Antidepressants for chronic pain: an important evidence gap

A recent Cochrane Review – the largest ever investigation into antidepressants used for chronic pain – shows insufficient evidence to determine how effective or harmful they may be. In this blog, principal investigator Professor Tamar Pincus explains the findings, and a clinician (Dr Peter Cole), an anonymous patient, and a researcher (Dr Hollie Birkinshaw) share their reflections. 

Take-home points

A recent Cochrane Review – the largest ever investigation into antidepressants used for chronic pain - shows insufficient evidence to determine how effective or harmful they may be. Duloxetine is the only antidepressant for which there is reliable evidence; it is consistently the highest‐ranked antidepressant. The standard dose is probably equally effective as a higher dose – which is important as higher doses may be more likely to have side-effects. There is a lack of reliable evidence about all the other 26 antidepressants investigated in the review. Especially concerning is the lack of data about long-term effects, including possible side-effects, given that people with chronic pain may be prescribed antidepressants long-term.

How our investigation into antidepressants for chronic pain all began…

 Some years back I [Tamar] was giving a talk to clinicians in a large pain management department in a hospital. I asked: “How many patients arrive on long-term antidepressants?”

The participants exchanged looks as if I asked a foolish question, and finally one replied: “pretty much all of them”.

“is their pain well-controlled”? I asked.

Vigorous head shakes.

“do they mostly have low mood?”

Unanimous nods.

“Well,” I thought, “I wonder how well these drugs work?”

What we set out to find out

We already knew that there were dozens of trials of antidepressants in specific pain conditions. We wanted to do a review that offers an answer to ALL people living with chronic pain, from any condition, on any antidepressant, of any dose.

We knew we had to include more than just pain intensity as an outcome – patients have told us that reducing pain is incredibly important, but equally important is improving mood, sleep, and physical function. We set out to carry out the largest ever review of antidepressants in chronic pain, and to do it meticulously. Throughout the review, right from the start, we had patients advising us.

What we found

We scrutinised findings from 176 trials, which included almost 30,000 patients.


Our review shows that – despite studies investigating 27 different antidepressants – the only antidepressant we are certain about for the treatment of chronic pain is duloxetine:

  • Duloxetine was consistently the highest‐ranked antidepressant, and we are pretty certain this finding can be trusted.
  • Standard dose was probably equally effective as high dose for the majority of outcomes. This is important, because we think high doses are more likely to have side effects.
  • Duloxetine reduced pain and increased function when used for three common pain conditions: there were a total of 43 duloxetine studies: 11 for fibromyalgia, 18 for neuropathic pain, and 14 for musculoskeletal pain.
  • The average length of the trials for all drugs was around 10 weeks, and for duloxetine, was 12.5 weeks, so we still don’t know about any long-term effects.
  • We couldn’t find out whether duloxetine (or any other antidepressant) improved mood, because almost all the trials excluded people with low mood and other mental health conditions.


There is also some promising evidence for milnacipran, but the studies were too few and small for us to be certain about this drug. Milnacipran was often ranked as the next most effective antidepressant after duloxetine, although the certainty of evidence was lower than that of duloxetine.

We have unanswered questions including a lack of information about long-term effects and side effects

Evidence for all other antidepressants was low or very low certainty. Meaning that there is insufficient evidence to draw robust conclusions about the effectiveness and safety of any other antidepressant for chronic pain.

We also couldn’t assess side effects because these were poorly reported. Our patient advisors told us that they are particularly disappointed about the lack of long-term outcomes with good tracking of side effects because – in their experience – antidepressants are prescribed for longer periods than 10 weeks and are quite hard to get off.

What we have learned: reflections from a clinician

Dr Peter Cole, Consultant in Pain Medicine, Oxford says:

“Of the antidepressant drugs used for nerve pain, fibromyalgia and musculoskeletal pain, we now know that duloxetine has the best chance of helping patients when compared to the other antidepressants.

Duloxetine is also easier to take as there is no need to keep increasing the dose as you often need to with the other drugs. Most people are ok starting on a single dose of 60mg each day, although they may choose to start on a lower dose and increase to 60mg after week or so. There is no need to increase the dose beyond 60mg.

For these reasons of best evidence of benefit and ease of use, duloxetine is the drug that I would recommend starting if patients wanted to trial an antidepressant to see if it helps with their nerve pain, fibromyalgia or musculoskeletal pain. It is really important to keep some sort of diary or record of the benefit and any side effects to determine whether it is worth continuing with the drug. Too many people carry on without reviewing this.

Patients should talk with their own clinician before starting – or changing – the medication they are currently taking for pain.  The lack of evidence of benefit from this review for many of the antidepressants for chronic pain does not mean that a particular drug won’t be helpful for an individual patient.

Before starting a new drug, I recommend patients reflect on whether changes to their lifestyle might help when living with persistent pain. This might include increasing their mobility or exercise, their diet or weight loss. Whether their daily routine, hobbies and their sleep could be improved. In addition, there are educational resources and healthcare professionals that can be helpful. I would prefer patients had the opportunity to consider these things before starting a new drug. If they do start a new drug, I’d advise them to review the benefits and side effects and stop taking it if it isn’t helping”.

What we have learned: reflections from a patient

Sarah (not her real name) says:

“I think it’s very difficult for anyone to have an informed decision about which antidepressants they would like to try or try next because there is not enough reliable evidence.

This kind of work, studying the effectiveness of different available antidepressants, should be paramount for informing clinicians – as one in four in the UK population and a third of the world suffer chronic pain. Not knowing how effective or safe these medications are is a major risk to the health of the population. It’s imperative we have further high-quality studies into this, as effectively there are no informed comparisons to help clinicians or patients make decisions.

As a member of the public and a patient who sufferers from chronic pain, I find the data concerning from an ethical point of view. I believe health care should be as safe as it can be for patients, it should be more strongly based on fact and evidence, with accurate information on what works and what doesn’t – or what is better or worse. Otherwise, I think patients could lack confidence in the health care they receive, and this might also affect their relationship with clinicians. It might also cause people more suffering and for longer.”

What we have learned: reflections from a researcher

Dr Hollie Birkinshaw, senior researcher and lead author of the review, says:

“Considering how common chronic pain is, and the growing criticism of many other drugs (such as opioids, and even paracetamol and ibuprofen), it is not surprising that doctors prescribe antidepressants to reduce pain. The physical systems processing emotions and pain are similar, so theoretically, it makes sense that antidepressants will have an effect.

This review took on a mountain of evidence and wrestled with it to produce trustworthy conclusions. It is disappointing that so much of the evidence is below par.

The good news, that duloxetine appears to reduce pain and increase function in the short term in three major pain groups (fibromyalgia, neuropathic pain, and musculoskeletal pain), is balanced against the gaps in evidence on longer-term use and on harm.”


Reference: Birkinshaw H, Friedrich CM, Cole P, Eccleston C, Serfaty M, Stewart G, White S, Moore RA, Phillippo D, Pincus T. Antidepressants for pain management in adults with chronic pain: a network meta-analysis. Cochrane Database of Systematic Reviews 2023, Issue 5. Art. No.: CD014682. DOI: 10.1002/14651858.CD014682.pub2.


This work was funded by the NIHR Health Technology Assessment (HTA) Programme, UK.

Tamar: “With thanks to Cochrane and to the diverse team who worked on this review: a health psychologist, a pain psychologist, a pain physician, an expert in systematic reviews, a clinical pharmacist, a psychiatrist, and an amazing statistician. Gavin Stewart, from Newcastle University led our analysis, using complex methods and wrestling with a mountain of data. Our senior researcher, Hollie Birkinshaw, spent hours making sure that every methodological T was crossed and i was dotted, and writing up a thesis.”

Antidepressants for chronic pain: an important evidence gap by Tamar Pincus

is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International

2 Comments on this post

  1. Great article! It’s surprising that there’s still so much we don’t know about using antidepressants for chronic pain management.

    Tamara Connaughton / Reply
  2. Really great to have all three perspectives on this – a really useful read! Thank you!

    Muriah Umoquit / Reply

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