Ketoprofen

Additional information

The scientific literature indicates that pain behavior and pain perception may vary between men and women. This could be influenced by differences in pharmacokinetics, sex hormones, differences in stress response, or type of pain test. Also, many variables other than a person’s sex/gender account for individual differences in pain sensitivity. The prevalence of several clinical pain conditions is higher in women than in men, which suggests that either different clinical pain mechanisms may operate in men vs. women, or different or additional risk factors are relevant in one sex, or a combination of differences [1-3]. Therefore, sex differences of pain releasing medication might thus be difficult to interpret [4].

Pharmacokinetics and dosing

The pharmacokinetics of ketoprofen enantiomers were evaluated in healthy volunteers (12 men, 13 women) in an unblinded, randomized crossover study. Doses of 25, 50, or 100 mg of (R)-ketoprofen and 100 mg of racemic ketoprofen (R+S) (Orudis®) were administered orally on four separate occasions at least a week apart. Fractional inversion of (R)-ketoprofen was not different between men and women. Women had a higher elimination rate constant for (R)-ketoprofen after the racemate dose. Clearance did not differ between men and women. Thus, the clinical significance is unclear [5]. No sex differentiation in dosing is recommended by the manufacturer [6].

Effects

The only study found regarding sex differences in the effect of ketoprofen was a small double-blind placebo-controlled clinical study (6 men, 11 women) on pain and inflammation in osteoarthritis. No differences between men and women were reported [7].

Adverse effects

The safety of ketoprofen was evaluated in a French multicenter study including patients suffering from painful rheumatic disorders and aged over 60 years (6748 men, 13 029 women). Patients received 200 mg ketoprofen once daily for one month. A multivariate analysis showed that women had more adverse side effects, especially those related to the gastro-intestinal (GI) tract (men: 15.2%; women: 18.4%). However, the sex of the patient was not prognostic for GI adverse drug reactions [8].

This is contrary to the findings in a large nested control study, which estimated the risk of upper gastrointestinal complications associated with selective cox 2-inhibitors and non-selective NSAIDs (including diclofenac, ibuprofen, ketoprofen, naproxen) compared with non-use of NSAIDs. In all > 600 000 individuals contributed to >1 million person-years of observation and 726 upper gastrointestinal complications were identified. Male sex and high age carried a higher risk of complication and suggested a synergistic effect between these factors and NSAIDs on the risk of upper gastrointestinal complications. The risk for upper gastrointestinal complications differed between the various NSAIDs. Adjusted for male sex and age, the OR for ketoprofen was 3.4, compared to 2.2 for diclofenac, 4.0 for naproxen, and 1.6 for ibuprofen [9].

A retrospective cohort study (625 307 patients with 2 130 820 prescriptions, one third of these were to men) found that incidence rates of NSAID-induced acute liver injury were similar for men and women and for the young and the elderly [10]. However, a case-control study (136 men, 130 women) found an association between NSAID exposure and liver injury in women but not in men (OR 6.49 vs. 1.06). This may be due to differences in pharmacokinetics or levels of circulating hormones and/or more poly-pharmacy in women [11] or to a generally higher risk of drug-induced liver injury in women [12].

A meta-analysis evaluated NSAID use and the risk of Parkinson’s disease. Pooled risk ratios of Parkinson’s disease were similar in men and women using NSAID (men 0.79 (95%CI 0.69, 0.92); women 0.72 (95%CI 0.45, 1.15)) [13].

Reproductive health issues

Studies on animal models shows that non-selective NSAIDs (diclofenac, ibuprofen, ketoprofen, ketorolac, naproxen) can affect implantation and ovulation and small clinical studies report that non-selective NSAIDS may cause decreased fertility in some women. However, the effect is reversible after treatment discontinuation [6, 14-17]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).