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.