Drug products: Alindrin®, Ardinex®, Brufen Retard, Brufen®, Burana, Burana Comp, Burana®, Childrens Ibuprofen, Comboval, Dolerin, Ibetin, Ibumax, Ibumetin, Ibumetin®, Ibuprofen 2care4, Ibuprofen ABECE, Ibuprofen Actavis, Ibuprofen Apofri, Ibuprofen Aristo, Ibuprofen B. Braun, Ibuprofen Bril, Ibuprofen Evolan, Ibuprofen Fyro, Ibuprofen NET, Ibuprofen Orifarm, Ibuprofen Orion, Ibuprofen Pfleger, Ibuprofen ratiopharm, Ibuprofen Zentiva, Ibux, Ifenin, Ipren, Ipren®, Iprensa, Neoprofen, Nurofen, Nurofen Apelsin, Nurofen Jordgubb, Nurofen Junior, Nurofen voor Kinderen, Pedea®, Perdophen Pediatrie
ATC code: C01EB, C01EB16, M01AE01, M02AA13, N02AJ08, N02BE51
Substances: ibuprofen, ibuprofen arginate, ibuprofen D,L-lysine, ibuprofen DC 85, ibuprofen sodium dihydrate
Ibuprofen provide pain relief in both men and women. However, studies have shown conflicting results on the effect of ibuprofen in men and women. A meta-analysis of dental pain showed no differences in the effect between men and women. Some small studies have shown a better pain relief in men/boys.
A large epidemiologic pain study of many analgesics has shown that women have more side effects. Men were at higher risk than women for gastric bleedings from NSAID treatment in a large retrospective study. Women had a higher risk of NSAID-induced liver affection in a small case-control study, while a large cohort study did not find any differences in risk between men and women. No sex differences in the risk of cardiovascular events have been shown.
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 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 . No sex differentiation in dosing is recommended by the pharmaceutical company .
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 . 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 .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 .Small experimental studies in healthy individuals have shown that men receiving ibuprofen responded to electrically induced pain while women did not [10, 11].
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 .
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 .
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 circulating level hormones and/or greater use of multiple medications in women  or to a generally higher risk of drug-induced liver injury in women .
The large PRECISION trial (8636 men, 15445 women) compared the cardiovascular safety of celecoxib, naproxen, or ibuprofen. No sex differences were shown . 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 .
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)) .
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 .
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).
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
- Greenblatt DJ, Abernethy DR, Matlis R, Harmatz JS, Shader RI. Absorption and disposition of ibuprofen in the elderly. Arthritis Rheum. 1984;27:1066-9. PubMed
- Ipren (ibuprofen). Summary of Products Characteristics. Swedish Medical Products Agency (MPA) [updated 2021-02-17, cited 2021-12-13].
- Averbuch M, Katzper M. A search for sex differences in response to analgesia. Arch Intern Med. 2000;160:3424-8. PubMed
- Ryan JL, Jureidini B, Hodges JS, Baisden M, Swift JQ, Bowles WR. Gender differences in analgesia for endodontic pain. J Endod. 2008;34:552-6. PubMed
- Lewis DW, Kellstein D, Dahl G, Burke B, Frank LM, Toor S et al. Children's ibuprofen suspension for the acute treatment of pediatric migraine. Headache. 2002;42:780-6. PubMed
- Butcher BE, Carmody JJ. Sex differences in analgesic response to ibuprofen are influenced by expectancy: a randomized, crossover, balanced placebo-designed study. Eur J Pain. 2012;16:1005-13. PubMed
- Walker JS, Carmody JJ. Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen. Anesth Analg. 1998;86:1257-62. PubMed
- Moore N, Charlesworth A, Van Ganse E, LeParc JM, Jones JK, Wall R et al. Risk factors for adverse events in analgesic drug users: results from the PAIN study. Pharmacoepidemiol Drug Saf. 2003;12:601-10. 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
- Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95-106. PubMed
- Nissen SE, Yeomans ND, Solomon DH, Lüscher TF, Libby P, Husni ME et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis. N Engl J Med. 2016;375(26):2519-29. PubMed
- Solomon DH, Shao M, Wolski K, Nissen S, Husni ME, Paynter N. Derivation and Validation of a Major Toxicity Risk Score Among Nonsteroidal Antiinflammatory Drug Users Based on Data From a Randomized Controlled Trial. Arthritis Rheumatol. 2019;71(8):1225-1231. PubMed
- 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
- Johnson CC, Hayes RB, Schoen RE, Gunter MJ, Huang WY, PLCO Trial Team. Non-steroidal anti-inflammatory drug use and colorectal polyps in the Prostate, Lung, Colorectal, And Ovarian Cancer Screening Trial. Am J Gastroenterol. 2010;105:2646-55. 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
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Reviewed by: Carl-Olav Stiller, Diana Rydberg
Approved by: Karin Schenck-Gustafsson