A randomised, placebo-controlled study comparing two formulations of dimenhydrinate with respect to efficacy in motion sickness and sedation.
It is known that sedation by H1 antihistaminic drugs can be reduced or avoided if slow release formulations are used for their administration, probably because of a slower increase of the drug concentration in plasma and brain. The aim of this study was to compare two different formulations of dimenhydrinate (CAS 523-87-5), a single fast release tablet with three chewing gums (divided dose principle), with regard to their efficacy in a motion sickness model and their detrimental effect on vigilance and central nervous system (CNS) performance. Caloric stimulation of the eardrum (air at 44 degrees C) was used to induce the symptoms of motion sickness in 24 symptomatic volunteers in a three-way cross-over design comparing three chewing gums (Superpep forte, chewed for 30 min each) containing 20 mg dimenthydrinate each with a 50 mg dimenhydrinate tablet and placebo. During caloric stimulation the following parameters were measured in order to compare efficacy: Quantitative analysis of sodium excretion by sweat (main target parameter), subjective well being (vertigo) by visual analogue scales (VAS) and frequency of binocular nystagmus by computer nystagmography. Unwanted effects on vigilance and CNS performance were measured by means of the N1-P2 peak to peak amplitudes of auditory evoked potentials (AEPs) as an objective, quantitative parameter of vigilance and the latency to correct responses and the number of correct responses (complex choice reaction task) in the oculodynamic test (ODT) as parameters of complex choice reaction ability. As a main efficacy result sodium excretion by sweat was markedly reduced by the chewing gums and by the tablet. The differences to placebo were highly significant (chewing gums vs. placebo p < 0.0001, tablet vs. placebo p < 0.0001). There was no relevant and no significant difference between both medications (p = 0.308). The secondary efficacy parameters, frequency of binocular nystagm and the VAS vertigo were markedly reduced by both medications in comparison to placebo, i.e. both medications were markedly effective. In both cases, however, this result failed statistical significance. The unwanted depressing effects on vigilance and CNS performance of the chewing gums were less pronounced than that of tablets. The N1/P2 peak-to-peak amplitudes of the AEPs were significantly reduced by both the chewing gums and the tablets. The effect of the tablets was, however, larger than that of the chewing gums. This highly significant (tablet vs. chewing gums, p = 0.0003) difference shows that the tablet had a larger depressing effect on vigilance (greater sedation). In line with this result, the number of correct responses in the ODT was markedly and significantly reduced by the tablet (p = 0.0027) but not significantly by the chewing gums (p = 0.8140). The difference between the tablet and the chewing gums was highly significant (p = 0.0052). The complex choice reaction time was markedly and nearly significantly (p = 0.0558) prolonged by the tablet whereas the chewing gums produced only a very small and insignificant prolongation. That the objective measurements of vigilance and CNS performance showed significantly larger detrimental effects of the tablet than of the chewing gums is probably a consequence of a faster increase of the dimenhydrinate concentration in the CNS after administration of the tablet in comparison to the divided dose principle of the chewing gums.
Seibel
Klaus
K
HPR-Human Pharmacodynamic Research, Schaffer & Seibel GmbH, Munich, Germany. HPR.Pharmacodynamics@t-online.de
Schaffler
Klaus
K
Reitmeir
Peter
P
Golly
Ines
I
D000932:Antiemetics / Q000009:adverse effects / Q000627:therapeutic use*; D001143:Arousal / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D002638:Chewing Gum; D018592:Cross-Over Studies; D004111:Dimenhydrinate / Q000009:adverse effects / Q000627:therapeutic use*; D005072:Evoked Potentials, Auditory / Q000187:drug effects; D005260:Female; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008875:Middle Aged; D009041:Motion Sickness / Q000188:drug therapy*; D009760:Nystagmus, Physiologic / Q000187:drug effects; D009801:Oculomotor Muscles / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects; D012964:Sodium / Q000378:metabolism; D013546:Sweating / Q000187:drug effects; D013607:Tablets
D000932:Antiemetics; D002638:Chewing Gum; D006634:Histamine H1 Antagonists; D013607:Tablets; D012964:Sodium; D004111:Dimenhydrinate