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Diclofenac

Classification: A

Drug products: Arthrotec forte, Arthrotec®, Arthrotec® forte, Diclofenac Bluefish, Diclofenac T ratiopharm, Dicuno, Diklofenak Mylan, Diklofenak Orifarm, Diklofenak Sandoz, Diklofenak T ABECE, Diklofenak T Apofri, Diklofenak T Orifarm, Diklofenak/Misoprostol Actavis, Eeze, Eezeneo, Ignorin, Modifenac, Voltaren, Voltaren Dispers, Voltaren T, Voltaren®, Voltaren® T

ATC code: M01AB05, M01AB55, M01BX

Substances: diclofenac, diclofenac diethylamine, diclofenac epolamine, diclofenac potassium, diclofenac sodium

Summary

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. Published controlled studies on differences between men and women in effect and pharmacokinetics of diclofenac are lacking.

Additional information

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 [4].

Pharmacokinetics and dosing

No studies with a clinically relevant sex analysis regarding the pharmacokinetics or dosing of diclofenac have been found.

Effects

No studies with a clinically relevant sex analysis regarding the effects of diclofenac have been found.

Adverse effects

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 diclofenac was 2.2 compared to 4.0 for naproxen, and 1.6 for ibuprofen [5].

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 [6]. 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 polypharmacy in women [7] or to a generally higher risk of drug-induced liver injury in women [8].

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)) [9].

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 [10-14]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Updated: 2022-12-22

Date of litterature search: 2021-12-13

References

  1. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB et al. Studying sex and gender differences in pain and analgesia: a consensus report. Pain. 2007;132 Suppl 1:S26-45. PubMed
  2. 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
  3. Sorge RE, Totsch SK. Sex Differences in Pain. J Neurosci Res. 2017;95(6):1271-1281. PubMed
  4. Dance A. Why the sexes don't feel pain the same way. Nature. 2019;567(7749):448-450. PubMed
  5. 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
  6. 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
  7. 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
  8. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95-106. PubMed
  9. 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
  10. Voltaren (diklofenak). Summary of Product Characteristics. Swedish Medical Products Agency (MPA) [updated 2020-11-25, cited 2021-12-13]
  11. 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
  12. 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
  13. 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
  14. 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
  15. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk
  16. Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.] länk

Authors: Alan Fotoohi, Linnéa Karlsson Lind

Reviewed by: Carl-Olav Stiller, Diana Rydberg

Approved by: Karin Schenck-Gustafsson