Drug products: Ketoflex, Ketoprofen Mylan, Ketospray, Orudis®, Orudis® Retard, Profenid, Siduro®, Siduro® Retard, Zon
ATC code: M01AE03, M02AA10
Men were at higher risk than women for gastric bleedings from NSAID treatment in a large retrospective study, while women were at higher risk of gastric bleeding during ketoprofen treatment of rheumatoid arthritis. Women had a higher risk of NSAID-induced liver affection in a small case-control study larger in women, while a large cohort study did not find any differences in risk between men and women.
The prevalence of several clinical pain conditions is higher in women than in men. Differences in pharmacokinetics, sex hormones, stress response, or socio-cultural aspects may be of importance [1-3]. Therefore, sex and gender differences of pain medications are difficult to interpret .
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 . No sex differentiation in dosing is recommended by the manufacturer .
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 .
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 .
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 .
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 . 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  or to a generally higher risk of drug-induced liver injury in women .
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)) .
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).
Date of litterature search: 2021-12-13
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- Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth. 2013;111(1):52-8. PubMed
- Sorge RE, Totsch SK. Sex Differences in Pain. J Neurosci Res. 2017;95(6):1271-1281. PubMed
- Dance A. Why the sexes don't feel pain the same way. Nature. 2019;567(7749):448-450. PubMed
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- Orudis (ketoprofen). Summary of Product Characteristics. Swedish Medical Products Agency (MPA [updated 2021-02-08, cited 2021-12-20]
- Famaey JP, Colinet E. A double-blind trial of ketoprofen in the treatment of osteoarthritis of the hip. Rheumatol Rehabil. 1976;Suppl:45-9. PubMed
- Le Loet X. Safety of ketoprofen in the elderly: a prospective study on 20,000 patients. Scand J Rheumatol Suppl. 1989;83:21-7. PubMed
- Castellsague J, Holick CN, Hoffman CC, Gimeno V, Stang MR, Perez-Gutthann S. Risk of upper gastrointestinal complications associated with cyclooxygenase-2 selective and nonselective nonsteroidal antiinflammatory drugs. Pharmacotherapy. 2009;29:1397-407. PubMed
- García Rodríguez LA, Williams R, Derby LE, Dean AD, Jick H. Acute liver injury associated with nonsteroidal anti-inflammatory drugs and the role of risk factors. Arch Intern Med. 1994;154:311-6. PubMed
- Lacroix I, Lapeyre-Mestre M, Bagheri H, Pathak A, Montastruc JL, Club de Reflexion des cabinets de Groupe de Gastro-Enterologie (CREGG) et al. Nonsteroidal anti-inflammatory drug-induced liver injury: a case-control study in primary care. Fundam Clin Pharmacol. 2004;18:201-6. PubMed
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- Samii A, Etminan M, Wiens MO, Jafari S. NSAID use and the risk of Parkinson's disease: systematic review and meta-analysis of observational studies. Drugs Aging. 2009;26:769-79. PubMed
- Salman S, Sherif B, and Al-Zohyri A. OP0131 Effects of Some Non Steroidal Anti-Inflammatory Drugs on Ovulation in Women with Mild Musculoskeletal Pain. Annals of the Rheumatic Diseases. 2015;74(suppl 2):117-118. länk
- Stone S, Khamashta MA, Nelson-Piercy C. Nonsteroidal anti-inflammatory drugs and reversible female infertility: is there a link?. Drug Saf. 2002;25:545-51. PubMed
- Uhler ML, Hsu JW, Fisher SG, Zinaman MJ. The effect of nonsteroidal anti-inflammatory drugs on ovulation: a prospective, randomized clinical trial. Fertil Steril. 2001;76(5):957-61. PubMed
- Matyas RA, Mumford SL, Schliep KC, Ahrens KA, Sjaarda LA, Perkins NJ et al. Effects of over-the-counter analgesic use on reproductive hormones and ovulation in healthy, premenopausal women. Hum Reprod. 2015;30(7):1714-23. PubMed
- Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk
Reviewed by: Carl-Olav Stiller, Diana Rydberg
Approved by: Karin Schenck-Gustafsson