Little Evidence That Antidepressants Work for Chronic Pain

By Drs. Hollie Birkinshaw and Tamar Pincus

About one in five people globally live with chronic pain, and it is a common reason for seeing a doctor, accounting for one in five GP appointments in the UK.

With growing caution around prescribing opioids – given their potential for addiction – many doctors are looking to prescribe other drugs, “off-label”, to treat long-term pain. A popular option is antidepressants.

In the UK, doctors can prescribe the following antidepressants for “chronic primary pain” (pain without a known underlying cause): amitriptyline, citalopram, duloxetine, fluoxetine, paroxetine and sertraline. Amitriptyline and duloxetine are also recommended for nerve pain, such as sciatica.

However, our review of studies investigating the effectiveness of antidepressants at treating chronic pain found that there is only evidence for one of these drugs: duloxetine.

We found 178 relevant studies with a total of 28,664 participants. It is the largest-ever review of antidepressants for chronic pain and the first to include all antidepressants for all types of chronic pain.

Forty-three of the studies (11,608 people) investigated duloxetine (Cymbalta). We found that it moderately reduces pain and improves mobility. It is the only antidepressant that we are certain has an effect. We also found that a 60mg dose of duloxetine was equally effective in providing pain relief as a 120mg dose.

In comparison, while 43 studies also investigated amitriptyline (Elavil), the total number of participants was only 3,372, indicating that most of these studies are very small and susceptible to biased results.

The number of studies and participants for the other antidepressants are:

• Citalopram (Celexa): five studies with 209 participants

• Fluoxetine (Prozac): 11 studies with 622 participants

• Paroxetine (Paxil): nine studies with 960 participants

• Sertraline (Zoloft): three studies with 210 participants.

The evidence for amitriptyline, citalopram, fluoxetine, paroxetine and sertraline was very poor, and no conclusions could be drawn about their ability to relieve pain.

This is particularly important as UK prescribing data shows 15,784,225 prescriptions of amitriptyline in the last year. It is reasonable to assume that a large proportion of these may be for pain relief because amitriptyline is no longer recommended for treating depression.

This suggests that millions of people may be taking an antidepressant to treat pain even though there is no evidence for its usefulness. In comparison, 3,973,129 duloxetine prescriptions were issued during the same period, for a mixture of depression and pain.

In light of our findings, which were published in May 2023, the UK’s National Institute for Health and Care Excellence (Nice) recently updated its advice to doctors on how to treat chronic pain.

The updated Nice guidance now suggests 60mg of duloxetine to treat [chronic primary pain] and the same drug and dose to treat nerve pain.

Limited Treatments Options

GPs often report frustration at the limited options available to them to treat patients experiencing chronic pain. Amitriptyline is cheap to prescribe – only 66p per pack (US 82.5 cents) – which may explain the high number of prescriptions for this drug.

This is an example of how the gap between evidence and clinical practice could harm patients. Although our review was unable to establish the long-term safety of antidepressant use, previous research has highlighted the high rates of side-effects for amitriptyline, including dizziness, nausea, headaches and constipation.

It’s important to bear in mind, though, that pain is a very individual experience, and the evidence in our review is based on groups of people. We acknowledge that certain drugs may work for people even when the research evidence is inconclusive or unavailable. If you have any concerns about your pain medication, you should discuss this with your doctor.

Hollie Birkinshaw, PhD, is a Research Fellow at University of Southampton. She specializes in research involving chronic musculoskeletal pain, and the integration of psychology in pain and health services. Birkinshaw receives funding from the UK’s National Institute for Health and Care Research (NIHR).

Tamar Pincus, PhD, is a Professor of Health Psychology at University of Southampton. Her research focuses on the psychological aspects of chronic pain. Pincus receives funding from NIHR, Medical Research Council and Versus Arthritis.  

This article originally appeared in The Conversation and is republished with permission.

Study Finds Antidepressants Make Tramadol Less Effective for Pain Relief

By Pat Anson, PNN Editor

Common antidepressants interact with the opioid medication tramadol to make it less effective for pain relief, according to a small new study from University Hospitals (UH) in Cleveland. The findings suggest that some patients who exceed their prescribed dose of tramadol may be under-medicated and are seeking more effective pain relief.

Prescriptions for tramadol – which is sold under the brand names Ultram and ConZip – have increased in recent years because it is widely perceived as a “safer” opioid with less rick of addiction. Many patients, however, say tramadol is not as effective as hydrocodone, oxycodone and other opioids.  

UH researchers reviewed the prescription records of 152 patients who received tramadol for at least 24 hours.

Those patients who were also taking the antidepressants Prozac (fluoxetine), Paxil (paroxetine) or Wellbutrin (bupropion) required three times more tramadol per day to control their breakthrough pain, compared to patients not taking the antidepressants.

Previous studies on healthy volunteers have shown effects on blood levels when combining tramadol with those particular antidepressants. However, this was the first study to document the effects of this interaction in a real-world setting with pain patients.

"We knew that there was a theoretical problem, but we didn't know what it meant as far as what's happening to pain control for patients," said Derek Frost, PharmD, a UH pharmacist and lead author of the study, which was published in the journal Pharmacotherapy.

Frost says millions of Americans may be suffering the ill effects of this drug-to-drug interaction.

"Tramadol relies on activation of the CYP2D6 enzyme to give you that pain control," Frost said. "This enzyme can be inhibited by medications that are strong CYP2D6 inhibitors, such as fluoxetine, paroxetine and bupropion.

“Many chronic pain patients are taking antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), which many of these CYP2D6 inhibitors fit into. There are a lot of patients who experience both, unfortunately. The likelihood that somebody on one of these offending agents and tramadol is relatively high."

Frost says the problem has a relatively easy fix.

"We have a lot of other antidepressants available that are in the same class of medication that don't inhibit this particular enzyme, such as Zoloft (sertraline), (Celexa) citalopram and Lexapro (escitalopram)," he said. "You also have other options for pain control - non-opioid medications such as NSAIDs. If we need to use opioids, a scheduled morphine or a scheduled oxycodone would avoid this interaction."

Tramadol is a synthetic opioid that was rescheduled by the Drug Enforcement Administration in 2014 as a Schedule IV controlled substance, a category that means it has a low potential for abuse. That same year, hydrocodone was rescheduled as a Schedule II drug, meaning it has a high potential for abuse. Many patients who were taking hydrocodone were switched to tramadol as a result of the rescheduling.