Can one of the following drugs (pramipexole, zolpidem, sertraline, diphenhydramine or cetirizine),

Fråga: Can one of the following drugs (pramipexole, zolpidem, sertraline, diphenhydramine or cetirizine), or the combination of them, cause amnesia, disorientation, and severe tremor in the legs?

A 37-year-old man has been treated with pramipexole (Sifrol/Mirapex) 0.125 mg x3 for restless legs. Due to insomnia he has used zolpidem (Stilnoct/Ambien) occasionally. The dose taken in Sweden was 10 mg and in the US 20 mg, according to differences in recommended doses between the countries. This medication was initiated two years ago. More recently the patient was also prescribed sertraline (Zoloft) 150 mg x1. He also suffers from allergy and has been taking over-the-counter medication diphenhydramine 50 mg and cetirizine (Accura) 10 mg daily during this spring.

After a severe attack of restless legs and sleep deprivation of more than 24 hours the patient took 20 mg zolpidem and has no recollection of the following 24 hours. During this time he has ordered pizza, watched a movie, e-mailed and called his girlfriend and talked in a very disoriented fashion. He also went to work where he was incapable of standing up due to severe tremor in the legs, seemed to be hallucinating, had severe transpiration and dysarthria. He was transported to the ER where he was observed for two hours. No tests were taken.

Sammanfattning: There is an obvious risk of pharmacodynamic interactions between all of the drugs acting on the central nervous system active drugs in the present case. Furthermore, pharmacokinetic interactions might oocur, especially with respect to the zolpidem concentration, which in combination with the higher zolpiden dose recommended in the US, could explain the occurrence of hallucinations, amnesia and neurological symptoms. All of the described reactions are known, if not usual adverse effects, of the drugs taken.

Svar: Pramipexole is a dopamin agonist with confusion and hallucinosis as common adverse effects (1,2). The patient also used several other drugs with central nervous system (CNS) effects and side effects. In the Swedish adverse drug reaction register there are 10 reports of adverse reactions to diphenhydramine, including one case of hallucinations, one of confusion and two of muscle cramps. Sertraline is a widely prescribed drug and there are 296 reports of adverse drug reactions that have been considered having a relation to the drug. Ten of these concerns tremor, 2 dyskinesia, 2 extrapyramidal disorder, 6 amnesia, 9 hallucinations, 7 confusion, 2 psychosis, and one depersonalization. Zolpidem is also widely prescribed and out of 182 reports, 35 deal with hallucination, 41 with confusion, and 35 with amnesia. Several of the patients with amnesia in these reports had behaved in a bizarre fashion during rather extended periods of time, if not as long as 24 hours (3).

Thus, amnesia, confusion, and hallucinosis are well known adverse reactions to some of these drugs in the present case. There are also several reported similar adverse events to all the drugs taken.

When several CNS active drugs are taken concomitantly there is always a high risk of pharmacodynamic interactions, which, however, cannot be easily predicted. There are reports of patients who experienced visual hallucinations 1-7 h after zolpidem, when taken concomitantly with different types of selective serotonine re-uptake inhibitors (SSRI) (6). In doses below 100 mg of zolpidem, intoxications are mild, but the effect can be potentiated in combination with CNS-depressing drugs, and among the symptoms that be expected are hallucinosis (1). In standard pharmacological literature, it is noted that zolpidem has been associated with delusions, short-duration hallucinations or impaired cognition, and that if used in combination with SSRIs, the outcome should be monitored (7).

Furthermore, there is also the possibility of pharmacokinetic interactions. Eg, zolpidem and sertraline are both metabolized by CYP3A4, one of the cytochrome P450 enzymes. In repeated doses, an increase in the maximum concentration of zolpidem has been noted when the two drugs are taken concomitantly (4,5).

There is a case report describing a woman who experienced an augmented effect of sertraline on concomitant medication with pramipexole (8). This is a single case and no therapeutic drug monitoring is presented in the report.

There is evidence that diphenhydramine inhibits CYP2D6 (9). In vitro studies indicate that CYP2D6 and CYP1A2 are involved in the biotransformation of zolpidem to its alcohol derivates, although their contribution is minor, compared to that of CYP3A4 (10). Sertraline is also a moderate CYP2D6 inhibitor (11). Thus, there is a theoretical risk of an interaction here too. FASS 2004 (The Swedish catalogue of approved medical products). Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999 Swedis (cited 2004-05-12) Allard S, Sainati SM, Roth-Schechter BF. Coadministration of short-term zolpidem with sertraline in healthy women. J Clin Pharmacol 1999;39:184-91. Sjöqvist F. Interaktion mellan läkemedel. In: FASS 2003 (The Swedish catalogue of approved medical products). Elko CJ, Burgess JL, Robertson WO. Zolpidem-associated hallucinations and serotonin reuptake inhibition: a possible interaction. J Toxicol Clin Toxicol 1998;36(3):195-203 Stockley IH. Drug interactions. 6th ed. London: The Pharmaceutical Press; 2002 DeBattista C, Solvason HB, Breen JA, Schatzberg AF. Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression. J Clin Psychopharmacol 2000;20(2):274-5. Lessard E, Yessine MA, Hamelin BA, Gauvin C, Labbe L, O´Hara G, et al. Diphenhydramine alters the disposition of venlafaxine through inhibition of CYP2D6 activity in humans. J Clin Psychopharmacol 2001;21(2):175-84. Pichard L, Gillet G, Bonfils C, Domergue J, Thenot JP, Maurel P. Oxidative metabolism of zolpidem by human liver cytochrome P450S. Drug Metab Dispos. 1995;23(11):1253-62. Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002;3(1):13-37.