Sex differences in morphine PK and respiratory pharmacodynamics

Elise Sarton MD PhD

Department of Anesthesiology

Leiden University Medical Center

2300 RC Leiden, The Netherlands

Exogenous opioids, such as morphine, exert powerful pharmacological effects, including analgesia, sedation and respiratory depression. These effects exhibit marked interindividual differences. In addition to the well documented effetcs of age, development/behavior and genetic background, the contribution of sex and hormonal status as factor in the phramacology of opioids (e.g., potency) is become increasingly appreciated. Progress in this area has been slow, perhaps since most studies on analgesic and respiratory effects of opioids utilize male subjects to avoid the need to control for hormonal status. Studies in animals (mice and rats) show that opioids acting at mu-opioid receptors (MOR) are more potent in male compared to female animals. In humans, studies that compare the analgesic effects of opioids in men and women, gender comparisons were not the primary focus of attention of investigation resulting in inadequate controls for confounding variables such as weight, age, opioid plasma concentration, placebo effect, emotional status, fear for addicition, and the fact that men and women modulate pain using neurochemically and genetically distinct mechanisms.

In Leiden, we recently launched an N.W.O. (Netherlands Organization for Pure Research) supported project on the influence of gender on opioid-induced behavior in humans, focussing on analgesia and respiratory depression. Opioids tested so far are morphine and morphine-6-glucuronide (M6G). Furthermore, we assessed the importance of the mu-opioid receptor in morphine and M6G respiratory effects and antinociception by examining the effect of these potent opioids in mice lacking the mu-opioid receptor gene and hence the gene product (i.e., the MOR).

Animal Studies: The studies in the mice lacking exon 2 of the mu-opioid receptor (muORm/m) and their wildtype littermates (WT) indicate the importance of the MOR in morphine and M6G-induced respiratory depression and spinal and supraspinal analgesia. This is of importance since it confirms the concept that MOR’s are the essential targets on both respiratory control and pain response. Furthermore, these studies indicated that the endogenous delta-opioid system plays an important role in the control of breathing frequency.

Human Studies:

1. After iv morphine, arterial plasma concentrations of morphine, M6G and morphine-3-glucuronide did not differ between men and women (as measured over an 8-h period).

2. In women, morphine caused an initial reduction in metabolism in women causing an short term decrease in arterial PCO₂ followed by a slow but persistent increase; In men, a slow incerase in arterial PCO₂was seen without any initial decrease. This suggests that morphine is able to override the metabolicc effects of progesterone but not those of testosterone.

3. Depression of hypoxic and hypercapnic ventilatory responses was greater in women than men by a factor of 2 (P < 0.01). This effect was independent of the hormonal status of the women.

4. Baseline pain parameters (pain threshold, pain tolerance) did not differ between men and women: 20 mA for pain threshold and 40 mA for pai tolerance when tested at 1 Hz, 8 mA for pain threshold and 12 mA for pain tolerance when tested at 10 Hz.

5. Relative to men, women showed greater morphine potency but with slower speed of on- and offset. The C₅₀ was about 70 nM in men vs. 42 nM in women, the k_e0 was 0.007 min^-1 in men vs. 0.003 min^-1 in women (P < 0.01).

6. Side effects due to morphine, such as nausea/vomiting, headache, vertigo, heavy feeling, tiredness, sedation, orthostatic hypotension, flushing, etc. were 40% more commen in women than men.

7. Placebo effect was similar in men and women (re: respiration and analgesia).

These data indicate sex differences in opioid effect of similar direction and magnitude in analgesic and respiratory studies. This suggests that a similar molecular mechanism is responsible for this sex-dependent behavior. The animal studies point towards the MOR. However, since the MOR was absent in the muORm/m mice, a definite conclusion regarding specific subtypes or mu-receptor splice variants is not possible. Delta and kappa-opioid receptors seem unimportant in morphine and M6G-induced analgesia and respiratory depression.

Our data are in agreement with the majority of retrospective and prospective studies on the effecst of opioids in men vs. women. For example, PCA morphine-consumption is less in women relative to men (Pain Forum 1999; 8: 34-44), female gender associates with increased duration of intubation and length of stay after coronary artery surgery. (Anesthesiology 2000, 92: 414-424) and girls display more frequent respiratory adverse events than boys after iv fentanyl + midazolam (Pediatric Emergency Care 1996; 12: 31-35).

The importance of the active metabolite M6G in morphine-behavior remains unresolved at this point. At the appropriate dose M6G is a potent and long lasting analgesic, exhibiting mild to moderate respiratory depression (in term of respiratory frequency an increase is observed, most probably due to an increase in arterial PCO₂). However, whether these effects occur at plasma concentrations (60 nM) observed after 0.10-0.15 mg/kg iv morphine remains unresolved but is not probable. Further studies will focus on sex differences in M6G respiratory and analgesic effects.