Morphine

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

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 [5].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 [6]. 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 [7].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 [8].

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 [9].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 [5, 10].

Adverse effects

An observational study of elderly people (520 men, 827 women, mean age 73 years) has shown that postoperative nausea and vomiting are more common in women (+91%) [11]. Also, studies on postoperative opioid-induced nausea and emesis have shown this to be higher in women than in men [12, 13]. If this is due to the medication was not explored in these studies.

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (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, 14].Studies have shown that women experience more opioid-induced respiratory depression than men [12]. 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 [10, 15].