Health Technology Assessment (Oct 2024)
Antidepressants for pain management in adults with chronic pain: a network meta-analysis
Abstract
Background 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. Objective 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. Design 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). Setting We analysed trials from all settings. Participants We included trials in which participants had chronic pain, defined as longer than 3 months, from any condition excluding headache. Interventions We included all antidepressants. Main outcome measures 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. Results We identified 176 studies with a total of 28,664 participants. Most studies were placebo-controlled (n = 83) and parallel armed (n = 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. Limitations 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. Conclusions 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. Future work 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. Study registration This study is registered as PROSPERO CRD42020171855. Funding 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 Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? Chronic pain is pain that lasts for more than 3 months. Over one-third of people across the world experience chronic pain. This often has a detrimental impact on people’s mood, disability and well-being. Antidepressants are often prescribed to reduce pain, but we are not sure which antidepressants work best for different types of pain, or whether they are safe. We wanted to find out whether antidepressants were effective and safe for management of chronic pain. What did we do? We searched for studies that had compared any antidepressant with any other treatment for any type of chronic pain (except headache). We compared all the treatments against each other using a statistical method called network meta-analysis. This method allows us to rank the treatments in order of best to worst for each outcome. What did we find? We found 176 studies that included a total of 28,664 people with chronic pain. Most of the studies (83/176) compared an antidepressant with a placebo (which looks like the real medicine but does not have any medicine in it). The evidence from our analysis suggests that: Duloxetine is the antidepressant that we have the most confidence in. It was the best antidepressant for reducing pain and improving physical function. A standard dose of duloxetine was equally as effective for reducing pain as a high dose of duloxetine. Milnacipran was also effective at reducing pain, but we are not as confident in this result as in the one for duloxetine because there were fewer studies with fewer people involved. Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review, and even for duloxetine and milnacipran, we do not know the long-term effects. It is important to recognise that the lack of evidence for the majority of antidepressants in this review does not necessarily equal a lack of benefit. Rather, this means that the large, high-quality trials required for us to be certain of an antidepressant’s effectiveness have not been undertaken. Altogether, although duloxetine and milnacipran are effective, the results of this review 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. These conclusions were informed by our patient and public involvement group. Scientific summary Background Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients’ global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis examining all antidepressants across all chronic pain conditions. Objectives Our objective was 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 (PGIC), serious adverse events and withdrawal. Search methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, LILACS, AMED and PsycINFO databases for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions up until 4 January 2022. Selection criteria We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant or the same antidepressant at different doses, then the study was required to be double-blind. RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) were included but rated as at high risk of bias. We excluded RCTs where the follow-up was < 2 weeks and those with < 10 participants in each trial arm. We included any antidepressant at any dose, for any indication but used primarily for treatment of people with chronic pain and compared to placebo or active intervention. Participants We included adults (aged 18 years or older) reporting primary or secondary pain in any part of their body (except headache) as their primary complaint, that matched the International Association for the Study of Pain definition of chronic pain (i.e. at least 3 months’ duration). We included all trials regardless of the severity of participants’ chronic pain, although we extracted whether severity was part of the inclusion criteria of the individual studies. We excluded studies where the participants’ primary pain condition was headache or migraine. Data collection and analysis Two authors separately screened, extracted data and judged risk of bias. We synthesised the data using Bayesian network meta-analysis (NMA) and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve. We primarily used the Confidence in Network Meta-Analysis (CINeMA) framework and ‘Risk Of Bias due to Missing Evidence in Network meta-analysis’ (ROB-MEN) tool to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used Grading of Recommendations, Assessment, Development and Evaluations (GRADE) to assess the certainty of the evidence. Main results This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (n = 83) and parallel-armed (n = 141). The most common pain conditions examined were fibromyalgia (59 studies), neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks; seven studies provided no useable data and were omitted from the NMAs. The majority of 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. In duloxetine trials, 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 of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes For pain relief, duloxetine standard dose showed a small to moderate effect for substantial pain relief [odds ratio 0.91, 95% confidence interval (CI) 0.56 to 0.84] and continuous pain intensity [standardised mean difference (SMD) −0.31, 95% CI −0.39 to −0.24]. For pain intensity, milnacipran standard dose also showed a small effect (SMD −0.22, 95% CI −0.39 to 0.06) with moderate-certainty evidence. For mood, mirtazapine had a moderate effect (SMD −0.5, 95% CI −0.78 to −0.22), while duloxetine showed a small effect (−0.16, 95% CI −0.22 to −0.1); however, it is important to note that most trials excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the ‘normal’ or ‘subclinical’ ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were equally as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. Authors’ conclusions Our review and NMAs show that despite studies investigating 25 different antidepressants, there is reliable evidence for only 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. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy and safety of any antidepressant. Study registration This study is registered as PROSPERO CRD42020171855. Funding 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 Health Technology Assessment; Vol. 28, No. 62. See the NIHR Funding and Awards website for further award information.
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