Evaluating early RA patients who had at least 3 months of methotrexate treatment, Cecilia Lourdudoss, PhD, of the Karolinska University Hospital in Stockholm, and colleagues reported that omega-3 fatty acid intake was inversely associated with unacceptable pain (OR=0.57, 95% CI 0.35-0.95) and refractory pain (OR=0.47, 95% CI 0.26-0.84).

The omega-6 to omega-3 ratio — but not omega-6 alone — was directly associated with unacceptable pain (OR=1.70, 95% CI 1.03-2.82) and refractory pain (OR=2.33, 95% CI 1.28-4.24). These associations appeared to be independent of inflammation.

“The inverse association between omega-3 fatty acid and refractory pain may have a role in pain suppression in RA,” the authors stated.

They noted that this was the first study to examine connections between polyunsaturated fatty acids and non-inflammatory pain in a large group of patients with early RA.

The study included 591 newly diagnosed RA patients enrolled from October 2005 to March 2012 who had been on methotrexate monotherapy for at least 3 months and who had completed a food frequency questionnaire at baseline. The sample was part of the Epidemiological Investigation of Rheumatoid Arthritis (EIRA), a prospective case-control study consisting primarily of women (70.6%) with an average age of 52.8±13.0 years and an average body mass index of 25.8±4.7.

The food frequency questionnaire asked about patients’ diet, frequency of eating, and portion sizes. The researchers calculated polyunsaturated fatty acid intake by multiplying the average frequency of each food consumed by its nutrient content. The questionnaire also asked about patients’ use of omega-3 fatty acid and fish oil supplements.

The researchers measured pain at baseline and at 3 months of treatment using a visual analog scale (VAS) with a range of 0-100 mm, with VAS>40 mm defined as indicating unacceptable pain. Refractory pain was defined as VAS>40 mm and C-reactive protein (CRP) <10 mg/L after methotrexate treatment — i.e., pain in spite of inflammatory control. Inflammatory pain was defined as VAS>40 mm and CRP >10 mg/L after methotrexate.

After 3 months of methotrexate treatment, 15.6% of the patients had refractory pain, which the team noted was consistent with other studies. “Widespread pain is common in RA and has been associated with high levels of pain, fatigue, and sleep problems, especially during the first year after RA diagnosis,” the researchers wrote, adding that immunosuppressive therapy is not likely to decrease pain further in these cases.

Omega-3 intake was lower in patients with refractory pain than in those without it (0.6±0.3 g/day versus 0.7±0.4 g/day, P=0.006), Lourdudoss and colleagues reported. “Higher intake of omega-3 fatty acid may have reduced the central sensitization in the control group.”

There was no correlation found between omega-6 fatty acid alone and refractory or unacceptable pain. However, the omega-6 to omega-3 ratio was significantly associated with an increased risk of both types of pain.

“The results of this study may be interpreted as omega-3 fatty acid having inflammation-independent actions on pain,” the authors wrote. “This was also supported by the lack of associations between omega-3 fatty acid and inflammatory parameters at the 3-month follow-up, including inflammatory pain.”

The team suggested several possible reasons for the results, including omega-3’s role in producing resolvins, which have been shown to directly suppress pain in experimental models, and omega-3’s possible neuroprotective actions or suggested ability to decrease neuro-inflammation in animals. The investigators also speculated that omega-3’s interaction with gut microbiota might have affected nociceptive mechanisms.

Although 19.5% of the study participants used omega-3 fatty acid or fish oil supplements, the researchers found no association between supplements and pain patterns: “Our data on potential protective effects of omega-3 fatty acid on pain should not be interpreted to mean that supplementation can be used therapeutically to reduce pain.”

Study limitations noted by the authors included the dietary data from food frequency questionnaires, which were based on estimated intake and were subject to possible recall bias and under- or over-reporting. The study also assumed that patients did not change their dietary patterns during the first 3 months from baseline. The investigators said that they did not consider any other effects of methotrexate and said they had no information about depression or psychological factors that might be associated with pain.

The authors noted that VAS referred to overall pain in their study, not disease-related pain. And although they defined refractory pain as non-inflammatory, CRP below 10 mg/L still might indicate some degree of inflammation, they said.

• Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner