British Journal of Clinical DOI:10.1111/j.1365-2125.2008.03342.x Pharmacology Correspondence Dr Pål Gjerden, Department of Psychiatry, The use and potential abuse Telemark Hospital, N-3710 Skien, Norway. Tel: + 47 3500 3476 Fax: + 47 3500 3187 of anticholinergic E-mail: [email protected] ---------------------------------------------------------------------- antiparkinson drugs in Keywords adverse effects, anticholinergic agents, antiparkinson agents, antipsychotic Norway: a agents, drug abuse ---------------------------------------------------------------------- Received pharmacoepidemiological 9 June 2008 Accepted 18 October 2008 study Published Early View 16 December 2008 Pål Gjerden, Jørgen G. Bramness1 & Lars Slørdal2 Department of Psychiatry,Telemark Hospital, Skien, 1Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo and 2Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology,Trondheim, Norway WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Anticholinergic antiparkinson drugs are used to ameliorate extrapyramidal AIMS symptoms caused by either Parkinson’s The use of anticholinergic antiparkinson drugs is assumed to have disease or antipsychotic drugs, but their use shifted from the therapy of Parkinson’s disease to the amelioration in the treatment of Parkinson’s disease is of extrapyramidal adverse effects induced by antipsychotic drugs. There is a considerable body of data suggesting that anticholinergic assumed to be in decline. antiparkinson drugs have a potential for abuse.The aim was to • Patients with psychotic conditions have a investigate the use and potential abuse of this class of drugs in Norway. high prevalence of abuse of drugs, including anticholinergic antiparkinson drugs. METHODS Data were drawn from the Norwegian Prescription Database on sales to a total of 73 964 patients in 2004 of biperiden and orphenadrine, and use in patients with Parkinson’s disease or in patients who were WHAT THIS STUDY ADDS also prescribed antipsychotic agents. Possible abuse of these drugs • Anticholinergic antiparkinson drugs in was assessed by the level of use, skewedness of use, indications of Norway were primarily prescribed to drug-seeking behaviour and concomitant use of benzodiazepine patients using antipsychotic medication. tranquillizers, a group of prescription drugs with a recognized potential • The risk of abuse of this group of drugs was for abuse. small, even among patients who probably RESULTS abused other drugs. Anticholinergic antiparkinson drugs were prescribed to 4.5% of all outpatients who used antipsychotic drugs. This outnumbered sales to patients with Parkinson’s disease by >20 to 1. We found indications of abuse of benzodiazepine tranquillizers among patients using antipsychotics, but there were no clear indications of abuse of anticholinergics, even among patients who were strongly suspected of abuse of benzodiazepines. CONCLUSIONS Anticholinergic antiparkinson drugs were used primarily by patients with psychotic illnesses. These patients have a very high prevalence of legal and illegal drug abuse, but the risk of abuse of anticholinergic antiparkinson drugs seemed small. 228 / Br J Clin Pharmacol / 67:2 / 228–233 © 2008 The Authors Journal compilation © 2008 The British Pharmacological Society Use and potential abuse of anticholinergic antiparkinson drugs Introduction to obtain prescriptions, and the concomitant use of other prescription drugs with a recognized potential for abuse The first anticholinergic antiparkinson drugs were synthe- [16]. sized in the 1940s. Until the introduction of levodopa they The aim of this study was to gain information about the were the mainstay of Parkinson’s disease treatment. Their use of biperiden and orphenadrine in Norway and explore primary use now is assumed to be the amelioration of possible cases of abuse by investigating prescriptions extrapyramidal adverse effects induced by antipsychotic given to individual patients, with an emphasis on the medication, but there is not much documentation thereof. differences between the drugs. One of these anticholinergic agents, orphenadrine, has also been used as a muscle relaxant [1] and a pain killer [2, 3], but these indications were not approved in Norway at Materials and methods the time of our study.There have been reports of misuse of anticholinergic agents since the 1980s, but the reported Prescription database prevalence varies considerably, up to 34% in relevant The Norwegian Prescription Database (NorPD) contains patient groups [4]. information on all drugs prescribed to individual patients When introduced, these drugs were not subject to living outside institutions from 1 January 2004. It covers comprehensive premarketing evaluations. Little informa- the entire population of 4.6 million inhabitants [17]. tion is available for either of the anticholinergic antiparkin- The data collected and used in this study are: patients’ son compounds marketed in Norway at the time of this unique identifiers (encrypted), gender, age, date of dis- study, biperiden and orphenadrine. Pharmacokinetic data pensing and drug information (brand name, package size, are largely restricted to studies involving healthy volun- number of packages, Anatomical Therapeutic Chemical teers given single doses [5]. Orphenadrine in particular classification code (ATC code) and defined daily dose has a complex metabolism, with one of its metabolites (DDD), i.e. the assumed average maintenance dose per acting as an autoinhibitor, causing unexpectedly high day for a drug used for its main indication in adults [18]). blood levels of the parent compound with continuous If the drug is reimbursed by the government, as it will be as opposed to single-dose use [6]. These two agents if it is used for a chronic condition like idiopathic Parkin- are also different from a pharmacodynamic perspective; son’s disease or a psychotic condition requiring long- orphenadrine is a derivative of the first-generation antihis- term medication, a reimbursement code will also be tamine diphenhydramine and confers a wide range of noted. This code will indicate whether the drug is pre- effects in addition to muscarinic cholinoceptor blockade, scribed for Parkinson’s disease or a serious psychiatric whereas biperiden resembles the classical anticholinergic condition. compound atropine [7]. In 1998, we identified more than 80 reported deaths Study population following orphenadrine overdoses in the literature [8], and Potential indications for the use of anticholinergic antipar- reported 21 deaths over an 11-year period in Norway [9]. kinson drugs are either adverse effects caused by anti- The high fatality rate linked to orphenadrine has subse- psychotic drugs, primarily parkinsonian symptoms, or quently been confirmed by others [10]. Especially note- Parkinson’s disease, or both at the same time. Data were worthy are the low doses that sometimes cause lethal drawn from the NorPD for the year 2004 for patients from intoxications and the short time span between exposure 18 to 69 years of age. The total amounts of biperiden, and death.By contrast,there are no reports in the literature orphenadrine and benzodiazepines prescribed as tranquil- of deaths due to overdose of biperiden. Orphenadrine was lizers were noted for four subgroups: (i) patients using any withdrawn from the Scandinavian market in 2005 but is antipsychotic drug, (ii) patients assumed to be suffering still marketed in many parts of the world, including the UK, from idiopathic Parkinson’s disease either because they USA and Canada.It is available as an over-the-counter drug used a dopaminergic antiparkinson drug or because they in some countries. Its use in connection with euthanasia in were prescribed anticholinergic antiparkinson drugs that the Netherlands [11] is a thought-provoking contrast to were reimbursed for Parkinson’s disease, (iii) patients with this practice. Parkinson’s disease who were also using an antipsychotic The abuse potential of medicinal drugs is difficult to drug,and (iv) patients who neither had Parkinson’s disease assess in premarketing studies [12]. A prescription data- nor were prescribed antipsychotic medication, but were base allows the possibility of postmarketing surveillance of using anticholinergic drugs off-label. At the time of the patterns of drug use [13, 14]. Several different parameters study only three benzodiazepines were marketed as tran- indicating drug abuse on the basis of prescription data quillizers in Norway: diazepam, oxazepam and alprazolam. have been assessed. In the absence of other explanations, A small number of patients using lorazepam, bromazepam extensive use and skewed distribution of drug use can or clobazam (10, one and 19 patients, respectively) were indicate abuse [15]. Other caveats include doctor shop- also included. Fifteen patients (five from Group 1, three ping, i.e. the sequential consulting of different doctors from Group 2 and seven from Group 4) using either Br J Clin Pharmacol / 67:2 / 229 P.Gjerden et al. trihexylphenidyl/benzhexol or procyclidine, two anticho- statistical software used was SPSS 15.0 (SPSS Inc., Chicago, linergic antiparkinson drugs not marketed in Norway at IL, USA). the time of the study, were excluded. Results Pharmacoepidemiological parameters One-year prevalence of use of antipsychotic drugs and Table 1 shows the number of patients in each of the four concomitant use of anticholinergics and benzodiazepine groups, including the subgroups using