Ibuprofen

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 effect of patient’s sex on the pharmacokinetics after a single dose 600 mg ibuprofen was evaluated in healthy volunteers (18 men, 19 women). Patient’s sex did not influence peak plasma concentration or the extent of binding to plasma protein. However, half-life was shorter and oral clearance was higher in young men compared to elderly men and women of all ages [5]. No sex differentiation in dosing is recommended by the pharmaceutical company [6].

Effects

A meta-analysis evaluated the effect of patient’s sex on ibuprofen 400 mg in men and non-pregnant women with moderate to severe dental pain (119 men, 195 women, 15-35 years of age). No sex differences in analgesic response to ibuprofen were found [7]. A small study investigated the analgesic efficacy of ibuprofen 600 mg on postoperative endodontic pain (8 men, 7 women). There were no differences in pain reduction between men or women in the ibuprofen and placebo group [8].

Pain relief in children with migraine was examined in a randomized, double-blind, placebo-controlled study (49 boys, 35 girls, age 6-12 years). They were given ibuprofen 7.5 mg/kg or placebo. Boys taking ibuprofen responded effectively while girls did not. No analysis of pharmacokinetics variables was performed [9].

Small experimental studies in healthy individuals have shown that men receiving ibuprofen responded to electrically induced pain while women did not [10, 11].

Adverse effects

The PAIN study (3611 men, 5009 women) was a large randomized double-blind trial of the tolerability of paracetamol, aspirin and ibuprofen. Analysis of potential risk factors for all adverse events among patients in the PAIN study shows that female sex is one risk factor [12].

A nested control study 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 [13].

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 [14]. 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 circulating level hormones and/or greater use of multiple medications in women [15] or to a generally higher risk of drug-induced liver injury in women [16].

The large PRECISION trial (8636 men, 15445 women) compared the cardiovascular safety of celecoxib, naproxen, or ibuprofen. No sex differences were shown [17]. A post hoc study of the PRECISION trial (8591 men, 15359 women) enrolled patients with known cardiovascular disease or risk factors as well as osteoarthritis or rheumatoid arthritis and required regular daily treatment with an NSAID. The risk score was designed to predict the 1-year occurrence of major toxicity including major adverse cardiovascular events, clinically significant gastrointestinal events, acute kidney injury, and death. Male sex and higher age were correlated to higher risk of major toxicities. However, sex-stratified data were not presented for each NSAID and therefore information about which of the studied substances caused the changes in effect and/or adverse events is lacking [18].

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)) [19].

The relationship between use of aspirin or ibuprofen and reduced risk of colorectal polyp prevalence was analysed in a cross-sectional study (19 756 men, 18 640 women). Dose-dependent risk reductions were seen in men using aspirin and ibuprofen > 2 times/day. Protective effects in women were only found among those with BMI <25 and a regular use of aspirin or ibuprofen [20].

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, 21-24]. Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).