Abstract

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 (NMA) examining all antidepressants across all chronic pain conditions.

Objectives

To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache).

Search methods

We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in 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 we required the study to be double‐blind. We included RCTs with active comparators that were unable to be double‐blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow‐up was less than two weeks and those with fewer than 10 participants in each arm. 

Data collection and analysis

Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian 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 (SUCRA). We primarily used Confidence in Meta‐Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta‐analysis (ROB‐MEN) 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 GRADE to assess the certainty of the evidence.

Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal.

Main results

This review and NMA included 176 studies with a total of 28,664 participants. The majority of 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 RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. 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 studies, 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

Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate‐certainty evidence) and continuous pain intensity (standardised mean difference (SMD) −0.31, 95% CI −0.39 to −0.24; 18 studies, 4959 participants; moderate‐certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD −0.22, 95% CI −0.39 to 0.06; 4 studies, 1866 participants; moderate‐certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD −0.5, 95% CI −0.78 to −0.22; 1 study, 406 participants; low‐certainty evidence), while duloxetine showed a small effect (SMD −0.16, 95% CI −0.22 to −0.1; 26 studies, 7952 participants; moderate‐certainty evidence); however it is important to note that most studies 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 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, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. 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. Evidence for all other antidepressants was 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 of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point. 

Author(s)

Hollie Birkinshaw, Claire M Friedrich, Peter Cole, Christopher Eccleston, Marc Serfaty, Gavin Stewart, Simon White, R Andrew Moore, David Phillippo, Tamar Pincus

Abstract

Plain language summary

How effective are antidepressants used to treat chronic pain and do they cause unwanted effects?

Key messages

• We are only confident in the effectiveness of one antidepressant: duloxetine. We found that a standard dose (60 mg) was effective, and that there is no benefit to using a higher dose.

• We are uncertain about unwanted effects for any antidepressant as the data for this were very poor. Future research should address this.

• In clinical practice for chronic pain, a standard dose of duloxetine may be considered before trying other antidepressants.

• Adopting a person‐centred approach is critical. Pain is a very individual experience and certain medications may work for people even while the research evidence is inconclusive or unavailable. Future studies should last longer and focus on unwanted effects of antidepressants.

What is chronic pain?

Chronic pain is pain of any kind that lasts for more than three months. Over one‐third of people across the world experience chronic pain. This often affects people's mood and well‐being, and their ability to work and carry out daily tasks.

How do antidepressants treat chronic pain?

Antidepressants are medications originally developed to treat depression. Different types of antidepressants work in different ways. Antidepressants that work in the same way are grouped into classes. The most common classes are selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and serotonin‐noradrenalin reuptake inhibitors (SNRIs). Research suggests that antidepressants may be effective for pain because the same chemicals that affect mood might also affect pain.

What did we want to find out?

We wanted to find out if antidepressants were effective for managing chronic pain and whether they cause unwanted effects.

What did we do?

We searched for studies that 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 effectiveness of the different antidepressants from best to worst.

What did we find?

We found 176 studies including 28,664 people with chronic pain. These studies investigated 89 different types or combinations of treatment. Studies mainly investigated the effect of antidepressants on three different types of pain: fibromyalgia (59 studies), nerve pain (49 studies), and musculoskeletal pain (e.g. osteoarthritis or low back pain; 40 studies). The most common antidepressant classes investigated were SNRIs (74 studies), TCAs (72 studies), and SSRIs (34 studies). The most common antidepressants investigated were: amitriptyline (a TCA; 43 studies); duloxetine (an SNRI; 43 studies), and milnacipran (an SNRI; 18 studies). Of the 146 studies that reported where their funding came from, pharmaceutical companies funded 72 studies. The average study lasted 10 weeks. 

Most of the studies compared an antidepressant with a placebo (which looks like the real medicine but doesn’t have any medicine in it), but some studies compared an antidepressant against a different type of medicine, a different antidepressant, a different type of treatment (like physiotherapy), or different doses of the same antidepressant.

Most of the studies in this review reported information on pain relief and unwanted effects. Fewer studies reported on quality of life, sleep, and physical function. 

Main results

• Duloxetine probably has a moderate effect on reducing pain and improving physical function. It was the antidepressant that we have the most confidence in. Higher doses of duloxetine probably provided no extra benefits than standard doses. For every 1000 people taking standard‐dose duloxetine, 435 will experience 50% pain relief compared with 287 who will experience 50% pain relief taking placebo. 

• Milnacipran may reduce pain, but we are not as confident in this result as duloxetine because there were fewer studies with fewer people involved. 

• Most studies excluded people with mental health conditions, meaning that participants were already in the 'normal' ranges for anxiety and depression at the beginning of studies. This limited our analysis for mood. Mirtazapine and duloxetine may improve mood, but we are very uncertain about the results.

• We do not know about unwanted effects of using antidepressants for chronic pain; there are not enough data to be certain about the results.

What are the limitations of the evidence?

There are still a number of questions that we were unable to answer:

• Aside from duloxetine and milnacipran, we do not have confidence in the results from any other antidepressant included in this review because there are not enough studies.

• We do not know whether antidepressants are effective at treating pain in the long term. The average length of studies was 10 weeks.

• There was no reliable evidence on the safety of taking antidepressants for chronic pain, both short‐ and long‐term.

• We do not know how effective antidepressants are for people with both chronic pain and depression as the most studies excluded participants with depression and anxiety.

How up to date is this evidence?

This review is up to date to January 2022.

Author(s)

Hollie Birkinshaw, Claire M Friedrich, Peter Cole, Christopher Eccleston, Marc Serfaty, Gavin Stewart, Simon White, R Andrew Moore, David Phillippo, Tamar Pincus

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

For people with chronic pain

Research from randomised controlled trials suggests that duloxetine is more effective than other antidepressants (including amitriptyline) for management of chronic pain. For people with chronic pain considering trying an antidepressant for pain relief, it may be worth trying duloxetine first before other antidepressants. However, it is important to acknowledge that there is no 'one size fits all' with both antidepressants and pain. Adopting a person‐centred approach is critical. 

For clinicians

Amitriptyline was not among the highest‐ranked antidepressants in terms of efficacy for either substantial pain relief or reduction in pain intensity. The evidence suggests that generic duloxetine could be the first option when considering the use antidepressants for chronic pain management. Additionally, for duloxetine there is often no benefit to using a high dose; using a standard dose (60 mg) is often as effective as using a high dose (> 60 mg). We were unable to be certain about the adverse events and harms for any antidepressant, so this is important to consider when prescribing antidepressants for chronic pain.

For policy makers

A full analysis of international guidelines is out of scope, but the National Institute for Health and Care Excellence (NICE) guidelines for the treatment of chronic primary pain recommends antidepressants as the only pharmacological treatment option (NICE 2021). In these guidelines, NICE specifically recommend amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine, or sertraline, with no recommendations regarding dose. Our review and analyses found only moderate‐ to high‐certainty evidence for duloxetine in the management of chronic pain, evidence for amitriptyline, citalopram, fluoxetine, paroxetine or sertraline was low quality and of very low certainty.

For funders of the intervention

Currently, amitriptyline is the most common and first‐line antidepressant prescribed for the management of chronic pain; however, there are no large, high‐quality studies to support this position. There is also a lack of head‐to‐head studies where multiple antidepressants are compared in the same study. It is important to recognise that there are no long‐term safety data available for any antidepressant used for chronic pain treatment, and that collection and reporting of these data during trials is essential.

Implications for research 

General implications

• For all antidepressants aside from duloxetine, there is a lack of high‐quality, robust studies to establish effectiveness and safety. Amitriptyline and milnacipran particularly require further research; amitriptyline because it is the most common antidepressant prescribed for chronic pain management, and milnacipran because it has consistently ranked equivalent or very close to duloxetine. 
• Serotonin‐noradrenalin reuptake inhibitors (SNRIs) as a class require further research. Duloxetine and milnacipran were consistently the highest‐ranked antidepressants across outcomes. Research to identify and explore the mechanisms underpinning the effectiveness of these antidepressants is required.
• The relationship between chronic pain and depression deserves further attention. It is common in studies of analgesics to exclude participants with comorbid mental health disorders such as clinical depression, anxiety, or psychosis. As a consequence, we know nothing of the effects of antidepressants on pain in these populations. Further, depression and anxiety are common consequences of chronic pain, and often co‐exist. Although the dosing schedules of anti‐depressant medicines are different when prescribed for analgesia rather than depression (typically smaller) there is a possibility of dual effect, but this is not possible to study in these trials. 

Design implications

• Longer trials are required: there is no evidence regarding the long‐term efficacy or safety of using antidepressants for the treatment of chronic pain. This is critical as it is likely that patients will be prescribed antidepressants for long periods of time, and currently we do not know if there are likely to be any harms related to this.
• Head‐to‐head trials between antidepressants are required to accurately measure the effects of antidepressants for chronic pain.
• Larger sample sizes: there is no need for small trials; sufficient sizes are required to establish effect.
• There is a need for pragmatic trials with more complex designs to address changes in medication. Pragmatic trial designs that account for individual difference have been recommended for over a decade (Moore 2010c), yet the majority of studies are still designed as two‐arm placebo‐controlled trials.

Measurement implications

• There is now guidance on the optimal conduct and reporting of clinical trials, and specific guidance on the reporting of pain trials, the Consolidated Standards of Reporting Trials (CONSORT; Schulz 2010), and Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT; Dworkin 2008). These recommendations should be adhered to in order to reduce research waste and efficiently inform clinical decision making.
• Where applicable, both post‐intervention and change scores should be reported to enable comprehensive evidence synthesis.
• If trials are reporting responder analyses (e.g. 50% pain relief), then they should also report the continuous data, to reduce the chance of Type 1 errors. Some studies in our review only reported responder analyses and could not be included in the counterpart continuous measures.
• Adverse events should be reported following the CONSORT guidelines, as highlighted many times previously (Edwards 1999; Phillips 2019).

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