Opioids increase risk of all-cause mortality in rheumatoid arthritis vs. NSAID drugs

PHILADELPHIA – For patients with rheumatoid arthritis who are already at increased risk for major adverse cardiovascular events (MACE), NSAIDs may be safer than opioids, new user active-control study results suggest.



Dr. Gulsen Ozen

Among 6,866 patients with RA who started opioids and 13,698 patients who started NSAIDs for pain, use of both weak and strong opioids was associated with a 33% increased risk of all-cause mortality and a trend toward higher rates of VTE. (VTE), compared with the use of NSAIDs, reported Gulsen Ozen, MD, of the University of Nebraska Medical Center, Omaha.

“Pain in RA is a very complex process and we know that it is not solely dependent on the activity of the disease, but there is no evidence that opioids have any benefit in long-term pain management and it can even cause dehydration. And as we show, it is not safer than NSAIDs,” she said in an oral abstract session at the annual meeting of the American College of Rheumatology.

She emphasized that patients should be evaluated for non-rheumatoid pain and should use nonpharmacologic methods whenever possible.

“If pharmacologic therapy is needed and NSAIDs are contraindicated, the lowest possible dose of weak opioids can be used for a very limited time for acute pain only,” she said.

Pain despite disease control

Even when the disease is well controlled, approximately 60% of patients with RA still report pain. NSAIDs are commonly used to treat pain in patients with RA, but they are associated with modest increases in the risk of cardiovascular disease (CVD), gastrointestinal bleeding, kidney damage, and hypertension.

Some providers are leery of NSAIDs and will instead prescribe either regular or intermittent opioids to manage their patients’ pain.

DMARDs have only minimal pain relief benefits, “and even worse, opioids can delay the onset of DMARDs in RA,” Ozen said.

Opioids have been shown to increase oxidative stress, platelet aggregation, and myocardial fibrosis, as well as hypogonadism, weight gain, and heart disease risk factors.

However, there is little evidence that opioids are associated with cardiovascular disease in patients with RA. This lack of data prompted Ozen and colleagues to investigate the relative risk for MACE in patients with RA who are initiated on opioids or NSAIDs for pain.

Corresponding cohorts

They used data from FORWARD, a joint Canadian-US database for rheumatic diseases, to conduct an active-control study of new users. The cohort included adults with RA without cancer who participated in FORWARD for at least 1 year between 1998 and 2021.

The patients were followed either from the initiation of the drug until 3 months after the end of treatment, defined as either discontinuation of treatment or switching to another analgesic, follow-up at the end of the study, or the development of a MACE outcome.

The researchers used propensity score matching to compare each opioid and the two NSAIDs. Participants were matched for age, sex, body mass index, smoking, alcohol, RA duration, disease activity, health assessment questionnaire, visual analogue scale for pain, arthroplasty, previous cardiovascular disease, hypertension, diabetes, rheumatic disease, comorbidity, osteoporosis/fracture, thyroid , chronic liver, kidney, lung, and mental health conditions, hospitalizations, 36-item brief health survey, and sleep scores.

The two groups were well matched, except for a slightly higher incidence of VTE with opioids, although rates were low in both groups (0.9% vs 0.6% for NSAIDs).

Higher death rates for opioid users

The incidence of MACE among opioids was 20.6% versus 18.9% among NSAIDs, a difference that was not statistically significant. There was also no significant difference in the incidence of individual components of the MACE composite outcome: myocardial infarction, stroke, heart failure, cardiovascular death, or venous thromboembolism.

However, there were significantly more deaths from any cause among patients in the opioid group, with a rate of 13.5% versus 10.8% in the NSAID group.

Analysis of the association of drug type with outcome, adjusted for propensity score weights and previous VTE, showed that patients on opioids had a statistically significant hazard ratio for death from any cause of 1.33 (95% CI, 1.06-1.67).

An increased risk of all-cause mortality was observed in patients starting on both weak opioids (hydrocodone, tramadol, codeine, pentazocine, and propoxyphene) and strong opioids (hydromorphone, dihydromorphone, oxymorphone, butorphanol, methadone, morphine, oxycodone, meperidine, and fentanyl ).

As previously noted, there was a trend towards an increased risk of VTE among opioids, but this was not statistically significant.

The increase in risk was greater among patients on strong than weak opioids, suggesting a dose-dependent relationship, Ozen said.

Comparison of opioid-related risk for all-cause mortality vs. NSAIDs by type (non-specific or specific) showed that the majority of the increased risk was relative to selective cyclooxygenase-2 inhibitors.

“Beautiful” diagnosis

“It’s a beautiful analysis of a very difficult question to tackle because it’s very difficult to find the confounder,” said James Galloway, MBBS, deputy head of the rheumatology center at King’s College London and consultant rheumatologist at King’s College Hospital. , also in London.

“The promising message is that there didn’t seem to be any clear evidence that NSAIDs were worse, which I thought was the view. So it could be that people are paradoxically prescribing opioids in favor of NSAIDs in a person with cardiovascular risk ,” he said in an interview. Galloway attended the oral briefing but did not participate in the investigation.

The study was supported by a grant to Ozen from the Rheumatology Research Institute. Galloway reported having no relevant information.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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