Muddled Picture for Antidepressant as Osteoarthritis Pain Reliever

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

Among 132 patients with hip or knee OA in primary care clinics randomized to duloxetine plus usual care (acetaminophen and/or nonsteroidal anti-inflammatory drugs, a.k.a. NSAIDs) versus 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 colleagues.

The intervention group showed a mean score on the 20-point Western Ontario McMaster Universities (WOMAC) Osteoarthritis Index that was just 0.26 points lower than with usual care alone (95% CI -1.86 to 1.34), the group reported in Arthritis & Rheumatology.

This was also true for patients who had centralized pain in addition to sore joints, the group thought likely to benefit most from duloxetine (difference at 12 months -0.32, 95% CI -2.32 to 1.67).

Duloxetine showed slightly better WOMAC results at 3 months, but these too failed to reach statistical significance. In the end, more patients in the duloxetine group were referred to orthopedic surgeons; five proceeded to total joint replacement by month 12 versus only one in the control group.

This cluster-randomized trial‘s findings stand in contrast to several conducted with placebo control in which clinically and statistically significant improvements were seen with the drug. These studies were predicated on the belief that duloxetine’s dual inhibition of serotonin and norepinephrine reuptake should interfere with central pain pathways that play a role in OA patients’ overall pain perception (which is not confined to nociception within the affected joint).

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

On the basis of those studies, both the American College of Rheumatology and the Osteoarthritis Research Society International recommend duloxetine for certain OA patients.

But van den Driest’s group noted that the earlier trials were conducted in specialty clinics, whereas 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 in explaining the new trial’s rationale.

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

Eligibility criteria included definite OA, chronic pain (“pain most days of the last three months”), and inadequate response or contraindications to NSAIDs. The latter makes most patients eligible for next-line treatment under current guidelines.

In all, the 132 patients were under treatment at 66 clinics; randomization was by clinic (31 to duloxetine plus usual care, 35 to usual care alone), but the number of patients was equal at 66 in each arm. Duloxetine was dosed at 30 mg/day during the first week to check tolerability and 60 mg/day after; it was then gradually withdrawn after 3 months in patients showing excessive side effects or no pain relief.

Usual care consisted of acetaminophen/NSAIDs, education, physical therapy, and dietary and other lifestyle recommendations. Patients could receive intra-articular steroid injections and treatment in specialty clinics, if physicians judged it necessary, without being dropped from the trial.

The study authors had no definite explanation for the divergent results in their study versus the earlier placebo-controlled trials, but they offered some speculation.

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

The researchers also noted that their eligibility criteria were actually a bit stricter, in that they required an inadequate response to first-line drug treatment, whereas “this was not a prerequisite” in most of the previous trials. Finally, the current study followed patients for a full year, considerably longer than in the other studies.

Limitations most prominently included the tiny percentage of patients initially screened who were ultimately enrolled (in fact, the trial leaders suspended recruitment after 3 years because of the low level of voluntary participation; they had sought to enroll 362), detracting substantially from the planned statistical power.

As a result, at least for OA patients with centralized pain, the group called for additional studies to examine duloxetine’s potential benefits.

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    John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Disclosures

The study was funded by the Dutch government.

One co-author reported a relationship with Pfizer; other authors declared they had no relevant financial interests.

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