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Ketorolac

Classification: A

Drug products: Ketorolac EG, Ketorolac S.A.L.F., Lixidol, Toradol, Tora-dol, Toradol®

ATC code: M01AB15

Substances: ketorolac, ketorolac trometamol

Summary

Women had a higher risk of NSAID-induced liver injury in a small case-control study. No difference in the effect of ketorolac in men and women could be found in an experimental pain model.

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

Ketorolac is primarily eliminated renally (91%) [5]. Pooled data from two pharmacokinetic studies showed that after a single dose of ketorolac (i.v. 0.5 mg/kg), clearance was 37% higher in men than a non-pregnant woman of the same body weight. This sex difference was suggested to be explained by higher renal elimination and higher glucuronidation activity in men. Furthermore, clearance of 20 mg ketorolac administrated to women at the time of delivery were 55% higher than in non-pregnant women with the same body weight [6].

Effects

The analgesic efficacy of ketorolac (10 mg p.o.) was evaluated in a double-blind, placebo-controlled experimental pain method using cold pressor test (25 men, 25 women). No difference between men and women in ketorolac response was found [7].

Adverse effects

 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 [8] or to a generally higher risk of drug-induced liver injury in women [9]. If this is an adverse effect for NSAIDs in general or only associated with certain NSAIDs is unclear. If ketorolac was included is not specified.

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)) [10]. If this is an effect for NSAIDs in general or only associated with certain NSAIDs is unclear. If ketorolac was included is not specified.

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 [5, 11-14]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Updated: 2022-05-05

Date of litterature search: 2022-04-12

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. Toradol (ketorolac). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2021-12-09, cited 2022-04-12]
  6. Välitalo PA, Kemppainen H, Kulo A, Smits A, van Calsteren K, Olkkola KT et al. Body weight, gender and pregnancy affect enantiomer-specific ketorolac pharmacokinetics. Br J Clin Pharmacol. 2017;83(9):1966-1975. PubMed
  7. Compton P, Charuvastra VC, Ling W. Effect of oral ketorolac and gender on human cold pressor pain tolerance. Clin Exp Pharmacol Physiol. 2003;30:759-63. PubMed
  8. 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
  9. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95-106. PubMed
  10. 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
  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. Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.] länk

Authors: Linnéa Karlsson Lind

Reviewed by: Diana Rydberg

Approved by: Karin Schenck-Gustafsson