September 22, 2022

Confused picture for antidepressant as pain reliever for osteoarthritis

Previous studies had shown that the antidepressant drug duloxetine (Cymbalta) helped relieve pain in patients with osteoarthritis (OA), leading to the recommendation that it be part of the clinical toolkit. But now comes a new lawsuit questioning the advantage in real world settings.

Among 132 patients with osteoarthritis of the hip or knee in primary care clinics randomized to receive duloxetine plus usual care (acetaminophen and / or nonsteroidal anti-inflammatory drugs, aka NSAIDs) compared to usual care alone, Scores on a standardized assessment were no different at 12 months, according to Jacoline van den Driest, MD, of Erasmus Medical Center in Rotterdam, the Netherlands, and her colleagues.

The intervention group showed an average score on the University of Western Ontario McMaster’s Osteoarthritis Index of 20 points (WOMAC) that was only 0.26 points lower than usual care alone (CI at 95% -1.86 to 1.34), the group reported in Arthritis and rheumatology.

This was also true for those patients who had centralized pain in addition to joint pain, the group probably thought they would benefit the most from duloxetine (12 month difference -0.32, 95% CI -2.32 to 1.67 ).

Duloxetine showed slightly better WOMAC results at 3 months, but these also did not reach statistical significance. In the end, more patients in the duloxetine group were referred to orthopedic surgeons; five underwent total arthroplasty at month 12 compared to only one in the control group.

The results of this cluster randomized trial contrast with those conducted with a placebo control in which clinically and statistically significant improvements were seen with the drug. These studies were based on the belief that the dual inhibition of serotonin and norepinephrine reuptake by duloxetine should interfere with central pain pathways that play a role in the overall pain perception of OA patients (who do not not limited to nociception in the affected joint).

“This centrally sensitized pain can occur after intense, repeated or prolonged nociceptive intake and is present in about 23% of patients with chronic pain due to osteoarthritis,” the authors explained.

Based on these studies, the American College of Rheumatology and the Osteoarthritis Research Society International recommend duloxetine for certain patients with osteoarthritis.

But van den Driest’s group noted that the first trials were conducted in specialist clinics, when most OA patients are treated in primary care.

“The effectiveness of duloxetine added to usual care compared to usual care alone in a primary care setting is unknown,” the researchers wrote to explain the rationale for the new trial.

For the trial, doctors from Dutch primary care clinics were invited to participate; in turn, those who choose to do so have then issued invitations to their patients. Thus, while the participating clinics had nearly 5,000 OA patients on treatment, only 132 were ultimately treated. The vast majority were excluded because their osteoarthritis was well controlled, they had contraindications to duloxetine or had other diagnoses or medications that might have influenced responses to treatment, and most of those considered eligible refused to. register.

Eligibility criteria included defined osteoarthritis, chronic pain (“pain on most days in past three months”), and inadequate response or contraindications to NSAIDs. The latter makes most patients eligible for next-line treatment under current guidelines.

In total, the 132 patients were under treatment in 66 clinics; randomization was performed by clinic (31 for duloxetine plus usual care, 35 for usual care only), but the number of patients was 66 in each arm. Duloxetine was administered at 30 mg / day for the first week to check tolerance and at 60 mg / day thereafter; it was then gradually withdrawn after 3 months in patients with excessive side effects or no pain relief.

Usual care consisted of acetaminophen / NSAIDs, education, physiotherapy, and dietary and other lifestyle recommendations. Patients could receive intra-articular steroid injections and treatment at specialist clinics, if doctors deemed it necessary, without being excluded from the trial.

The study authors did not have a specific explanation for their study’s diverging results from previous placebo-controlled trials, but they offered some speculation.

Of course, van den Driest and his colleagues cited the fact that theirs had been conducted in primary care settings, but, in addition, “the patients in our trial were older, had complaints of osteoarthritis for a longer period of time. and had more comorbidities than those in the other trial. studies.”

The researchers also noted that their eligibility criteria were actually a bit more stringent, as they required an inadequate response to first-line drug therapy, while “it was not a prerequisite” in most cases. previous tests. Finally, the present study followed patients for a full year, considerably longer than in the other studies.

Limitations most prominently included the small percentage of initially screened patients who were eventually recruited (in fact, trial officials suspended recruitment after 3 years due to low level of voluntary participation; they had sought to enter 362), which significantly affected the expected statistical results. Powerful.

Accordingly, at least for OA patients with centralized pain, the group requested additional studies to examine the potential benefits of duloxetine.

  • John Gever was editor-in-chief from 2014 to 2021; he is now a regular contributor.


The study was funded by the Dutch government.

A co-author reported a relationship with Pfizer; other authors have stated that they have no relevant financial interest.