Department of Psychology, University of Southampton, Southampton, UK.
Oxford Pain Relief Unit, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
Health Technol Assess. 2024 Oct;28(62):1-155. doi: 10.3310/MKRT2948.
Chronic pain is common and costly. Antidepressants are prescribed to reduce pain. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions, so effectiveness and safety for most antidepressants for pain conditions remain unknown.
To assess the efficacy and safety of antidepressants for chronic pain (except headache) in adults. Our primary outcomes were as follows: substantial pain relief (50%), pain intensity, mood and adverse events. Our secondary outcomes were as follows: moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change, serious adverse events and withdrawal.
This was a systematic review with a network meta-analysis. We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials of antidepressants for chronic pain conditions up until 4 January 2022. The review was registered in PROSPERO (CRD42020171855), and the protocol was published in the Cochrane Library (https://doi.org/10.1002/14651858.CD014682).
We analysed trials from all settings.
We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache.
We included all antidepressants.
Our primary outcome was substantial pain relief, defined as a reduction ˃ 50%. We also measured pain intensity, mood and adverse events. Secondary measures included moderate pain relief (above 30% reduction), physical function, sleep, quality of life, Global Impression of Change, serious adverse events, and withdrawal from trial.
We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled ( = 83) and parallel armed ( = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of randomised controlled trials was 10 weeks. Most studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. Standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that for duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain.
The evidence for antidepressants other than duloxetine is poor. For duloxetine, it is not clear whether the effect applies to groups with both pain and low mood, since these groups were excluded from trials. There is also insufficient evidence on long-term outcomes and on adverse effects.
There is only reliable evidence for duloxetine in the treatment of chronic pain. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Data for all other antidepressants were of low certainty. However, the findings should not be read as an encouragement to prescribe antidepressants where other non-pharmacological intervention could be equally effective, especially in the absence of good evidence on side effects and safety.
There is a need for large, methodologically sound trials testing the effectiveness of antidepressants for chronic pain. These trials should examine long-term outcomes (> 6 months) and include people with low mood. There should also be better reporting of adverse events, tolerance of drugs, and long-term compliance.
This study is registered as PROSPERO CRD42020171855.
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR128782) and is published in full in ; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.
慢性疼痛很常见，也很昂贵。医生会开抗抑郁药来减轻疼痛。但是，还没有对所有慢性疼痛进行网络荟萃分析，因此大多数抗抑郁药治疗疼痛的疗效和安全性仍不清楚。
评估抗抑郁药治疗成人慢性疼痛（头痛除外）的疗效和安全性。我们的主要结局如下：明显缓解疼痛（50%）、疼痛强度、情绪和不良事件。我们的次要结局如下：中度缓解疼痛（30%）、身体功能、睡眠、生活质量、患者总体印象变化、严重不良事件和停药。
这是一项系统评价和网络荟萃分析。我们检索了 CENTRAL、MEDLINE、EMBASE、CINAHL、LILACS、AMED 和 PsycINFO 数据库，以获取截至 2022 年 1 月 4 日治疗慢性疼痛的抗抑郁药随机对照试验。该综述在 PROSPERO（CRD42020171855）中进行了注册，并在 Cochrane Library 上发布了方案（https://doi.org/10.1002/14651858.CD014682）。
我们分析了来自所有环境的试验。
我们纳入了有慢性疼痛的参与者，定义为疼痛持续时间超过 3 个月，且疼痛来自任何疾病，但不包括头痛。
我们纳入了所有的抗抑郁药。
我们的主要结局是明显缓解疼痛，定义为疼痛减轻超过 50%。我们还测量了疼痛强度、情绪和不良事件。次要结局包括中度缓解疼痛（疼痛减轻超过 30%）、身体功能、睡眠、生活质量、总体印象变化、严重不良事件和退出试验。
我们确定了 176 项研究，共涉及 28664 名参与者。大多数研究为安慰剂对照（=83）和平行分组（=141）。研究中最常见的疼痛疾病包括纤维肌痛（59 项研究）、神经病理性疼痛（49 项研究）和肌肉骨骼疼痛（40 项研究）。随机对照试验的平均长度为 10 周。大多数研究仅测量短期结局，且排除了情绪低落和其他心理健康状况的参与者。在疗效结局方面，度洛西汀始终是最有效的抗抑郁药，具有中高度确定性证据。标准剂量与大多数结局的高剂量同样有效。米那普仑常被列为下一个最有效的抗抑郁药，但证据的确定性低于度洛西汀。对于慢性疼痛的任何其他抗抑郁药的疗效和安全性，都没有足够的证据来得出可靠的结论。
除了度洛西汀之外，其他抗抑郁药的证据质量较差。对于度洛西汀，由于试验排除了既有疼痛又有情绪低落的人群，因此尚不清楚其疗效是否适用于这些人群。此外，关于长期结局和不良反应的证据也不足。
只有度洛西汀在慢性疼痛治疗方面有可靠的证据。度洛西汀在标准剂量下对所有结局均有中度疗效。米那普仑也有有前景的证据，但需要更多高质量的研究来确认这些结论。所有其他抗抑郁药的数据确定性都较低。然而，这些发现不应被视为鼓励在可能同样有效的非药物干预措施缺乏良好的副作用和安全性证据的情况下开抗抑郁药处方。
需要进行大型、方法学严谨的试验，以测试抗抑郁药治疗慢性疼痛的有效性。这些试验应检测长期结局（>6 个月），并包括情绪低落的人群。还应更好地报告不良事件、药物耐受性和长期依从性。
本研究在 PROSPERO 中注册为 CRD42020171855。
该奖项由英国国家卫生与保健优化研究所（NIHR）卫生技术评估计划（NIHR 奖 REF：NIHR128782）资助，并全文发表在；第 28 卷，第 62 期。欲了解更多有关该奖项的信息，请访问 NIHR 资助和奖项网站。
