Gabapentinoid Benefit and Risk Stratification: Mechanisms Over Myth.
Gabapentinoid Benefit and Risk Stratification: Mechanisms Over Myth.
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DOI：
10.1007/s40122-020-00189-x
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发表时间：
2020-12
期刊：
影响因子：
4
通讯作者：
Kaye AD
中科院分区：
文献类型：
--
作者：
McAnally H;Bonnet U;Kaye AD
近年来，加巴喷丁和普瑞巴林（加巴喷丁类药物）的标签外处方急剧增加，部分原因是过去二十年中每种药物的仿制药上市，部分原因是对多模式和非阿片类疼痛管理策略的呼声日益高涨。在这种背景下，最近发表的几篇文章声称存在广泛的滥用，并对加巴喷丁类药物未被认识到的成瘾潜力进行了猜测。英国的一项互联网调查显示，人口水平的滥用发生率为 1%，而极其微小的不良事件结果数据并不支持这样的频率。在这篇有针对性的叙述性综述中，我们的目的是消除疼痛医生和其他临床医生、药剂师和政策制定者对加巴喷丁类药物的正面和负面神话。加巴喷丁类药物抑制电压门控钙通道 (VGCC) α2δ 亚基与 n-甲基-d-天冬氨酸 (NMDA) 受体的联合作用，随后通过作用于血小板反应蛋白，下调 VGCC 表达和兴奋性神经递质释放，并可能导致突触发生。这些活动降低了中枢敏化的可能性，这部分解释了加巴喷丁类药物在治疗神经性疼痛中的功效。加巴喷丁类药物还可以促进慢波睡眠，这是中枢神经系统作用药物中相对罕见的现象，这也被认为解释了该类药物在纤维肌痛等疾病中的一些治疗益处。需要治疗才能看到疗效的人数与非甾体抗炎药的人数重叠，但安全性显着提高。沿着这些思路，仅在美国每年就有超过 5000 万张处方，加巴喷丁类药物的风险非常低，包括误用、滥用和依赖的风险。此外，这些药物的神经生物学并没有为这些指控提供合理性，因为它们从未被证明能够在伏隔核内引发多巴胺能活性，此外，它们还可能通过充当功能性 NMDA 拮抗剂（可能是通过它们对血小板反应蛋白的作用）来赋予习惯和依赖性的“负反馈循环”。临床和流行病学成瘾学研究证实加巴喷丁类药物缺乏任何显着的成瘾潜力，并且这些药物越来越多地用于治疗对其他物质的成瘾，效果极佳，并且没有交叉成瘾的证据。然而，在患有其他物质使用障碍，特别是阿片类药物使用障碍的个体中，一致的数据显示，高达 20% 的人群滥用加巴喷丁类药物。尽管有人指控使用加巴喷丁类药物来放大阿片类药物的快感效果，但绝大多数滥用事件似乎是为了改善阿片类药物戒断症状而发生的。此外，可能会发生罕见但可能严重的呼吸抑制，在使用阿片类药物或其他镇静剂的情况下再次加剧。谨慎的风险：在考虑开加巴喷丁类药物时，特别是在使用阿片类药物的个体中，需要进行效益评估和分层。加巴喷丁类药物仍然是疼痛医师多模式治疗中的重要工具，但这些药物可能并非对每种临床情况都有效。患有中枢敏感度和与慢波睡眠缺陷相关的疼痛的人以及可能患有共病成瘾的人可能受益最多。根据实验室和临床数据，加巴喷丁类药物本身似乎不具有成瘾潜力，但阿片类药物使用障碍患者可能会滥用它们；因此，必须进行谨慎的风险分层。
Recent years have seen a dramatic escalation of off-label prescribing for gabapentin and pregabalin (gabapentinoids) owing in part to generic versions of each being released over the past two decades, but also in part as a response to increasing calls for multimodal and non-opioid pain management strategies. In this context, several recent articles have been published alleging widespread misuse, with speculations on the unappreciated addictive potential of the gabapentinoid class of drugs. Reports of a 1% population-level abuse prevalence stem from a single internet survey in the UK, and the vanishingly small adverse event outcomes data do not support such frequency. In this targeted narrative review, we aim to disabuse pain physicians and other clinicians, pharmacists, and policymakers of both the positive and negative myths concerning gabapentinoid medications. Gabapentinoids inhibit the joint action of voltage-gated calcium channel (VGCC) α2δ subunits in conjunction with the n-methyl-d-aspartate (NMDA) receptor, with subsequent downregulation of VGCC expression and excitatory neurotransmitter release, and possibly synaptogenesis as well, through actions on thrombospondins. These activities reduce the likelihood of central sensitization, which explains in part the efficacy of the gabapentinoids in the management of neuropathic pain. Gabapentinoids also facilitate slow-wave sleep, a relatively rare phenomenon among central nerve system-acting agents, which is also thought to explain some of the therapeutic benefit of the class in conditions such as fibromyalgia. The number needed to treat to see benefit overlaps that of the nonsteroidal anti-inflammatory drugs, but with a considerably improved safety profile. Along these lines, in the context of over 50 million prescriptions per year in the USA alone, the gabapentinoids display remarkably low risk, including risks of misuse, abuse, and dependence. Furthermore, the neurobiology of these agents does not lend plausibility to the allegations, as they have never been shown to elicit dopaminergic activity within the nucleus accumbens, and in addition likely confer a "negative-feedback loop" for habituation and dependence by serving as functional NMDA antagonists, possibly through their actions on thrombospondins. Clinical and epidemiological addictionology studies corroborate the lack of any significant addictive potential of the gabapentinoids, and these drugs are increasingly being used in the treatment of addiction to other substances, with excellent results and no evidence of cross-addiction. However, among individuals with other substance use disorders and, in particular opioid use disorder, there are consistent data showing misuse of gabapentinoids in up to 20% of this population. Although there are allegations of using gabapentinoids to amplify the hedonic effects of opioids, the vast majority of misuse events appear to occur in an attempt to ameliorate opioid withdrawal symptoms. Furthermore, rare but potentially serious respiratory depression may occur, again amplified in the context of opioid or other sedative use. Careful risk:benefit assessment and stratification are warranted when prescription of a gabapentinoid is under consideration, in particular among individuals using opioids. Gabapentinoids remain a vital tool in the pain physician’s multimodal armamentarium, but these drugs may not be effective in every clinical situation. Individuals with central sensitization and pain associated with slow-wave sleep deficits and potentially persons with comorbid addictions may benefit the most. The gabapentinoids appear to possess no addictive potential on their own, based on laboratory and clinical data, but they may be abused by persons with opioid use disorders; consequently, cautious risk stratification must take place.
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影响因子：
5.3
作者：
Eller-Smith OC;Nicol AL;Christianson JA
通讯作者：
Christianson JA
影响因子：
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作者：
Dolphin, Annette C
通讯作者：
Dolphin, Annette C
影响因子：
5.1
作者：
Attal, N.;Cruccu, G.;Nurmikko, T.
通讯作者：
Nurmikko, T.
DOI：
10.1016/j.sapharm.2018.06.018
发表时间：
2019-08-01
影响因子：
3.9
作者：
Evoy, Kirk E.;Covvey, Jordan R.;Hultgren, Kyle E.
通讯作者：
Hultgren, Kyle E.
影响因子：
8.8
作者：
Chen J;Li L;Chen SR;Chen H;Xie JD;Sirrieh RE;MacLean DM;Zhang Y;Zhou MH;Jayaraman V;Pan HL
通讯作者：
Pan HL