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Naproxen

Klassificering: A

Preparat: Alpoxen, Bonyl, Eox, Ipaflex, Miranax, Naprocur, Naprosyn, Naprosyn® Entero, Naproxen 2care4, Naproxen ABECE, Naproxen Apofri, Naproxen Bluefish, Naproxen Ebb, Naproxen Evolan, Naproxen Mylan, Naproxen NET, Naproxen Orifarm, Pronaxen, Pronaxen®, Vimovo

ATC kod: M01AE02, M01AE52

Substanser: naproxen, naproxennatrium

Sammanfattning

Män hade högre risk än kvinnor för magblödning av NSAID-behandling i en stor retrospektiv studie. Kvinnor hade högre risk för NSAID-inducerad leverskada i en liten fall-kontrollstudie, medan en stor kohortstudie inte visade någon könsskillnad. Inga könsskillnader i risken för kardiovaskulära bieffekter har visats. Det saknas publicerade kontrollerade studier om skillnader mellan könen avseende effekt av naproxen. Studier har visat att kvinnor har högre fri koncentration av naproxen men den kliniska effekten av detta är oklar.

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

Plasma samples from patients (62 men, 173 women) with osteoarthritis treated with 750 mg naproxen, showed that women had 65% higher free concentration and 41% higher unbound fraction than men. However, no association between free concentration and effect or adverse events was found within the naproxen concentration ranges in this study [5]. Another larger study found similar results (192 men, 433 women) [6]. No sex differentiation in dosing is recommended by the manufacturer [7].

Effects

No studies with a clinically relevant sex analysis regarding the effects of naproxen 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 ketoprofen was 3.4, compared to 2.2 for diclofenac, 4.0 for naproxen, and 1.6 for ibuprofen [8].

A retrospective cohort study (625 307 patients with 2 130 820 prescriptions, one third of these 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 [9]. 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 hormone and/or more polypharmacy in women [10] or to a generally higher risk of drug-induced liver injury in women [11].

The large PRECISION trial (8636 men, 15445 women) compared the cardiovascular safety of celecoxib, naproxen, and ibuprofen. No sex differences were shown [12]. A post-hoc study of the PRECISION trial (8591 men, 15 359 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 [13].

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)) [14].

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 [7, 15-18]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Försäljning på recept

Fler kvinnor än män hämtade ut läkemedel innehållande naproxen (ATC-kod M01AE02) på recept i Sverige år 2020, totalt 245 935 kvinnor och 181 322 män. Det motsvarar 48 respektive 35 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 50-64 år hos båda könen. I genomsnitt var läkemedel innehållande naproxen 1,5 gånger vanligare hos kvinnor [19].

Fler kvinnor än män hämtade ut tabletter innehållande kombination av naproxen och esomeprazol (ATC-kod M01AE52) på recept i Sverige år 2020, totalt 1 505 kvinnor och 929 män. Det motsvarar 0,3 respektive 0,2 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 45-64 år hos båda könen. I genomsnitt var tabletter innehållande kombination av naproxen och esomeprazol 1,6 gånger vanligare hos kvinnor [19].

Receptförskrivet naproxen står för 70 % av försäljningsvolymen [20].

Uppdaterat: 2022-04-06

Litteratursökningsdatum: 2021-12-13

Referenser

  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. Hundal O, Rugstad HE, Husby G. Naproxen free plasma concentrations and unbound fractions in patients with osteoarthritis: relation to age, sex, efficacy, and adverse events. Ther Drug Monit. 1991;13:478-84. PubMed
  6. Rugstad HE, Hundal O, Holme I, Herland OB, Husby G, Giercksky KE. Piroxicam and naproxen plasma concentrations in patients with osteoarthritis: relation to age, sex, efficacy and adverse events. Clin Rheumatol. 1986;5:389-98. PubMed
  7. Pronaxen (naproxen). Summary of Product Characteristics. Swedish Medical Products Agency (MPA [updated 2019-12-11, cited 2021-12-13]
  8. 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
  9. 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
  10. 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
  11. Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89:95-106. PubMed
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk
  20. Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.] länk

Författare: Alan Fotoohi, Linnéa Karlsson Lind

Faktagranskat av: Carl-Olav Stiller, Diana Rydberg

Godkänt av: Karin Schenck-Gustafsson