The Controversial Case of Biperiden from Prescription Drug to Drug Of

LETTER TO THE EDITORS

The Controversial Case having used clonazepam 8 mg/d, cocaine increasing the dose up to 16 mg daily (3 times/wk), cannabis, and alcohol since (criteria 1); he was taking biperiden in such of Biperiden his arrival in Italy. The patient met Diag- an amount that he developed severe ad- From Prescription Drug to nostic and Statistical Manual of Mental verse effects (criteria 3); he was reporting Disorders, Fourth Edition, Text Revision cri- persistent desire and unsuccessful efforts Drug of Abuse teria for polysubstance dependence. There- to cut down the dosage (criteria 4); and de- To the Editors: fore, he was treated with diazepam 20 mg/d spite having suffered from a vesical globe, nticholinergic drugs such as biperiden to prevent alcohol and benzodiazepine he admitted to be unable to stop (criteria 7). A are commonly used in psychiatry for withdrawal syndromes and he denied ad- The mental status examination revealed a the prophylaxis and treatment of extrapyra- verse effects to this therapy. In the next mild confusional state with temporal and midal symptoms caused by antipsychotics, few days, after the abrupt discontinuation spatial disorientation and impairment of as well as for tremors in Parkinson disease. of the different substances that he was using attention and concentration that precluded Anticholinergic abuse has been reported in before the imprisonment, he reported in- the possibility to complete a mini-mental nonpsychotic patients probably because of creasing dysphoria, mild psychomotor ag- status examination. Moreover, the patient inducing mild euphoria with increased so- itation, anxiety, headache, and difficulty suffered from psychomotor agitation; the ciability and energy through an increase of falling asleep and he requested biperiden. speech was only partially informative with dopaminergic activity.1–3 The psychiatrist denied that medica- disorganization of thought, although delu- Since 1960, anticholinergic abuse has tion, until the patient started to deliberately sions or perceptual disturbances were not been described in various countries by indi- cut his arms to induce the physician to pre- present. Three days after, the patient was viduals taking them without prescription.4,5 scribe him the drug. Therefore, biperiden released from the emergency department Recent evidence from the literature is mainly (4 mg/d in the evening) was prescribed. and was readmitted back to the prison. limited to low- and middle-income coun- One week after the initiation of this treat- Biperiden was gradually tapered from 16 tries such as Saudi Arabia, Jordan, Iraq, and ment, he reported improved mood, reduced to 4 mg/d with reductions of 4 mg/wk. Af- Brazil, and patients described are often un- agitation, decreased anxiety, and regulari- ter a period of initial compliance without married, unemployed, marginalized, smokers, zation of his sleep-wake schedule and the any symptom, the patient reported craving, polysubstance abusers, and with a positive prescription was refilled for months at the mild dysphoria, fatigue, lack of motivation, family history for mental disorders. Pris- same dose. Six months later, the patient and insomnia. Therefore, the patient oners, adolescents, and heroin abusers seem was admitted to the hospital emergency ser- was treated with quetiapine, 50 mg/d, and to represent the highest risk populations.3,6 vice because of an episode of acute urinary only after 6 months, he definitely stopped Recently, this phenomenon has also retention with vesical globe that required using biperiden. been observed in Italy, mainly in immi- catheterization. He reported that he was The case we described underlines a grants from North Africa. However, biper- consuming biperiden 16 mg/d, illegally ob- widespread phenomenon probably under- iden abuse is also growing among native tained from other prisoners. Despite the estimated by recent epidemiological stud- Italians (Table 1).7 potential adverse effects, he admitted being ies.8 The marked increase of anticholinergic We present the case of a patient unable to give up this drug because of in- abusers among both immigrants to Italy with anticholinergic abuse. A 27-year-old tense dependence and fear of withdrawal and its native population has important Tunisian man came to Italy in 2010. He re- symptoms. The patient met the following 4 therapeutic and diagnostic implications: ported a previous history for polysubstance of the 7 Diagnostic and Statistical Manual anticholinergic abusers do not necessar- abuse (including trihexyphenidyl, an anti- of Mental Disorders, Fourth Edition, Text ily access substance abuse services and muscarinic drug). When initially seen in a Revision criteria for biperiden dependence: thus they frequently do not receive ade- prison dispensary in May 2013, he reported he showed tolerance because he had been quate diagnosis and treatment. Different pharmacological effects of antimuscarinic TABLE 1. Nationality of Biperiden Abusers Attending Substance Use Disorders Service drugs could justify the drug-seeking be- of Parma Inside and Outside Prison. havior described in our report. Firstly, there is evidence that the blockade of the Biperiden Abuse cholinergic receptors enhances striatal do- Ye s N o Fisher Exact Test pamine release. The resulting dopaminer- P gic hyperactivity could be responsible for n(%) n(%) both the psychotomimetic effects reported SUD service <0.001 by the abusers (euphoria, elevated energy Inside the prison (N.116) 18 15.5 98 84.5 and mood, increased social interactions) Outside the prison (N.725) 9 1.2 716 98.8 and for the toxic syndrome described with higher doses of central anticholinergics Nationality <0.001 (delirium, visual hallucinations, confusion, Italian (N.729) 9 1.2 720 98.8 dream-like state, apraxia, agnosia, amne- Non-Italian (N.112) 18 16.1 94 83.9 sia, and intellectual impairment). In this North-African (N.57) 16 28.0 41 72.0 abuser at the beginning of the incarcera- Adapted from Substance Use Disorders Service Anonymized Administrative Database. Parma, tion period, the biperiden was requested Italy: Mental Health and Addiction Department, Azienda Unità Sanitaria Locale of Parma; 2014.7 to obtain its psychotomimetic effects. Sec- SUD indicates substance use disorder. ondly, antimuscarinic drugs seem to induce rapid tolerance to the euphoriant effects

Journal of Clinical Psychopharmacology • Volume 35, Number 6, December 2015 www.psychopharmacology.com 1

that promotes the abuse and dependence is particularly abused by prisoners coming 2. Modell JG, Tandon R, Beresford TP. mechanisms. The clinical reports of pa- from North-African countries. The high Dopaminergic activity of the antimuscarinic tients who increased the doses of anticholin- prevalence in this population could be at- antiparkinsonian agents. JClin – ergics to achieve the mood-elevating effects tributed both to the strong law enforcement Psychopharmacol.1989;9:347 351. support that there might occur a pharmaco- efforts that have been the customary ap- 3. Dose M, Tempel HD. Abuse potential of logical tolerance to M1 antagonist.9–13 This proach to cannabis, opiates, and cocaine anticholinergics. Pharmacopsychiatry.2000; hypothesis is also suggested by the find- consumption in North African countries 33(suppl 1):43–46. ing that tolerance to the biperiden inhibit- and to the low prices and the easier avail- 4. Dilsaver SC. Antimuscarinic agents as ing effect of REM sleep can develop after ability of antimuscarinics compared with substances of abuse: a review. JClin treatment.14,15 Anticholinergic abusers de- other substances of abuse on the black mar- Psychopharmacol.1988;8:14–22. velop a “cholinergic overdrive” (a complex ket. These environmental conditions push 5. Marken P, Stoner SC, Bunker MT. of symptoms secondary to the withdrawal the abusers to shift to the more disposable Anticholinergic drug abuse and misuse. of muscarinic blockade and attributed to and cheaper substances that are associated CNS Drugs. 1996;5:190–199. the upregulated cholinergic receptor un- with the brain mechanisms of abuse and 6. Caplan JP, Epstein LA, Quinn DK, et al. masking). The clinical presentation includes dependence. Interestingly, some prisoners Neuropsychiatric effects of prescription drug dysphoria, anxiety, fatigue, insomnia with reported that the anticholinergic drug was abuse. Neuropsychol Rev. 2007;17:363–380. terrifying dreams, myalgia, malaise, dia- the only substance abused before incar- 7. Substance Use Disorders Service Anonymized phoresis, paresthesia, coryza, gastroin- ceration. To shed a light on the specific Administrative Database. Parma, Italy: Mental testinal distress, and headaches and it is brain mechanisms underlying anticholiner- Health and Addiction Department, Azienda described as a rapid symptoms resolution gic abuse and dependence, patients with Unità Sanitaria Locale of Parma; 2014. 4 isolated “primary” abuse of biperiden are after giving biperiden. Therefore, our pa- 8. Gjerden P,Bramness JG, Slørdal L. The use and tients, after a short period, would have worth identifying. potential abuse of anticholinergic antiparkinson continued to abuse biperiden to avoid with- AUTHOR DISCLOSURE drugs in Norway: a pharmacoepidemiological drawal symptoms rather than to achieve the – INFORMATION study. Br J Clin Pharmacol. 2009;67:228 233. pleasurable effects. The third point of dis- This research received no specific 9. Shariatmadari ME. Letter: Orphenadrine cussion concerns the role of acetylcholine dependence. Br Med J. 1975;3:486. in learning and memory. Consolidated re- grant from any funding agency in the pub- lic, commercial, or not-for-profit sectors. 10. Marriott P. Letter: Dependence on search demonstrated that the blockade of antiparkinsonian drugs. Br Med J. 1976;1:152. muscarinic receptors impairs the encoding The authors declare no conflicts of interest. 16 11. Sofair J, Campion J, Angrist B. High dose of new memories. Recent animal studies Andrea Affaticati, MD trihexyphenidyl abuse with psychological reported that biperiden blocks the consoli- Department of Mental Health dependence. JClinPsychopharmacol.1983;3: Local Health Service dation of cocaine conditioned place prefer- 263–264. ence (CPP),17 which is a learned behavior Parma, Italy that occurs when a subject comes to prefer 12. McInnis M, Petursson H. Trihexyphenidyl Maria Lidia Gerra, MD dependence. Acta Psychiatr Scand.1984;69: 1 place more than others because the pre- Department of Neuroscience 538–542. ferred location has been paired previously Unit of Psychiatry 13. Espi Martinez F, Espi Forcen F, Shapov A, et al. with rewarding events. Typically, drugs of University of Parma abuse such as cocaine produce CPP. Thus, Parma, Italy Biperiden dependence: case report and literature review. Case Rep Psychiatry.2012; in this abuser, biperiden might have had [email protected] 2012:949256. a positive effect on addictive behavior re- Andrea Amerio, MD ducing the conditioned learning and con- 14. Salin-Pascual RJ, Granados-Fuentes D, Department of Neuroscience Galicia-Polo L, et al. Development of tolerance sequently reducing the reinforcing effects Unit of Psychiatry 18 after repeated administration of a selective of cocaine. Finally, this observation con- University of Parma muscarinic M1 antagonist biperiden in healthy firms that the occurrence of adverse ef- Parma, Italy human volunteers. Biol Psychiatry.1993;33: fects of anticholinergics is dose dependent; and Mood Disorders Program 188–193. the peripheral effects of biperiden appear Tufts Medical Center Boston, MA 15. Sitaram N, Moore AM, Gillin JC. only rarely in our population of abusers Scopolamine-induced muscarinic and the patient described was 1 of the rare Maria Inglese, MD supersensitivity in normal man: changes in ones who had adverse effects. Another pos- Maria Caterina Antonioni, MD sleep. Psychiatry Res. 1979;1:9–16. sible explanation of the infrequency of the Department of Mental Health 16. Williams MJ, Adinoff B. The role of peripheral effects could be that many of Local Health Service acetylcholine in cocaine addiction. the troublesome effects of these drugs re- Parma, Italy Neuropsychopharmacology. 2008;33: sult from interaction with specific receptor 1779–1797. subtypes. Considering that biperiden is a Carlo Marchesi, MD Department of Mental Health 17. Ramos AC, Andersen ML, Oliveira MG, et al. selective muscarinic M1 antagonist and Biperiden (M antagonist) impairs the that the M1 receptor is the most significant Local Health Service Parma, Italy expression of cocaine conditioned place receptor in the central nervous system, there and Department of Neuroscience preference but potentiates the expression of is the possibility that biperiden, at low doses, Unit of Psychiatry cocaine-induced behavioral sensitization. has the central nervous system as its spe- University of Parma Behav Brain Res. 2012;231:213–216. cific target. Parma, Italy 18. Dieckmann LH, Ramos AC, Silva EA, et al. Further studies are needed to estimate REFERENCES Effects of biperiden on the treatment of the impact of biperiden as a substance of cocaine/crack addiction: a randomised, abuse, especially among marginalized peo- 1. Schulte RM. Biperiden abuse as a partial factor double-blind, placebo-controlled trial. ple. Concerning Italy, the preliminary data in polytoxicomania [in German]. Psychiatr Eur Neuropsychopharmacol.2014;24: presented in Table 1 support that biperiden Prax. 1988;15:53–56. 1196–1202.

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