Abstract
AIMS
Extrapyramidal side-effects induced by antipsychotic drugs are treated with dose reduction or substitution with another antipsychotic drug or by the addition of anticholinergic antiparkinson agents. The withdrawal of orphenadrine from the Norwegian market provided a possibility to investigate to what degree these alternative measures were taken in clinical practice.
METHODS
Data were drawn from the Norwegian Prescription Database on the sales of antipsychotics and one of the two anticholinergic antiparkinson agents marketed in 2004, orphenadrine and biperiden, to a total of 39 758 outpatients. The patients were reinvestigated in 2007. The consequences of the withdrawal of orphenadrine from the Norwegian market in 2005 regarding dosing, switching and cessation of antipsychotics and use of anticholinergics were assessed for orphenadrine users compared with biperiden users.
RESULTS
Of the patients originally using orphenadrine, 28.4% stopped using the drug without reducing the antipsychotic dose or replacing orphenadrine with another anticholinergic agent. The corresponding number for biperiden users was 19.3%. Only 11.8% of patients switched to another antipsychotic drug, but they used significantly lower antipsychotic doses than those who stayed on the same drug.
CONCLUSION
The use of anticholinergic antiparkinson agents could be seen as superfluous for at least one-third of patients.
Keywords: adverse effects, anticholinergic agents, antiparkinson agents, antipsychotic agents, extrapyramidal side-effects
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
Extrapyramidal side-effects induced by antipsychotic agents are treated with dose reduction, switching of antipsychotic medication or the addition of anticholinergic antiparkinson drugs.
WHAT THIS STUDY ADDS
The use of anticholinergic antiparkinson drugs appears to be superfluous in a large number of patients.
Introduction
The use of anticholinergic antiparkinson agents in Norway has almost exclusively been confined to the amelioration of extrapyramidal side-effects induced by antipsychotic medication [1]. Orphenadrine is a derivative of the first-generation antihistamine diphenhydramine and confers a wide range of effects in addition to muscarinic cholinoceptor blockade [2]. In contrast to the other compounds of this class, it is particularly toxic in overdose with a high fatality rate [3, 4]. Orphenadrine was withdrawn from the Scandinavian market in 2005, leaving biperiden as the only anticholinergic antiparkinson drug marketed in Norway [5].
The use of anticholinergic agents against antipsychotic-induced side-effects has been extensive [1]. These compounds should be used only when other measures, such as dose reduction or alteration of antipsychotic drug, have proven ineffective [6, 7]. Concomitant use of antipsychotic and anticholinergic agents has been studied in several recent reports [8, 9], but we are not aware of any study aiming to evaluate the indications for the use of anticholinergics in clinical practice.
The study group was patients who were using antipsychotics and anticholinergic antiparkinson agents in Norway in 2004. The aim of the study was to explore the consequences of the withdrawal of orphenadrine from the Norwegian market in 2005. We assessed the execution of drug treatment with respect to whether antipsychotic drug doses were reduced or stopped, whether the patients were switched from one antipsychotic to another, or whether the patients just substituted orphenadrine with biperiden. Patients using orphenadrine were compared with those using biperiden over a 3-year time span.
Material and methods
Prescription database
The Norwegian Prescription Database (NorPD) contains information on all drugs prescribed to individual patients living outside institutions from 1 January 2004. It covers the entire population of 4.6 million inhabitants [10]. Data on institutionalized patients (nursing homes or hospitals) are also collected, but are not registered on an individual level. The data collected and used in this study were: patients' unique personal identifiers (encrypted), gender, age, date of dispensing and drug information [brand name, package size, number of packages, Anatomical Therapeutic Chemical classification code and defined daily dose (DDD), i.e. the assumed average maintenance dose per day for a drug used for its main indication in adults [11]]. Prescription data were collected from pharmacies, thus capturing prescriptions that were actually dispensed. We also assessed the number of patients being hospitalized from 2004 to 2007, and patients hospitalized through the year 2007, from national health service databases.
Study population
Original data were drawn from NorPD for the year 2004 and 2007. In 2004 two anticholinergic antiparkinson agents were marketed in Norway: biperiden and orphenadrine. Orphenadrine was withdrawn from the Norwegian market on 1 August 2005. The study group consisted of outpatients between 18 and 69 years of age in 2004. They filled at least one prescription for biperiden or orphenadrine and a prescription for an antipsychotic drug in 2004. The antipsychotic drugs included were those used by >30 patients in 2004 and that were marketed in both 2004 and 2007. Four antipsychotic agents were marketed in Norway in 2004 but not in 2007 and were therefore excluded; thioridazine was withdrawn from the Norwegian market on 1 April 2005, fluphenazine was withdrawn on 16 November 2005, dixyrazine and chlorpromazine were withdrawn on 30 January and 22 May 2007, respectively. Prochlorperazine, flupentixol and chlorprotixene, antipsychotic agents that were marketed but assumed to be widely used in small or moderate dosages for nonpsychotic conditions, were also excluded. The following 11 antipsychotic agents were included: levomepromazine, perphenazine, haloperidol, ziprasidone, zuclopentixole, clozapine, olanzapine, quetiapine, amisulpiride, risperidone and aripiprazole. All the drugs were reimbursed by the government and patient expenditure was identical, regardless of choice of drugs. We assumed that patients receiving dopaminergic antiparkinson drugs were primarily suffering from Parkinson's disease, and these patients were excluded from the study group, even if they also used both antipsychotic and anticholinergic antiparkinson drugs.
End-points
We reinvestigated the 2004 study group in 2007 and defined four mutually exclusive end-points: if they were using the same antipsychotic drug (Persisters), if they had switched to another antipsychotic (Switchers), if they had stopped using any of the above-mentioned antipsychotics (Stoppers), or if they were deceased. If patients had used several antipsychotics in 2004 they were grouped as Persisters if they used at least one of these drugs in 2007. In addition to the number of patients, we noted the dosage of the antipsychotic drug (in DDDs per year) used by each patient in both 2004 and 2007, and if they concomitantly had been prescribed biperiden in 2007.
Statistics
The statistical calculations were mainly descriptive. Pearson's χ2 test was used in the assessment of significant differences. The statistical software used was SPSS 15.0 (SPSS Inc., Chicago, IL, USA).
Results
The study included 39 758 patients. The users in 2004 of the 11 antipsychotic agents that were marketed in both 2004 and 2007, and who concomitantly were using either orphenadrine or biperiden, are described in Table 1. Twice as many patients used biperiden compared with orphenadrine. The numbers of anticholinergic using patients in Table 1 are higher than in Tables 2 and 3 because some patients were using more than one antipsychotic agent.
Table 1.
Patients using at least one of 11 selected antipsychotic agents concomitantly with either orphenadrine or biperiden in 2004 (data from NorPD)
| Patients in study n | Female gender n(%) | Age, mean (SD) | Patients using anticholinergics n | Patients using orphenadrine n | Percent of patients using orphenadrine % (95% CI) | Patients using biperiden n | Percent of patients using biperiden % (95% CI) | |
|---|---|---|---|---|---|---|---|---|
| Levomepromazine | 6 856 | 3775 (55.1) | 50.7 (11.6) | 603 | 276 | 4.0 (3.6, 4.5) | 500 | 7.3 (6.7, 7.9) |
| Perphenazine | 5 310 | 3000 (56.5) | 48.7 (11.6) | 974 | 390 | 7.3 (6.6, 8.0) | 619 | 11.7 (10.8, 12.5) |
| Haloperidol | 1 883 | 934 (49.6) | 50.8 (12.5) | 388 | 156 | 8.3 (7.0, 9.5) | 245 | 13.0 (11.5, 14.5) |
| Ziprasidone | 2 042 | 1191 (58.3) | 38.6 (12.1) | 194 | 63 | 3.1 (2.3, 3.8) | 139 | 6.8 (5.7, 7.9) |
| Zuclopentixol | 2 384 | 1188 (49.8) | 48.8 (11.2) | 661 | 209 | 8.8 (7.6, 9.9) | 486 | 20.4 (18.8, 22.0) |
| Clozapine | 1 686 | 661 (39.2) | 42.1 (10.5) | 119 | 41 | 2.4 (1.7, 3.2) | 83 | 4.9 (3.9, 6.0) |
| Olanzapine | 11 444 | 6285 (54.9) | 42.9 (12.9) | 586 | 182 | 1.6 (1.4, 1.8) | 423 | 3.7 (3.4, 4.0) |
| Quetiapine | 2 825 | 1599 (56.6) | 38.8 (12.4) | 216 | 71 | 2.5 (1.9, 3.1) | 162 | 5.7 (4.9, 6.6) |
| Amisulpiride | 576 | 282 (49.0) | 38.7 (12.2) | 63 | 16 | 2.8 (1.4, 4.1) | 52 | 9.0 (6.7, 11.4) |
| Risperidone | 4 720 | 2206 (46.7) | 42.3 (13.6) | 471 | 146 | 3.1 (2.6, 3.6) | 344 | 7.3 (6.5, 8.0) |
| Aripiprazole | 32 | 7 (21.9) | 32.8 (10.3) | 9 | 0 | 9 | 28.1 (12.5, 43.7) |
Table 2.
Status in 2007 of patients using 11 selected antipsychotics who also used anticholinergic antiparkinson drugs in 2004
| Status in 2007 | Orphenadrine users in 2004 (n= 953) n (%) | Biperiden users in 2004 (n= 1 891) n (%) | RR (95% CI) |
|---|---|---|---|
| Dead | 82 (8.6) | 142 (7.5) | 1.2 (1.0, 1.3) |
| Stoppers | 73 (7.7) | 199 (10.5)* | 0.7 (0.6, 0.9) |
| Persisters without anticholinergics | 271 (28.4) | 365 (19.3)* | 1.5 (1.4, 1.6) |
| Persisters with anticholinergics | 422 (44.3) | 954 (50.4)* | 0.9 (0.8, 1.0) |
| Switchers without anticholinergics | 73 (7.7) | 155 (8.2) | 0.9 (0.8, 1.1) |
| Switchers with anticholinergics | 32 (3.4) | 76 (4.0) | 0.8 (0.6, 1.1) |
P < 0.001, χ2 test. The Stoppers had ceased using antipsychotic drugs altogether, the Persisters had stayed with the antipsychotic agent they used in 2004 and the Switchers had substituted the antipsychotic agent used in 2004 with another drug of this class. The relative risk (RR) is given with biperiden as reference.
Table 3.
Amount of 11 selected antipsychotics used in 2004 and 2007 in patients using biperiden or orphenadrine as co-medication in 2004, according to their status in 2007
| Status in 2007 | Orphenadrine users in 2004 still using an antipsychotic in 2007 (n= 798) Amount of antipsychotics in 2004/2007 in DDDs Mean (SD) | Biperiden users in 2004 still using an antipsychotic in 2007 (n= 1550) |
|---|---|---|
| Persisters without anticholinergics | 438 (409)/445 (396) | 442 (365)/472 (405) |
| Persisters with anticholinergics | 456 (416)/483 (409) | 478 (395)/511 (418) |
| Switchers without anticholinergics | 351 (404)/360 (263) | 330 (272)/411 (320) |
| Switchers with anticholinergics | 344 (372)/376 (289) | 372 (270)/456 (314) |
DDD, defined daily dose.
Table 2 shows the number of deceased patients and the degree of continuity of medication for individuals who used both antipsychotic and anticholinergic agents in 2004. In the Persisters group, significantly more original orphenadrine users were off anticholinergics than biperiden users (28.4% vs. 19.3%). Consequently, fewer orphenadrine users were dispensed a prescription for anticholinergics than biperiden users (44.3% vs. 50.4%). Approximately the same number of patients had switched to a different antipsychotic drug in both the orphenadrine and biperiden groups (11.0% and 12.2%, 11.8% taken together). Cessation of use of antipsychotic drugs was significantly more frequent among biperiden users than among orphenadrine users (10.5% vs. 7.7%). The Stoppers category included both patients who stopped taking antipsychotics and patients missing inclusion in the NorPD because they were hospitalized during the entire 2007. NorPD does not recognize this last group of patients on an individual basis, but 63 patients were hospitalized from 2004 to 2007 and 503 patients were hospitalized through 2007. The number of patients who were hospitalized in psychiatric hospitals or nursing homes for the entire year 2007 thus cannot exceed 440. This amounts to approximately 1% of the number of patients included in the study group. Table 3 shows the level of use of the 12 included antipsychotic agents in 2007 compared with 2004, divided into biperiden users and orphenadrine users. There was an increase in the level of use of antipsychotics for all patient groups, but Switchers used fewer antipsychotic drugs than Persisters (P < 0.001).
Discussion
This study reports the results of a natural experiment where a group of patients who used antipsychotic agents had to stop using orphenadrine, an agent they were given for the treatment of anticipated or actual extrapyramidal side-effects. The setting was outpatient general and specialist practice. The most obvious result of this intervention was that 28.4% of the patients seemed to manage without replacing orphenadrine with another anticholinergic antiparkinson agent or lowering or switching antipsychotic medication (Table 1). They did not seem to need the drug and even appeared to tolerate a slight increase in antipsychotic use without needing anticholinergic medication (Table 2).
Compared with orphenadrine users, fewer biperiden users in 2004 were off anticholinergics in 2007. They had the possibility of continuing biperiden and a significantly higher number of patients did so. There is no reason to assume that biperiden users were more seriously ill than orphenadrine users; they used a similar amount of anticholinergics in 2004 and more biperiden users than orphenadrine users stopped using antipsychotic medication during the 3-year period. A small number of patients hospitalized during the entire 2007 would be included in NorPD in 2004 and thus erroneously defined as Stoppers. As available health service databases in Norway cannot follow individual institutionalized patients from 2004 to 2007, we cannot identify the number of ‘hospitalized Stoppers’, but they must constitute <1% of the study population. We also do not know the prevalence of anticholinergic use among these patients. Assuming that this was a patient group mainly comprising chronic schizophrenic patients, one might estimate that about half of them were using anticholinergics [9]. Thus, the potentially mislabelled patients must be comparatively few. Some patients may also have stopped taking antipsychotic agents against doctors' recommendations. It seems fair to assume that the indication for the use of biperiden or orphenadrine was the same. If one-third of orphenadrine users managed without the drug, so might a similar proportion of biperiden users, if challenged likewise.
Patients who switched antipsychotic medication from 2004 to 2007 used a lower dose of antipsychotics compared with those who stayed on the same antipsychotic drug, regardless of whether they concomitantly were using anticholinergics or not (Table 3). However, the Switchers were few compared with the Persisters, making it difficult to draw a conclusion with any certainty. The most seriously ill patients were probably given the highest doses of antipsychotics and might also be the patients most hesitant towards switching antipsychotics. This finding may nevertheless give reason to hypothesize that staying with a particular antipsychotic drug may infer a risk of using higher dosages of antipsychotic drugs than necessary.
If Switchers had their drug of choice substituted with a newer antipsychotic agent and the DDDs of more recent agents were lower than those of older preparations, an equipotency switch might result in a higher dosage measured as DDDs and could falsely be interpreted as a rise in antipsychotic dosing. For exemple, one might argue that the DDD of 10 mg for olanzapine, by far the most widely used second-generation antipsychotic, is rather low compared with the DDD of 30 mg for tablets of perphenazine. This should add weight to the argument that Switchers were indeed using lower doses of antipsychotic medication than Persisters.
A more troublesome result is the fact that all patient groups showed an increase in the use of antipsychotics from 2004 to 2007. This was not expected, as doctors are assumed to prescribe antipsychotic agents in lower doses today than they used to some years ago. This result could, however, be affected by the rather crude 1-year measure intervals used. Patients who started on a drug late in 2004 would show a greater increase in use in 2007 compared with patients who started early in 2004. The inverse situation should also occur; patients who stopped taking their drug early in 2007 would show a comparably low rise, or even a decline, in antipsychotic use. This phenomenon should affect all the different antipsychotic agents in the study in a similar fashion. However, the Stoppers group was smaller than both Persisters and Switchers, most probably rendering an increase in antipsychotic use from 2004 to 2007 as the net outcome.
Another sinister finding is that 8.6% of orphenadrine users and 7.5% of biperiden users in 2004 were dead 3 years later. These casualty rates are high compared with recently reported fatality rates among schizophrenic patients [12] but comparable to patients suffering from affective disorders [13].
We were able to collect information on the drug use of all patients in Norway outside of institutions, making the study group both large and representative. The study encompasses all antipsychotic drugs marketed in Norway from 2004 to 2007 rather than just a selection.
Disadvantages of the current approach include the limited amount of information that could be gathered on each patient, including the severity of their condition, the use of more than one antipsychotic drug, and lack of information as to whether prescribed drugs were actually taken.
We are not aware of any other study where regulatory measures concerning a specific drug have been used to evaluate prescription patterns transcending the drug in question. In the literature, such measures are almost exclusively confined to warnings from regulatory authorities, and the consequences are assessed as a decline in both sales of the targeted drug and the prevalence of the adverse effect that prompted the warning [14, 15].
The most important consequence of the withdrawal of orphenadrine from the Norwegian market was that 28.4% of the patients stopped taking a potentially dangerous drug without replacing it with another drug of this class. Similar results might be expected if such actions had been taken against biperiden, implying that at least one-third of patients who were using anticholinergic antiparkinson drugs did not need them.
Competing interests
None declared.
The authors thank Solfrid Lilleeng, SINTEF, for assessing the number of patients in psychiatric hospitals in the years 2004 and 2007.
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