Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study.
Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study.
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DOI：
10.1371/journal.pmed.1002396
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发表时间：
2017-10
期刊：
影响因子：
15.8
通讯作者：
van den Brink W
中科院分区：
文献类型：
--
作者：
Gomes T;Juurlink DN;Antoniou T;Mamdani MM;Paterson JM;van den Brink W
处方阿片类药物使用与阿片类药物相关死亡风险高度相关，每550名慢性阿片类药物使用者中就有1人在首次服用阿片类药物后约2.5年内死亡。虽然加巴喷丁被广泛认为是安全的，但当加巴喷丁单独使用或与其他药物联合使用时，药物性呼吸抑制已被描述。由于加巴喷丁和阿片类药物都是治疗疼痛的常用处方，因此联合处方的可能性很高。然而，没有发表的研究调查了加巴喷丁治疗是否与接受阿片类药物治疗的患者意外阿片类药物相关死亡的风险增加有关。本研究的目的是调查阿片类药物和加巴喷丁的联合处方是否与阿片类药物相关的意外死亡风险增加有关。我们对1997年8月1日至2013年12月31日期间居住在加拿大安大略省的阿片类药物使用者进行了一项基于人群的巢式病例对照研究，使用管理数据库。定义为阿片类药物使用者死于阿片类药物相关原因的病例，与多达4名也使用阿片类药物的对照者在年龄、性别、索引日期年份、慢性肾脏疾病史和疾病风险指数方面进行匹配。匹配后，我们纳入了1,256例病例和4,619个对照。主要暴露是在指数日期前120天内同时使用加巴喷丁。另一项分析将加巴喷丁的剂量分为低（<900 mg /天）、中（900 - 1799 mg /天）和高（≥1800 mg /天）。敏感性分析检查了在前120天内同时使用非甾体抗炎药（NSAID）的效果。总体而言，12.3%的病例（1,256例中的155例）和6.8%的对照（4,619例中的313例）在之前的120天内开了加巴喷丁。多变量校正后，阿片类药物和加巴喷丁联合处方与阿片类药物相关死亡的几率显著增加相关（比值比[OR] 1.99, 95% CI 1.61 ~ 2.47, p < 0.001；校正后比值比[aOR] 1.49, 95% CI 1.18 ~ 1.88, p < 0.001）。在剂量-反应分析中，中剂量（OR 2.05, 95% CI 1.46至2.87,p < 0.001; aOR 1.56, 95% CI 1.06至2.28,p = 0.024）和高剂量（OR 2.20, 95% CI 1.58至3.08,p < 0.001; aOR 1.58, 95% CI 1.09至2.27,p = 0.015）加巴喷丁的使用与不同时使用加巴喷丁相比，阿片类药物相关死亡的几率增加了近60%。正如预期的那样，我们发现阿片类药物和非甾体抗炎药联合处方与阿片类药物相关死亡之间没有显著关联（OR 1.11, 95% CI 0.98至1.27,p = 0.113; OR 1.14, 95% CI 0.98至1.32,p = 0.083）。在一项对阿片类药物和加巴喷丁联合使用风险患者的探索性分析中，我们发现2013年使用加巴喷丁的患者中有46.0%（98,288人中有45,173人）至少同时服用过一种阿片类药物。这项研究仅限于安大略省有资格享受公共药物覆盖的个人，我们只能确定由政府报销和零售药店分发的处方，并且没有关于加巴喷丁使用适应症的信息。此外，与所有观察性研究一样，由于未测量变量引起的混淆是偏见的潜在来源。在这项研究中，我们发现在接受处方阿片类药物的患者中，加巴喷丁的联合治疗与阿片类药物相关死亡风险的大幅增加有关。临床医生应仔细考虑是否继续使用这种联合用药，当认为有必要联合用药时，应密切监测患者并相应地调整阿片类药物剂量。未来的研究应该调查普瑞巴林和阿片类药物之间是否存在类似的相互作用。在一项匹配的病例对照研究中，在加拿大安大略省接受阿片类止痛药治疗的患者中，Tara Gomes及其同事调查了加巴喷丁的联合处方是否与阿片类药物相关的意外死亡风险增加有关。加巴喷丁通常与阿片类药物一起用于治疗慢性疼痛，这两种药物都被证明会抑制呼吸，这可能是致命的。同时使用阿片类药物也会增加人体对加巴喷丁的吸收量，当这些药物一起使用时，可能会导致更高的风险。尽管存在这些潜在风险，但迄今为止还没有研究证实加巴喷丁和阿片类药物的同时使用是否真的会增加阿片类药物相关意外死亡的可能性，以及这种风险是否依赖于加巴喷丁的剂量。如果这些药物之间存在重要的相互作用，考虑到这些药物的常见联合使用，这将具有很高的临床重要性。我们在加拿大人口最多的省份安大略省接受阿片类止痛药治疗的人群中进行了一项匹配的病例对照研究。我们在1,256例死于阿片类药物相关原因的个体（病例）和4,619例匹配对照中确定了加巴喷丁的伴随暴露。我们发现，同时服用加巴喷丁和阿片类药物与阿片类药物过量死亡的风险增加49%相关。临床医生在联合使用加巴喷丁和阿片类药物时应非常谨慎。接受阿片类药物和加巴喷丁治疗的患者应密切监测，并可能需要调整剂量以避免潜在的药物过量。
Prescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality. We conducted a population-based nested case–control study among opioid users who were residents of Ontario, Canada, between August 1, 1997, and December 31, 2013, using administrative databases. Cases, defined as opioid users who died of an opioid-related cause, were matched with up to 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily). A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256) and 6.8% of controls (313 of 4,619) were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio [OR] 1.99, 95% CI 1.61 to 2.47, p < 0.001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p < 0.001) compared to opioid prescription alone. In the dose–response analysis, moderate-dose (OR 2.05, 95% CI 1.46 to 2.87, p < 0.001; aOR 1.56, 95% CI 1.06 to 2.28, p = 0.024) and high-dose (OR 2.20, 95% CI 1.58 to 3.08, p < 0.001; aOR 1.58, 95% CI 1.09 to 2.27, p = 0.015) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death relative to no concomitant gabapentin use. As expected, we found no significant association between co-prescription of opioids and NSAIDs and opioid-related death (OR 1.11, 95% CI 0.98 to 1.27, p = 0.113; aOR 1.14, 95% CI 0.98 to 1.32, p = 0.083). In an exploratory analysis of patients at risk of combined opioid and gabapentin use, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least 1 concomitant prescription for an opioid. This study was limited to individuals eligible for public drug coverage in Ontario, we were only able to identify prescriptions reimbursed by the government and dispensed from retail pharmacies, and information on indication for gabapentin use was not available. Furthermore, as with all observational studies, confounding due to unmeasured variables is a potential source of bias. In this study we found that among patients receiving prescription opioids, concomitant treatment with gabapentin was associated with a substantial increase in the risk of opioid-related death. Clinicians should consider carefully whether to continue prescribing this combination of products and, when the combination is deemed necessary, should closely monitor their patients and adjust opioid dose accordingly. Future research should investigate whether a similar interaction exists between pregabalin and opioids. In a matched case-control-study among patients in Ontario, Canada treated with opioid painkillers, Tara Gomes and colleagues investigate whether co-prescription of gabapentin is associated with an increased risk of accidental opioid-related death. Gabapentin is a drug often used together with opioids to treat chronic pain, and both of these drugs have been shown to suppress breathing, which can be fatal. Concomitant opioid use can also increase the amount of gabapentin absorbed by the body, potentially leading to higher risks when these drugs are used together. Despite these potential risks, so far no studies have examined whether the concomitant use of gabapentin and opioids really increases the likelihood of accidental opioid-related death and whether this risk is dependent on gabapentin dose. If there is an important interaction between these drugs, this would be of high clinical importance given the common combined use of these drugs. We conducted a matched case–control study among people treated with opioid painkillers in Ontario, the most populous province of Canada. We determined concomitant gabapentin exposure among 1,256 individuals (cases) who died of an opioid-related cause and 4,619 matched controls. We found that concomitant gabapentin and opioid exposure was associated with a 49% higher risk of dying from an opioid overdose. Clinicians should take great caution when combining gabapentin and opioids. Patients treated with opioids and gabapentin should be closely monitored, and may need to have their doses adjusted to avoid potential drug overdose.
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影响因子：
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