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Morphine

Classification: C

Drug products: Avinza, Contalgin, Depolan®, Dolcontin, Dolcontin Unotard®, Dolcontin®, Kapanol, Morfin AB Unimedic, Morfin Abcur, Morfin Alternova, Morfin APL, Morfin APL med konserveringsmedel, Morfin Epidural Meda, Morfin Kalceks, Morfin Meda, Morfin Special, Morfin Special APL, Morphine Unimedic, Oramorph®, Sevre-Long®

ATC code: N02AA01

Substances: morphine, morphine hydrochloride, morphine methylbromide, morphine n-oxide, morphine sulfate, morphine sulfate pentahydrate

Summary

A meta-analysis has shown that women have more effect of morphine but time to onset of effect is longer. The lowest effective dose should always be titrated and the longer time to effect onset in women should be considered when evaluating the effect of morphine.

Studies in post-surgical pain patients show that women report more pain and require a higher weight-adjusted dose of morphine to achieve comparable effect to men in pain relief. The difference between the sexes disappeared in elderly men and women.

Additional information

The literature indicates that women and men differ in pain behavior. 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 are higher in women than men 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].

Pharmacokinetics and dosing

A small study (10 men, 10 women) evaluating pharmacokinetics after administration of morphine (bolus dose 0.1 mg/kg followed by an infusion of 0.03 mg/kg per h for 1h) reported that concentrations of morphine, morphine-6-glucoronide (M6G), and morphine-3-glucoronide (M3G) did not differ between men and women [3]. In a retrospective study (2344 men, 1933 women) on pain relief in the immediate postoperative period, women reported more pain and required higher doses (+11%) of morphine than men. However, this difference disappeared in elderly patients [4]. Similar results were reported in another prospective study (277 men, 423 women) which also found that women reported more pain and required higher doses (+30%) of morphine than men for postoperative pain relief [5].Factors influencing of opioid doses prescribed to cancer patients have been analyzed retrospectively according to pharmacy records in North America (3631 men, 3570 women). Patients received sustained-release morphine, sustained-release oxycodone, or transdermal fentanyl. Sustained-release doses were converted to OME (oral morphine equivalent). The mean opioid dose was 142.4 mg/day for women and 157.4 mg/day for men. However, when controlling for age and primary tumor site, this differences was not significant [2].

Effects

A systematic review (in total 6459 men, 6979 women) found sex differences in morphine-induced analgesia in both experimental pain studies and clinical patient-control analgesia studies. The included studies indicate differences in morphine efficacy between men and women. In the experimental studies (11 studies including 245 men, 352 women) a moderately higher effect in women was found for morphine but not for other opioids. In the clinical studies (25 studies, including 5971 men, 6388 women) the results varied, but the meta-analysis showed a higher effect of morphine in women, particularly if longer duration of PCA measurements were made. However, information about weight-adjustment of doses are often lacking [6].

The influence of morphine on experimentally induced pain has been examined in young healthy volunteers (10 men, 10 women; age 21-36 years) receiving intravenous morphine (bolus dose 0.1 mg/kg followed by an infusion of 0.03 mg/kg per h for 1h). Women had higher effect of morphine for both pain threshold and tolerance, but slower speed of onset and offset [3, 7].

Adverse effects

An observational study of elderly people (520 men, 827 women, mean age 73 years) showed that postoperative nausea and vomiting were more common in women (+91%) [8]. Also, studies on postoperative opioid-induced nausea and emesis have shown this to be higher in women than in men [9, 10]. If this is due to the medication was not explored in these studies.

Reproductive health issues

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

Other information

Sex differences in analgesic utilization and efficacy in pain syndromes may reflect pharmacodynamic and pharmacokinetic differences but could also reflect patient and/or prescriber characteristics. A possible explanation to sex differences in opioid consumption is that opioids may be more effective in women, women have more pain, or can have other explanations [1,11].

Studies have shown that women experience more opioid-induced respiratory depression than men [9]. A placebo-controlled randomized clinical trial (13 men, 13 women, ages 18-35 years) studied the influence of sex on morphine-induced respirational stress, as determined by ventilatory carbon dioxide and oxygen responses between men and women. Women treated with morphine showed a decreased sensitivity to ventilatory carbon dioxide and hypoxia by 30% and 50%, respectively. Men treated with morphine had a greater increase in apneic threshold than women. A higher apneic threshold indicates that a higher CO2 pressure is needed to trigger breathing. This suggests that the mechanism of ventilatory depression by morphine differs between the sexes [7, 12].

Updated: 2019-02-26

Date of litterature search: 2015-01-19

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. Hall S, Gallagher RM, Gracely E, Knowlton C, Wescules D. The terminal cancer patient: effects of age, gender, and primary tumor site on opioid dose. Pain Med. 2003;4:125-34. PubMed
  3. Sarton E, Olofsen E, Romberg R, den Hartigh J, Kest B, Nieuwenhuijs D et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology. 2000;93:1245-54; discussion 6A. PubMed
  4. Aubrun F, Salvi N, Coriat P, Riou B. Sex- and age-related differences in morphine requirements for postoperative pain relief. Anesthesiology. 2005;103:156-60. PubMed
  5. Cepeda MS, Carr DB. Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesth Analg. 2003;97:1464-8. PubMed
  6. Niesters M, Dahan A, Kest B, Zacny J, Stijnen T, Aarts L et al. Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies. Pain. 2010;151:61-8. PubMed
  7. Sarton E, Romberg R, Dahan A. Gender differences in morphine pharmacokinetics and dynamics. Adv Exp Med Biol. 2003;523:71-80. PubMed
  8. Conti D, Ballo P, Boccalini R, Boccherini A, Cantini S, Venni A et al. The effect of patient sex on the incidence of early adverse effects in a population of elderly patients. Anaesth Intensive Care. 2014;42:455-9. PubMed
  9. Barrett AC. Low efficacy opioids: implications for sex differences in opioid antinociception. Exp Clin Psychopharmacol. 2006;14:1-11. PubMed
  10. Zun LS, Downey LV, Gossman W, Rosenbaumdagger J, Sussman G. Gender differences in narcotic-induced emesis in the ED. Am J Emerg Med. 2002;20:151-4. PubMed
  11. Kest B, Sarton E, Dahan A. Gender differences in opioid-mediated analgesia: animal and human studies. Anesthesiology. 2000;93:539-47. PubMed
  12. Dahan A, Sarton E, Teppema L, Olievier C. Sex-related differences in the influence of morphine on ventilatory control in humans. Anesthesiology. 1998;88:903-13. PubMed
  13. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-29] länk
  14. Wändell P, Carlsson AC, Wettermark B, Lord G, Cars T, Ljunggren G. Most common diseases diagnosed in primary care in Stockholm, Sweden, in 2011. Fam Pract. 2013;30:506-13. PubMed
  15. Shega JW, Tiedt AD, Grant K, Dale W. Pain measurement in the National Social Life, Health, and Aging Project: presence, intensity, and location. J Gerontol B Psychol Sci Soc Sci. 2014;69 Suppl 2:S191-7. PubMed

Authors: Linnéa Karlsson Lind, Desirée Loikas

Reviewed by: Mia von Euler, Carl-Olav Stiller

Approved by: Karin Schenck-Gustafsson