Nalmefene Stimulation of the HPA Axis.
Background: The Hypothalamic-pituitary-adrenal (HPA) axis plays a vital role in the body's response to stress. The traditional gold standard for evaluating the HPA axis, the insulin hypoglycemia test (IHT), has several known limitations, and a second test, the standard ACTH stimulation test, can detect severe deficiencies of cortisol, but often misses mild or early cases. Therefore, a better test for the evaluation of the HPA axis is needed. This study evaluated the opiate antagonist nalmefene as a stimulation test of the HPA axis.
Methods: 25 healthy subjects were studied, 9 women and 16 men, mean age 30.4 yr. (range 21-55), and mean BMI 24.1 kg/m2 (range 18.6-34.2). Subjects received one of 3 doses of intravenously administered nalmefene: 2 mg (n = 6), 6 mg (n = 12), or 10 mg (n = 7). Serum cortisol and plasma ACTH were measured before and serially over two hours after the administration of nalmefene.
Results: ACTH and cortisol levels rose significantly and similarly after the 10 mg dose and the 6 mg dose. After the 10 mg dose, mean peak ACTH was 82.4 +/- 22.6 pg/ml and mean peak cortisol was 25.2 +/- 1.8 microg/dl. After the 6 mg dose, mean peak ACTH was 70.3 +/- 7.7 pg/ml and mean peak cortisol was 24.7 +/- 1.7 microg/dl. Cortisol levels rose above 18 microg/dl in all subjects receiving 10 mg of nalmefene, and in all but two of the subjects receiving 6 mg of nalmefene. Side effects to nalmefene were of greater duration and intensity in the subjects receiving 10 mg of nalmefene vs. those receiving 6 or 2 mg. These included most notably fatigue, lightheadedness, nausea and vomiting.
Conclusions: Of the nalmefene doses we studied, 6 mg achieved the best combination of stimulation of ACTH and cortisol and fewest side effects. If further studies show a concordance between nalmefene and IHT, nalmefene testing could be used to assess the HPA axis in patients at risk for dysfunction of this axis.