Antidepressants and pain: evidence stays fuzzy

A review has failed to find any high-certainty evidence regarding the benefits of SNRIs and tricyclic antidepressants for chronic pain.

---

GPs prescribing antidepressants off-label for chronic pain have been given more food for thought with the release today of a new review published in the BMJ. 

The international review analysed 26 systematic reviews involving over 25,000 participants, including data from eight antidepressant classes and 22 pain conditions, including back pain, fibromyalgia, headaches, postoperative pain and irritable bowel syndrome. 

Serotonin-norepinephrine reuptake inhibitors (SNRI) antidepressants such as duloxetine were found to be possibly effective for the largest number of pain conditions, including back pain, knee osteoarthritis, postoperative pain, fibromyalgia and neuropathic pain. 

By contrast, tricyclic antidepressants (TCAs), such as amitriptyline, the most commonly used antidepressant to treat pain in clinical practice, fared among the worst in the review. 

“No review reported high certainty evidence regarding the effects of antidepressants for pain,” the authors wrote.  

“There was moderate certainty evidence that SNRIs were efficacious for chronic back pain, postoperative pain (most trials in orthopaedic surgery), fibromyalgia and neuropathic pain. 

“Low certainty evidence supported the efficacy of SNRIs, selective serotonin reuptake inhibitors (SSRIs), and TCAs for some other conditions.  

“SNRIs were efficacious for aromatase inhibitor therapy-induced pain in breast cancer, depression and comorbid chronic pain, and knee osteoarthritis. SSRIs were efficacious for depression and comorbid chronic pain. TCAs were efficacious for irritable bowel syndrome, neuropathic pain and chronic tension-type headache.” 

Associate Professor Michael Vagg, immediate past dean of the faculty of pain medicine at the Australian and New Zealand College of Anaesthetists, and who was not connected with the review, told TMR he was “actually surprised the [results] came out so positively”. 

“To a pain specialist it is not a surprising conclusion that things are a bit of a mess, given the state of the literature,” he said. 

“One of the real strengths of the BMJ review is that it does throw the spotlight on the issues of off-label prescribing for chronic pain.” 

In Australia, only one antidepressant is recommended for chronic pain: duloxetine, an SNRI which is approved for diabetic neuropathic pain. 

According to OECD data, the use of antidepressants has been increasing, with prescriptions doubling from 2000 to 2015, and off-label use for chronic pain is believed to be a contributing factor. 

“Undoubtedly, a lot of the rise in antidepressant prescribing is driven by people trying to treat chronic pain effectively,” Associate Professor Vagg told TMR. 

“That’s not necessarily a problem, or unethical. It’s called ‘routine off-label prescribing’ – things like amitriptyline and nortriptyline, which are everyday drugs we use a lot [for treating chronic pain]. 

“They have never been on the PBS for neuropathic pain. Given the cost involved in getting them on-label, and the fact they are already well established and in use, they’re never going to be on-label,” he said. 

The problem with a drug being off-label is that it’s hard to measure how much it is being used for that particular purpose. 

Dr Giovanni Ferreira from Sydney Musculoskeletal Health at the university of Sydney and lead author of the BMJ review, said he believed the review was another tool for GPs to use when talking with patients about possible antidepressant use for their pain. 

“We hope that the findings of this study will help clinicians and also patients to actually weigh up the benefits and the harms of antidepressants for these conditions and help them make informed decisions,” Dr Ferreira told TMR.  

“Obviously, this review is only one piece of the puzzle. With antidepressants, you have to consider other things like drug interactions and patient preference.  

“There also seems to be a lot of stigma around prescribing antidepressants. It seems to be a particularly difficult conversation between patients and GPs when it comes to prescribing these drugs for pain. 

“Treating chronic pain is a challenging issue, and no drug will completely solve the problem, so you need to be taking a more holistic approach and consider other options as well, if they haven’t been tried yet.” 

Dr Ferreira also highlighted the issue of industry influence on drug trials for antidepressants, which were a possible confounder for results. 

“Industry ties were present in 69 (45%) [of the 154 trials under review where industry ties could be traced], absent in 45 (29%) and unclear in 40 (26%),” the authors wrote.  

“Of the trials with industry ties, 47 (68%) investigated SNRIs, 13 (18%) investigated SSRIs, 4 (6%) investigated TCAs, 2 (3%) investigated atypical antidepressants and SARIs each, and 1 (1%) investigated NDRIs and MAOIs each.” 

Dr Ferreira told TMR: “It’s important to look at industry funding, not because industry is malicious, or because they’re doing something that is of questionable ethics, [but because] trials funded by industry tend to overestimate the effects of treatments, compared with trials that are conducted by independent investigators.  

“[They] may not represent what actually happens in real life. 

BMJ 2023, online 1 February