Richardson Gary S, Roehrs Timothy A, Rosenthal Leon, Koshorek Gail, Roth Thomas
Sleep Disorders Clinic and Research Center, Henry Ford Hospital, Detroit, Michigan 48202, USA.
J Clin Psychopharmacol. 2002 Oct;22(5):511-5. doi: 10.1097/00004714-200210000-00012.
Sedation is the principal side effect of first generation H1 antihistamines, and recent studies have suggested that this side effect should limit the clinical application of these drugs. The sedative effect also underlies the use of these first-generation drugs as nonprescriptive remedies for insomnia. In both cases, the potential for tolerance to the sedative effect of these drugs is an important issue for which there are few objective data. In the study reported here, 15 healthy men age 18 to 50 years received either diphenhydramine 50 mg or placebo twice a day for 4 days in a randomized, double-blind, crossover trial design. Dependent measures included objective and subjective assessments of sleepiness and computer-based tests of psychomotor performance. Both objective and subjective measures of sleepiness showed significantly higher levels on day 1 for diphenhydramine compared to placebo. By day 4, however, levels of sleepiness on diphenhydramine were indistinguishable from placebo. Similarly, diphenhydramine produced significant impairment of performance that was completely reversed by day 4. These data provide the first objective confirmation that tolerance develops to the sedative effect of a prototypical first-generation H1 antihistamine, diphenhydramine. On this dosing regimen, tolerance was complete by the end of 3 days of administration. While other antihistamines and dosing regimens may differ, these results suggest that tolerance to the sedation produced by these drugs develops with remarkable rapidity.
镇静是第一代H1抗组胺药的主要副作用，最近的研究表明，这种副作用应限制这些药物的临床应用。镇静作用也是这些第一代药物被用作非处方失眠治疗药物的基础。在这两种情况下，对这些药物镇静作用产生耐受性的可能性都是一个重要问题，而关于这方面的客观数据很少。在本文报道的研究中，15名年龄在18至50岁之间的健康男性，在一项随机、双盲、交叉试验设计中，每天两次服用50毫克苯海拉明或安慰剂，持续4天。相关测量包括对嗜睡的客观和主观评估以及基于计算机的精神运动表现测试。与安慰剂相比，苯海拉明组在第1天的嗜睡客观和主观测量结果均显著更高。然而，到第4天，苯海拉明组的嗜睡水平与安慰剂组没有区别。同样，苯海拉明导致的表现显著受损在第4天完全逆转。这些数据首次提供了客观证实，即对典型的第一代H1抗组胺药苯海拉明的镇静作用会产生耐受性。按照这种给药方案，在给药3天结束时耐受性已完全形成。虽然其他抗组胺药和给药方案可能有所不同，但这些结果表明，对这些药物产生的镇静作用的耐受性发展得非常迅速。
