IMAGE DESCRIPTION: An image of many different medications. With two smaller circles with a doctor writing a prescription and someone holding their neck with a red patch representing pain. The ME Association logo (bottom right)

Antidepressants for chronic pain lack reliable evidence

Most antidepressants used for chronic pain are being prescribed with “insufficient” evidence of their effectiveness, scientists have warned. A major investigation into medications used to manage long-term pain found that harms of many of the commonly recommended drugs have not been well studied.

Newcastle University Press Release 09 May 2023

The Cochrane review, led by scientists from several UK universities including Newcastle and Southampton, examined 176 trials consisting of nearly 30,000 patients involved in assessments which prescribed antidepressants for chronic pain. Among the drugs studied were amitriptyline, fluoxetine, citalopram, paroxetine, sertraline, and duloxetine – with only the latter showing reliable evidence for pain relief.


One third of people globally are living with chronic pain, World Health Organisation data shows, with many prescribed antidepressants for relieving symptoms. Statistician Dr Gavin Stewart, review co-author from Newcastle University, said:

“Our study is one of the biggest of its kind and demonstrates the need for large-scale studies in this field. We would encourage funders to support high-quality studies into the use of antidepressants for chronic pain. Data is often complex and nuanced but the evidence underpinning the use of these treatments is not conclusive for most of the antidepressants we studied and, therefore, current treatment options are hard to justify.”

Amitriptyline is one of the most commonly prescribed antidepressants for pain management worldwide. In the last 12 months, around 10 million prescriptions were given to patients in England at the 10mg dose recommended for pain. By comparison, five million prescriptions were given at the higher doses recommended for depression. For duloxetine, three and a half million prescriptions were dispensed in England, but the recommended doses do not currently differ between conditions.

The two-year Cochrane study was the largest ever assessment of antidepressants recommended by leading bodies, including the UK’s National Institute for Health and Care Excellence (NICE) and the Food and Drug Administration (FDA) in the USA. The review revealed that duloxetine was consistently the highest-rated medication and was equally as effective for fibromyalgia, musculoskeletal, and neuropathic pain conditions.

Study's findings

Other results showed:

•             Standard doses of duloxetine are as successful for reducing pain as higher quantities.

•             Milnacipran was also effective at reducing pain, but scientists are not as confident as duloxetine due to fewer studies with fewer people.

Professor Tamar Pincus added:

“We simply cannot tell about other antidepressants because sufficiently good studies are not available – but it does not mean that people should stop taking prescribed medication without consulting their GP.”

“This well conducted review adds to the substantial evidence we now have that shows that the use of medicines to treat long term pain is disappointing.

“The study rightly highlights the significant adverse effect that chronic pain has on the quality of life for the people living with it. It’s equally important to emphasise the many social and psychological influences on the pain experience. 

“There is good evidence that for people with pain, compassionate and consistent relationships with clinicians remain the foundations of successful care.”

Dr Cathy Stannard, Clinical Lead on the NICE Guideline for Chronic Pain (Quoted in PULSE).

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ME Association Comment

“The recommendations in this Cochrane review on the use of antidepressants to treat pain need to be viewed with caution with regard to ME/CFS where there is little or no information on the safety and efficacy of these drugs from large and well conducted clinical trials. We have to consider the evidence from patients and clinicians on the options available to treat pain in ME/CFS.

“In very basic terms this evidence indicates that while over-the-counter analgesics such as aspirin, paracetamol, ibuprofen may be of help for mild pain, they are often of very limited value in relieving moderate to severe pain such as we see in ME/CFS. When such pain is encountered there are still a number of drug options that can be considered by a GP. These include antidepressant drugs such as amitriptyline and duloxetine (Cymbalta) and other drugs such as gabapentin (Neurontin) and pregabalin (Lyrica).

“Over the years the ME Association has collected a considerable amount of patient evidence on the use of these drugs and a very mixed picture emerges. Some people report that low-dose amitriptyline is helpful, or very helpful, for pain relief and quite often for sleep disturbance. However, other people seem to gain no benefit and/or are not able to tolerate the side-effects. Others report that gabapentin (Neurontin) and pregabalin (Lyrica) are helpful.

“The use of – and feedback on – duloxetine which received a favourable review in this research (it is a newer drug and has been subjected to more rigorous clinical trials) is much smaller. However, it is of concern to note that some people with ME/CFS have reported significant problems with side-effects when using this drug.

“Any of the drugs we have referred to above might still be worth considering but only after consultation with a GP. We have information about these drugs which can be downloaded from the website shop (see below).

Dr Charles Shepherd, Hon. Medical Adviser, ME Association.

ME Association Literature

NICD Guideline on Management of Neuropathic (nerve)Pain

The NICE Guideline on ME/CFS refers clinicians – who are considering pain relief for people with ME/CFS – to another Guideline about treating Neuropathic pain in adults: pharmacological management in non-specialist settings.  

Treatments that can be considered:

  • 1.1.8 Offer a choice of amitriptyline, duloxetine, gabapentin or pregabalin as initial treatment for neuropathic pain (except trigeminal neuralgia). See additional information for more on duloxetine, gabapentin and pregabalin.
  • 1.1.9 If the initial treatment is not effective or is not tolerated, offer one of the remaining 3 drugs, and consider switching again if the second and third drugs tried are also not effective or not tolerated.
  • 1.1.10 Consider tramadol only if acute rescue therapy is needed (see recommendation 1.1.12 about long‑term use).
  • 1.1.11 Consider capsaicin cream for people with localised neuropathic pain who wish to avoid, or who cannot tolerate, oral treatments. See additional information for more on capsaicin cream.

Treatments that should not be used

1.1.12 Do not start the following to treat neuropathic pain in non-specialist settings, unless advised by a specialist to do so:

  • cannabis sativa extract
  • capsaicin patch
  • lacosamide
  • lamotrigine
  • levetiracetam
  • morphine
  • oxcarbazepine
  • topiramate
  • tramadol (this is referring to long-term use; see recommendation 1.1.10 for short-term use)
  • venlafaxine

Duloxetine and ME/CFS

The use of duloxetine in ME/CFS has been assessed in one clinical trial:

Conclusion: The primary efficacy measure of general fatigue did not significantly improve with duloxetine when compared with placebo. Significant improvement in secondary measures of mental fatigue, pain, and global measure of severity suggests that duloxetine may be efficacious for some chronic fatigue syndrome symptom domains, but larger controlled trials are needed to confirm these results.

More Information

  • The section on Pain Management in the 2010 ME Association Illness Management Report (pages 14 to 16) contains a great deal of patient evidence on what people with ME/CFS find helpful and not helpful when it comes to pain relief.

Dr Charles Shepherd,
Trustee and
Hon. Medical Adviser
to the ME Association.
Member of the 2018-2021 NICE Guideline Committee.
Member of the 2002 Independent Working Group on ME/CFS.

Dr Charles Shepherd
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