Cod Liver Oil (n-3 fatty acids) as a Non-steroidal Anti-inflammatory Drug Sparing Agent
in Rheumatoid Arthritis

Background:  NSAID-induced side effects are a major concern in patients on chronic therapy, and there is a need to find alternative medications to help reduce their requirement.
 
Objective:  To determine if omega-3 fatty acids contained in fish oils could help reduce the daily NSAID requirement in patients with RA.

Methods:  The study utilized a dual-center, randomized, double-blind placebo-controlled design.  Treatment regimens were administered over 9 months.  Ninety-seven patients aged 37-78 were enrolled.  Inclusion criteria required regular NSAID use, a Steinbrocker functional class of I, II, or III, and non-NSAID RA medications and RA disease activity to be stable for at least 3 months prior to the start of the study.  Exclusion criteria consisted of ongoing RA disease activity requiring changes in therapy, prednisolone doses > 7.5 mg/day, severe intercurrent illnesses, and existing supplementation with omega-3 fatty acids.  49 subjects were randomized to receive the fish oil treatment and 48 were randomized to receive the placebo.  Treatment regimens consisted of either ten 1g capsules of Seven Seas Marine Oil 1 per day or ten identical air-filled placebo capsules.  The primary outcome measure was a > 30% reduction of daily NSAID use after 9 months of treatment.  Treatment effect on disease activity was a secondary outcome.  The power of the study was 90% and data was considered statistically significant at P-values of < 0.05.  Data was handled on both an intention to treat and per protocol basis. 

Results:  Thirty-two (65%) patients in the treatment group and 26 (54%) of the patients in the placebo group completed the study.  Results of the intention to treat analysis showed that 19 of the 49 (39%) patients in the treatment group and 5 of the 48 (10%) patients in the placebo group achieved a > 30% reduction in their daily NSAID requirement at 9 months (p = 0.002; CI 12.2% to 44.5%).  Per protocol analysis showed that 19 out of 32 (59%) of the treatment group and 5 out of 26 (19%) achieved the primary outcome (p = 0.003; CI 17.4% to 62.9%).  There were no significant differences between groups in the majority of the secondary parameters, except for the visual analogue scale for pain reduction from baseline to 9 months.  The treatment group showed a 6.7 ± 3.05mm reduction while the placebo group showed a 1.9 ± 2.40mm increase (p = 0.029; CI -16.38mm to -0.92mm).  The authors concluded that taking 10 grams of cod liver oil significantly reduces the daily NSAID requirement by > 30% in almost 40% of patients without worsening of disease activity. 

Strengths:  The rationale for conducting the study was backed by a justifiable need in the medical community.  Data was analyzed on both an intention to treat and a per protocol basis.  Inclusion and exclusion criteria were adequate for the objective.

Weaknesses:  Dropouts equated to about 40% of the study population.  Unblinding was compromised due to the type of placebo selected.  Results were reported as means ± standard errors rather than standard deviations.  Funding was provided by the company who manufactures the product studied.   Compliance was not adequately determined.  NSAID use was determined by relying on the patients to remember how many doses they took.  Patient NSAID regimens were changed from ER formulations to IR formulations.  Diet and activity levels were not assessed.  Secondary outcome means were based on all patients, not just patients who reduced their NSAID requirements.

Conclusion:  The study showed how fish oil products could be beneficial as NSAID-sparing agents.  However, these findings are overshadowed by the study’s many limitations.  The clinical significance of fish oil was not established through the study results.  Further investigation, under better designed studies, is needed to determine the actual significance of fish oil as an NSAID-sparing agent.

Galarraga B, Ho M, Youssef HM, Hill A, et al.  Cod liver oil (n-3 fatty acids) as an non-steroidal anti-inflammatory drug sparing agent in rheumatoid arthritis.  Rheumatology 2008;47:665-669.

Chris Costelnock, Pharm.D. Candidate