The new study included 176 trials and almost 30,000 patients.
Hundreds of thousands of people in the UK are being prescribed antidepressants for chronic pain without sufficient evidence they work, researchers have said.
In the largest study of its kind, experts looked at medicines commonly prescribed on the NHS including amitriptyline, duloxetine, fluoxetine (Prozac), citalopram, paroxetine (Seroxat) and sertraline.
Amitriptyline is one of the most commonly prescribed antidepressants for chronic pain in England, with the NHS website saying it can treat nerve pain, some back pain and can help prevent migraines.
But the new study, which included 176 trials and almost 30,000 patients, concluded that only duloxetine had reliable evidence for pain relief.
Researchers, including from the universities of Southampton, Bath, Bristol and University College London, also raised concerns about the lack of long-term data on safety.
The National Institute for Health and Care Excellence (Nice) recommends a range of antidepressants as an option for chronic primary pain (where the underlying cause is unknown) and neuropathic pain such as neuralgia, some cancer pain and conditions that can cause neuropathic pain such as stroke, spinal cord injury and multiple sclerosis.
It told the PA news agency it had reviewed the new evidence but concluded it was “not sufficient to warrant an update to the recommendations in our chronic pain guideline at this stage”.
But Professor Tamar Pincus, lead author of the new study from the University of Southampton, said: “This is a global public health concern.
“Chronic pain is a problem for millions who are prescribed antidepressants without sufficient scientific proof they help, nor an understanding of the long-term impact on health.
“Our review found no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for their safety for chronic pain at any point.
“Though we did find that duloxetine provided short-term pain relief for patients we studied, we remain concerned about its possible long-term harm due to the gaps in current evidence.”
Prof Pincus said around a quarter to a third of people are thought to suffer chronic pain.
She said the “societal cost is really, really heavy, both in terms of work absenteeism, disability allowance, personal costs… and there’s very little we can do for it”.
She told reporters that while physical activity is known to help, many patients turn to medics because they struggle to exercise when the pain hits them hard.
She added that amitriptyline “has been around for donkey’s years” and “is very, very cheap”.
“Because it’s been around for donkey’s years, it’s very easy to fall into a habit of prescribing it.
“It’s very likely that GPs anecdotally perceive a response, because placebo responses in chronic pain are incredibly high.
“One in three people will show a response to placebo. Is it safe? No, it’s not.
“Amitriptyline, certainly in high doses is toxic. It’s got side-effects we know about…,” she said.
Prof Pincus said amitriptyline “is probably not very healthy” but added “we don’t know whether it works”.
She added: “The fact that we don’t find evidence whether it works or not is not the same as finding evidence that it doesn’t work.
“We don’t know – the studies simply are not good enough and, similarly, we don’t know whether it harms or not.”
She said that in 2020 to 2021, there were around 15 million prescriptions in England at low dose for amitriptyline.
“Amitriptyline at low dose is almost always for things like pain and sleep, so a very, very rough estimate suggests that we have got hundreds of thousands of people being prescribed amitriptyline in the UK for pain…,” she said.
University of Southampton researcher Dr Hollie Birkinshaw said the clinical trials investigated three pain types: fibromyalgia, nerve pain and musculoskeletal pain (mainly low back pain and osteoarthritis), with duloxetine and amitriptyline among the most frequently studied antidepressants.
She said researchers found that the safety data for adverse events, serious adverse events and withdrawal “was very poor”, adding: “So we can’t draw any reliable conclusions, unfortunately, for the safety of antidepressants or unwanted effects, from our data.”
Dr Birkinshaw said the only “consistent picture” on effectiveness was for duloxetine” but not for other antidepressants used in the UK.
“This includes amitriptyline, so even though it’s the most common antidepressant used clinically, most of the studies were small and it’s not reliable evidence,” she said.
“We weren’t able to assess effects on mood and safety, but we were also unable to establish the effectiveness of long-term antidepressant use because the average length of studies was only 10 weeks.”
Statistician Gavin Stewart, review co-author from Newcastle University, said the team was now calling on Nice and the US Food and Drug Administration to update their guidelines “and on funders to stop supporting small and flawed trials”.
The authors urged people not to come off their drugs but to speak to a GP if they had concerns.
Dr Ryan Patel, from King’s College London, said of the study: “If you are someone living with chronic pain and taking antidepressant drugs to manage your symptoms, the best advice is to continue taking them if they work for you.
“The systems that regulate mood and pain overlap considerably, meaning some antidepressants can provide pain relief.
“What this comprehensive analysis demonstrates is that when clinical trials are designed poorly under the assumption that everyone’s experience of pain is uniform, most antidepressants appear to have limited use for treating chronic pain.”
Professor Kamila Hawthorne, chairwoman of the Royal College of GPs, said: “In the treatment of chronic pain, GPs will aim to create a plan which combines physical, psychological and pharmacological treatments, prescribing the lowest dose of medicines, for the shortest time and only where necessary.
“In cases when GPs do prescribe anti-depressants, this may be in conjunction with other pain medications and appropriate for the patient. In treating pain, GPs will always undertake a thorough assessment of an individual’s condition, ensuring that we build a comprehensive picture for diagnosis. With routine medication reviews, we can weigh up the effectiveness of a prescribed medicine and determine whether it’s appropriate for the individual on a regular basis.”
Prof Hawthorne added: “Patients shouldn’t panic as a result of this research and should not stop taking prescribed medication until they have discussed this with their GP at their next review.”
A Nice spokesman said: “Our guideline on chronic pain published in 2021 recommends antidepressants, including duloxetine, can be considered for people aged 18 years and over to manage chronic primary pain, after a full discussion of the benefits and harms. This is because the evidence shows these medicines may help with quality of life, pain, sleep and psychological distress, even in the absence of a diagnosis of depression.
“The committee considered that these could be beneficial to some patients and clinicians should be able to choose from the range of therapies based on the individual’s need, background and acceptance of adverse events.
“NICE has conducted a careful and comprehensive review of the recent Cochrane publication findings and we have concluded that there is insufficient new evidence since 2021 to warrant an update to the recommendations on antidepressant use in our chronic pain guideline at this stage.”