the treatment of the insomnia which followed the cocaine abuse. One year ago, he became a pathological gambler and as a result of the cocaine abuse, gambled a large amount of money via the Internet on the international stock market. He consumed 3 ± 4 g of cocaine daily in divided doses. Usually after 2 ± 3 hours from the last inhalation he was ingesting 3 ± 4 tablets of zolpidem, reaching 20 ± 30 tablets (200 ± 300 mg) per night. The patient claims that he never used zolpidem as a sedative ± hypnotic drug, but as a means
Int J Psych Clin Pract Downloaded from informahealthcare.com by Nyu Medical Center on 06/04/15 For personal use only.
218
IA Liappas et al
of progressive reduction of his cocaine craving. He pointed out that after zolpidem he became more excited, hyperactive and euphoric, often exhibiting childish behaviour and logorrhea. Moreover, under the effect of zolpidem he had memory blanks. This situation lasted for about a year and then he sought the help of a specialist psychiatrist. Under the doctor’s instructions he gradually discontinued both cocaine and zolpidem, without demonstrating any withdrawal symptoms except for hypersomnia, hyperhagia and depression, which are induced by cocaine interruption. The symptoms were treated with cognitive-behavioural psychotherapy and medication (fluoxetine 20 mg twice daily). After 8 months of follow-up observation, he reports total abstinence from the drugs, emotional stability and that he is adapting well. He is still receiving fluoxetine and his abstinence from the drugs is confirmed by twice-weekly urine analysis.
effective in this respect, possibly due to its selective binding 15 to o1 BZ receptors. On the other hand, the selectivity of zolpidem has been doubted, especially in high doses (such 17 ± 19 as were taken by our patient). In general, it would be expected that GABAergic agonists which stimulate GABAA 16 receptors would decrease extracellular dopamine and 1 antagonize the action of cocaine. Antagonists of the effects of cocaine, through dopamine diminution, are likely to reduce the euphoric effects of cocaine but unlikely to 1 decrease cocaine craving. Actually, cocaine abusers are forced to increase the dose of the drug to overcome this antagonism.1 Therefore, there seems to be a discrepancy between the opinions of different authors regarding the mechanism through which GABA agonists modulate the rewarding properties of cocaine, and whether indeed they do attenuate the cocaine craving.
DISCUSSION
CONCLUSION
The case that we have presented is, to our knowledge, the first case of simultaneous cocaine and zolpidem abuse. It is of great interest that our patient (a typical cocaine abuser) used a sedative-hypnotic drug for stimulation. Although he consumed high doses of zolpidem, which may make a difference to its expected action, it is still remarkable that he used a widely prescribed, novel hypnotic agent in order to reduce his craving for one of the most addictive illicit drugs in use today. Cocaine’s addictive liability has been linked to its action on the meso-telencephalic dopamine reinforcement/reward 5 pathways in the central nervous system. The action of cocaine on the dopaminergic system is due to its ability to bind to the dopamine transporter and prevent dopamine re5±9 uptake into the presynaptic terminal. There is also another way of increasing dopamine release, through switching-off the firing of GABA neurons that tonically 10 inhibit dopamine cell firing. Even though the pharmacodynamics of zolpidem do not directly involve the dopaminergic system, a certain number of patients have reported psychotic reactions and agitation 11 ± 14 after zolpidem ingestion. This could possibly be an indirect element in zolpidem’s interference in the dopaminergic system. It has also been proposed that dopaminergic transmission reinforcement/reward pathways are modulated by 5 ,1 5 GABA. It has been suggested that certain drugs that potentiate GABAergic transmission, such as g-vinyl GABA and gabapentin, may attenuate cocaine withdrawal and craving. 5 ,1 6 Also, diazepam is said to interfere with the rewarding properties of cocaine via its GABAergic action, unlike zolpidem, which has been suggested to be less
Our patient used zolpidem in order to reduce his cocaine craving, and received from it stimulation and euphoria. Being aware of the pharmacological relationship between cocaine and the dopaminergic system, we hypothesize that zolpidem’s euphoric action could be attributed to its interference with dopaminergic pathways, via hitherto unknown biochemical mechanisms.
ACKNOWLEDGEMENT We are grateful to Professor David Nutt for his valuable advice and for kindly reviewing this paper.
KEY POINTS . Zolpidem was used by the patient to induce the euphoric action of cocaine, indirect evidence that in high doses zolpidem causes euphoria . It is remarkable that shortly after the beginning of zolpidem’s use the patient became an abuser of and depended on the drug and he soon showed tolerance to high doses of zolpidem . Zolpidem was used by the patient not as a sedative drug as it was originally prescribed by his physician in order to treat his insomnia, and in a short period of time it became an euphoric agent of abuse
Cocaine and zolpidem abuse
219
Int J Psych Clin Pract Downloaded from informahealthcare.com by Nyu Medical Center on 06/04/15 For personal use only.
REFERENCES 1. Smith M, Hoepping A, Johnson K et al (1999) Dopaminergic agents for the treatment of cocaine abuse. Drug Discov Today 4: 322 ± 32. 2. Jaffe J (2000) Cocaine-related disorders. In: Kaplan & Sadock’s Textbook of Psychiatry 999 ± 1015. Lippincot Williams & Wilkins, Baltimore. 3. Holm K, Goa K (2000) Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 59: 865 ± 89. 4. Salva P, Costa J (1995) Clinical pharmacokinetics and pharmacodynamics of zolpidem, therapeutic implications. Clin Pharmacokinet 29: 142 ± 53. 5. Dewey S, Morgan A, Ashby C et al (1998) A novel strategy for the treatment of cocaine addiction. Synapse 30: 119 ± 29. 6. Ritz M, Lamb R, Goldberg S, Kuhar M (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237: 1219 ± 23. 7. Katz J, Newman A, Izenwasser S (1997) Relations between heterogeneity of dopamine transporter binding and function and the behavioral pharmacology of cocaine. Pharmacol Biochem Behav 57: 505 ± 12. 8. Howell L, Wilcox K (2001) The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates. J. Pharmacol Exper Ther 298: 1 ± 6. 9. Witkin J, Goldberg S, Katz J (1989) Lethal effects of cocaine are reduced by the dopamine-1 receptor antagonist SCH 23390 but not by haloperidol. Life Sci 44: 1285 ± 91.
10. Nutt D (1996) Addiction: brain mechanisms and their treatment implications. Lancet 347: 31 ± 36. 11. Pies R (1995) Dose-related sensory distortions with zolpidem. J Clin Psychiatry 56: 35 ± 36. 12. Hoyler C, Tekell J, Silva A (1996) Zolpidem-induced agitation and disorganization. Gen Hosp Psychiatry 18: 452 ± 53. 13. Iruela L, Rojo V, Baca E (1993) Zolpidem-induced macropsia in an anorexic woman. Lancet 342: 443 ± 44. 14. Ansseau M, Pichot W, Hansenne M, Moreno A (1992) Psychotic reactions to zolpidem. Lancet 339: 809. 15. Meririnne E, Kankaanpaa A, Lillsunde P, Seppala T (1999) The effects of diazepam and zolpidem on cocaine and amphetamine induced place preference. Pharm Biochem Behav 62: 159 ± 64. 16. Morgan A, Dewey S (1998) Effects of pharmacologic increases in brain GABA levels on cocaine-induced changes in extracellular dopamine. Synapse 28: 60 ± 65. 17. Weerts E, Ator N, Grech D, Griffiths R (1998) Zolpidem physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons. J Pharmacol Exper Ther 285: 41 ± 53. 18. Byrnes J, Greenblatt D, Miller L (1992) Benzodiazepine receptor binding of nonbenzodiazepines in vivo: alpidem, zolpidem and zopiclone. Brain Research Bull 29: 905 ± 908. 19. GoÈder R, Treskov V, Burmester J et al (2001) Zolpidem: Zur Entwicklung von Toleranz und AbhaÈngigkeit anhand von Fallberichten, systematischen Studien und aktuellen molekularbiologischen Daten. Fortschr Neurol Psychiatr 69: 592 ± 96.
2002 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 2002 Volume 6 Pages 217 ± 219
217
A zolpidem and cocaine abuse case report 1
1
IA LIAPPAS , PN MALITAS , 2 3 NP DIMOPOULOS , OE GITSA , 4 1 AI LIAPPAS , CH K NIKOLAOU 1 AND GN CHRISTODOULOU
Int J Psych Clin Pract Downloaded from informahealthcare.com by Nyu Medical Center on 06/04/15 For personal use only.
1
Department of Psychiatry, Eginition 2 Hospital, Athens; Department of Neurology, 3 Evangelismos Hospital, Athens; Department of Pathophysiology, Laiko Hospital, Athens 4 and School of Biological Sciences, University of Central Lancashire, UK Correspondence Address Dr IA Liappas, Eginition Hospital, Department of Psychiatry, University of Athens, 72-74 Vas. Sophias Ave., GR - 11528 Athens, Greece Tel: +301 07757692 Fax: +301 07753240 E-mail: [email protected] Received 12 June 2002; revised 25 July 2002; accepted for publication 4 September 2002
A case is presented of a 30-year-old man, prescribed zolpidem for insomnia arising from cocaine abuse, who sought to use this hypnotic to reduce his craving for cocaine. However, after taking cocaine and up to 300 mg/day zolpidem, he became euphoric and hyperactive. It is suggested that at high doses, zolpidem, like cocaine, has a stimulatory effect on the brain dopaminergic reward pathway. (Int J Psych Clin Pract 2002; 6: 217 ± 219)
Keywords cocaine abuse
INTRODUCTION
T
he recent escalation of cocaine abuse, mainly in the western world, has captured the attention of health officials and policymakers because of its devastating social, financial and public health consequences. Cocaine has long been recognized as a potent central nervous system (CNS) stimulant and one of the most addictive substances known.1 Additional psychiatric diagnoses are quite common among cocaine abusers, who frequently use other drugs such as sedatives and opioids to modulate the 2 stimulation and toxic effects of cocaine. We present a patient who was taking zolpidem and cocaine during the same period of time. Zolpidem is a short-acting, non-benzodiazepine hypnotic agent. It is an agonist at the gamma aminobutyric acid type A (GABAA ) receptor and it has been suggested that it is strongly sedative in action with only minor anxiolytic, myorelaxant 3 ,4 and anticonvulsant properties. Nevertheless, as described below, our patient used zolpidem not for sedation, but to induce euphoria and stimulation.
CASE REPORT A 30-year-old, single, independently-wealthy man presented to the Drug Free Outpatient Drug Addiction
zolpidem case report
Department of Athens University Psychiatric Clinic (ATHENA) with a history of abuse of, and dependence on, cocaine. He had no other major health problems and he had been smoking tobacco cigarettes since the age of 18. His history of cocaine abuse started with the use of cocaine when he was 20 years old. From that time until the age of 25, he used the drug socially at parties, always by inhalation. Five years ago his mother developed cancer and after a short time she died. At that time, the patient manifested symptoms which fulfilled the criteria for the diagnosis of dysthymic disorder. His use of cocaine became systematic (intensified abuser) and within the next 2 months he inhaled up to 5 g daily. Bcause of the intense craving that followed the substance use, the patient started to ingest zolpidem tablets (dose 10 mg) in order to calm down. Zolpidem was prescribed by his general practitioner for the treatment of the insomnia which followed the cocaine abuse. One year ago, he became a pathological gambler and as a result of the cocaine abuse, gambled a large amount of money via the Internet on the international stock market. He consumed 3 ± 4 g of cocaine daily in divided doses. Usually after 2 ± 3 hours from the last inhalation he was ingesting 3 ± 4 tablets of zolpidem, reaching 20 ± 30 tablets (200 ± 300 mg) per night. The patient claims that he never used zolpidem as a sedative ± hypnotic drug, but as a means
Int J Psych Clin Pract Downloaded from informahealthcare.com by Nyu Medical Center on 06/04/15 For personal use only.
218
IA Liappas et al
of progressive reduction of his cocaine craving. He pointed out that after zolpidem he became more excited, hyperactive and euphoric, often exhibiting childish behaviour and logorrhea. Moreover, under the effect of zolpidem he had memory blanks. This situation lasted for about a year and then he sought the help of a specialist psychiatrist. Under the doctor’s instructions he gradually discontinued both cocaine and zolpidem, without demonstrating any withdrawal symptoms except for hypersomnia, hyperhagia and depression, which are induced by cocaine interruption. The symptoms were treated with cognitive-behavioural psychotherapy and medication (fluoxetine 20 mg twice daily). After 8 months of follow-up observation, he reports total abstinence from the drugs, emotional stability and that he is adapting well. He is still receiving fluoxetine and his abstinence from the drugs is confirmed by twice-weekly urine analysis.
effective in this respect, possibly due to its selective binding 15 to o1 BZ receptors. On the other hand, the selectivity of zolpidem has been doubted, especially in high doses (such 17 ± 19 as were taken by our patient). In general, it would be expected that GABAergic agonists which stimulate GABAA 16 receptors would decrease extracellular dopamine and 1 antagonize the action of cocaine. Antagonists of the effects of cocaine, through dopamine diminution, are likely to reduce the euphoric effects of cocaine but unlikely to 1 decrease cocaine craving. Actually, cocaine abusers are forced to increase the dose of the drug to overcome this antagonism.1 Therefore, there seems to be a discrepancy between the opinions of different authors regarding the mechanism through which GABA agonists modulate the rewarding properties of cocaine, and whether indeed they do attenuate the cocaine craving.
DISCUSSION
CONCLUSION
The case that we have presented is, to our knowledge, the first case of simultaneous cocaine and zolpidem abuse. It is of great interest that our patient (a typical cocaine abuser) used a sedative-hypnotic drug for stimulation. Although he consumed high doses of zolpidem, which may make a difference to its expected action, it is still remarkable that he used a widely prescribed, novel hypnotic agent in order to reduce his craving for one of the most addictive illicit drugs in use today. Cocaine’s addictive liability has been linked to its action on the meso-telencephalic dopamine reinforcement/reward 5 pathways in the central nervous system. The action of cocaine on the dopaminergic system is due to its ability to bind to the dopamine transporter and prevent dopamine re5±9 uptake into the presynaptic terminal. There is also another way of increasing dopamine release, through switching-off the firing of GABA neurons that tonically 10 inhibit dopamine cell firing. Even though the pharmacodynamics of zolpidem do not directly involve the dopaminergic system, a certain number of patients have reported psychotic reactions and agitation 11 ± 14 after zolpidem ingestion. This could possibly be an indirect element in zolpidem’s interference in the dopaminergic system. It has also been proposed that dopaminergic transmission reinforcement/reward pathways are modulated by 5 ,1 5 GABA. It has been suggested that certain drugs that potentiate GABAergic transmission, such as g-vinyl GABA and gabapentin, may attenuate cocaine withdrawal and craving. 5 ,1 6 Also, diazepam is said to interfere with the rewarding properties of cocaine via its GABAergic action, unlike zolpidem, which has been suggested to be less
Our patient used zolpidem in order to reduce his cocaine craving, and received from it stimulation and euphoria. Being aware of the pharmacological relationship between cocaine and the dopaminergic system, we hypothesize that zolpidem’s euphoric action could be attributed to its interference with dopaminergic pathways, via hitherto unknown biochemical mechanisms.
ACKNOWLEDGEMENT We are grateful to Professor David Nutt for his valuable advice and for kindly reviewing this paper.
KEY POINTS . Zolpidem was used by the patient to induce the euphoric action of cocaine, indirect evidence that in high doses zolpidem causes euphoria . It is remarkable that shortly after the beginning of zolpidem’s use the patient became an abuser of and depended on the drug and he soon showed tolerance to high doses of zolpidem . Zolpidem was used by the patient not as a sedative drug as it was originally prescribed by his physician in order to treat his insomnia, and in a short period of time it became an euphoric agent of abuse
Cocaine and zolpidem abuse
219
Int J Psych Clin Pract Downloaded from informahealthcare.com by Nyu Medical Center on 06/04/15 For personal use only.
REFERENCES 1. Smith M, Hoepping A, Johnson K et al (1999) Dopaminergic agents for the treatment of cocaine abuse. Drug Discov Today 4: 322 ± 32. 2. Jaffe J (2000) Cocaine-related disorders. In: Kaplan & Sadock’s Textbook of Psychiatry 999 ± 1015. Lippincot Williams & Wilkins, Baltimore. 3. Holm K, Goa K (2000) Zolpidem: an update of its pharmacology, therapeutic efficacy and tolerability in the treatment of insomnia. Drugs 59: 865 ± 89. 4. Salva P, Costa J (1995) Clinical pharmacokinetics and pharmacodynamics of zolpidem, therapeutic implications. Clin Pharmacokinet 29: 142 ± 53. 5. Dewey S, Morgan A, Ashby C et al (1998) A novel strategy for the treatment of cocaine addiction. Synapse 30: 119 ± 29. 6. Ritz M, Lamb R, Goldberg S, Kuhar M (1987) Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237: 1219 ± 23. 7. Katz J, Newman A, Izenwasser S (1997) Relations between heterogeneity of dopamine transporter binding and function and the behavioral pharmacology of cocaine. Pharmacol Biochem Behav 57: 505 ± 12. 8. Howell L, Wilcox K (2001) The dopamine transporter and cocaine medication development: drug self-administration in nonhuman primates. J. Pharmacol Exper Ther 298: 1 ± 6. 9. Witkin J, Goldberg S, Katz J (1989) Lethal effects of cocaine are reduced by the dopamine-1 receptor antagonist SCH 23390 but not by haloperidol. Life Sci 44: 1285 ± 91.
10. Nutt D (1996) Addiction: brain mechanisms and their treatment implications. Lancet 347: 31 ± 36. 11. Pies R (1995) Dose-related sensory distortions with zolpidem. J Clin Psychiatry 56: 35 ± 36. 12. Hoyler C, Tekell J, Silva A (1996) Zolpidem-induced agitation and disorganization. Gen Hosp Psychiatry 18: 452 ± 53. 13. Iruela L, Rojo V, Baca E (1993) Zolpidem-induced macropsia in an anorexic woman. Lancet 342: 443 ± 44. 14. Ansseau M, Pichot W, Hansenne M, Moreno A (1992) Psychotic reactions to zolpidem. Lancet 339: 809. 15. Meririnne E, Kankaanpaa A, Lillsunde P, Seppala T (1999) The effects of diazepam and zolpidem on cocaine and amphetamine induced place preference. Pharm Biochem Behav 62: 159 ± 64. 16. Morgan A, Dewey S (1998) Effects of pharmacologic increases in brain GABA levels on cocaine-induced changes in extracellular dopamine. Synapse 28: 60 ± 65. 17. Weerts E, Ator N, Grech D, Griffiths R (1998) Zolpidem physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons. J Pharmacol Exper Ther 285: 41 ± 53. 18. Byrnes J, Greenblatt D, Miller L (1992) Benzodiazepine receptor binding of nonbenzodiazepines in vivo: alpidem, zolpidem and zopiclone. Brain Research Bull 29: 905 ± 908. 19. GoÈder R, Treskov V, Burmester J et al (2001) Zolpidem: Zur Entwicklung von Toleranz und AbhaÈngigkeit anhand von Fallberichten, systematischen Studien und aktuellen molekularbiologischen Daten. Fortschr Neurol Psychiatr 69: 592 ± 96.
