Pituitary

, Volume 8, Issue 2, pp 115–122 | Cite as

Stimulation of the Hypothalamic-Pituitary-Adrenal Axis with the Opioid Antagonist Nalmefene

  • Eliza B Geer
  • Rita E Landman
  • Sharon L Wardlaw
  • Irene M Conwell
  • Pamela U. Freda
Article
First Online:

Abstract

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 μg/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 μg/dl. Cortisol levels rose above 18 μg/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.

Key words

nalmefene hypothalamic-Pituitary-Adrenal axis opioid antagonist 
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Oelkers W. Adrenal insufficiency. New Engl J Med 1996;335:1206–1212.CrossRefPubMedGoogle Scholar
  2. 2.
    Grinspoon S, Biller B. Laboratory assessment of adrenal insufficiency. J Clin Endocrinol Metab 1994;79:923–931.CrossRefPubMedGoogle Scholar
  3. 3.
    Ammari F, Issa B, Millward E, Scanion M. A comparison between short ACTH and insulin stress tests for assessing hypothalamic-pituitary-adrenal function. Clin Endocrinol 1996;44:473–476.CrossRefGoogle Scholar
  4. 4.
    Hagg E, Asplund K, Lithner F. Value of basal plasma cortisol assays in the assessment of pituitary-adrenal insufficiency. Clinical Endocrinology 1987;26:221–226.PubMedCrossRefGoogle Scholar
  5. 5.
    Taylor T, Dluhy RG, Williams GH. B-endorphin suppresses adrenocorticoptropin and cortisol levels in normal human subjects. J Clin Endocrinol Metab 1983;57:592–595.PubMedGoogle Scholar
  6. 6.
    Rittmaster RS, Cutler GB J, Sobel DO, et al. Morphine inhibits the pituitary-adrenal response to ovine corticotropin-releasing hormone in normal subjects. J Clin Endocrinol Metab 1985;60:891–895.PubMedGoogle Scholar
  7. 7.
    Grossman A, Gaillard RC, McCartney P, Rees LH, Besser GM. Opiate modulation of the pituitary-adrenal axis: effects of stress and circadian rhythm. Clinical Endocrinology 1982;17:279–286.PubMedCrossRefGoogle Scholar
  8. 8.
    Volavka J. Short-term hormonal effects of naloxone in man. Psychoneuroendocrinology 1980;5:225–234.CrossRefPubMedGoogle Scholar
  9. 9.
    Morley J, Barnetsky N, Wingert T, et al. Endocrine effects of naloxone-induced opiate receptor blockade. J Clin Endocrinol Metab 1980;50:251–257.PubMedGoogle Scholar
  10. 10.
    Plotsky P. Opioid Inhibition of immunoreactive corticotropin-releasing factor secretion into the hypophysial-portal circulation of rats. Regulatory Peptides 1986;16:235–242.CrossRefPubMedGoogle Scholar
  11. 11.
    Nikolarakis K, Pfeiffer A, Stalla G, Herz A. The role of CRF in the release of ACTH by opiate agonists and antagonists in rats. Brain Research 1987;421:373–376.CrossRefPubMedGoogle Scholar
  12. 12.
    Blevins L, Dobs A, Wand G. Naloxone-induced activation of the hypothalamic-pituitary-adrenal axis in suspected central adrenal insufficiency. Am J Med Sci 1994;308(3):167–170.PubMedCrossRefGoogle Scholar
  13. 13.
    Nye E, Hockings G, Grice J, Strakosch C, Torpy D, Jackson R. The use of naloxone for investigating disorders of the hypothalamic-pituitary-adrenal axis. The Endocrinologist 1999;9:161–182.CrossRefGoogle Scholar
  14. 14.
    Schluger J, Ho A, Borg L, et al. Nalmefene causes greater hypothalamic-pituitary adrenal axis activation than naloxone in normal volunteers: implications for the treatment of alcoholism. Alcohol Clin Exp Res 1998;22(7):1430–1436.PubMedCrossRefGoogle Scholar
  15. 15.
    Schultz C, Rivers E, Feldkamp C. A characterization of hypothalamic-pituitary-adrenal axis function during and after human cardiac arrest. Crit Care Med 1993;21:1339–1347.PubMedCrossRefGoogle Scholar
  16. 16.
    Allen J, Cook D, Olsen J. Effect of insulin induced hypoglycemia on ACTH, cortisol, and growth hormone release in man. Mil Med 1975;12:837–840.Google Scholar
  17. 17.
    Raff H, Findling J. A new immunoradiometric assy for corticotropin evaluated in normal subjects and patients with cushings syndrome. Clin Chem 1989;35:596–600.PubMedGoogle Scholar
  18. 18.
    Harrison B, Lesley H, Cayton R, Nabarro J. Recovery of hypothalamic-pituitary-adrenal function in asthmatics whose oral steroids have been stopped or reduced. Clin Endocrinol (Oxf) 1982;17:109–118.CrossRefGoogle Scholar
  19. 19.
    Streck W, Lockwood A. Pituitary adrenal recovery following short term suppression with corticosteroids. Am J Med 1979;66:910–914.CrossRefPubMedGoogle Scholar
  20. 20.
    Hjortrup A, Kehlet H, Lindholm J, Stentoft P. Value of 30-minute adrenocorticotropin (ACTH) test in demonstrating hypothalamic-pituitary-adrenocortical insufficiency after acute ACTH deprivation. J Clin Endocrinol Metab 1983;57:668–670.PubMedGoogle Scholar
  21. 21.
    Dickstein G, Shechner C, Nicholson WE, et al. Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 1991;72:773–778.PubMedCrossRefGoogle Scholar
  22. 22.
    Talwar V, Lodha S, Dash RJ. Assessing the hypothalamo-pituitary-adrenocortical axis using physiological doses of adrenocorticotropic hormone. Q J Med 1998;91:285–290.Google Scholar
  23. 23.
    Rose SR, Lustig RH, Burstein S, Pitukcheewanont P, Broome DC, Burghen GA. Diagnosis of ACTH deficiency comparison of overnight metyrapone test to either low-dose or high-dose ACTH test. Horm Res 1999;52:73–79.CrossRefPubMedGoogle Scholar
  24. 24.
    Weintrob N, Sprecher E, Josefsberg Z, et al. Standard and low-dose short adrenocorticotropin test compared with insulin-induced hypoglycemia for assessment of the hypothalamic-pituitary-adrenal axis in children with idiopathic multiple pituitary hormone deficiencies. J Clin Endocrinol Metab 1998;83(1):88–92.CrossRefPubMedGoogle Scholar
  25. 25.
    Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998;83(5):1558–1562.CrossRefPubMedGoogle Scholar
  26. 26.
    Nye EJ, Grice JE, Hockings GI, et al. Adrenocorticotropin stimulation tests in patients with hypothalamic-pituitary disease: low dose, standard high dose and 8-h infusion tests. Clinical Endocrinology 2001;55:625–633.CrossRefPubMedGoogle Scholar
  27. 27.
    Abdu TAM, Elhadd TA, Neary R, Clayton RN. Comparison of the low dose short synacthen test (I ug), the conventional dose short synacthen test (250 ug), and the insulin tolerance test for the assessment of the hypothalamic-pituitary-adrenal axis in patients with pituitary disease. J Clin Endocrinol Metab 1999;84:838–843.CrossRefPubMedGoogle Scholar
  28. 28.
    Suliman AM, Smith TP, Labib M, Fiad TM, McKenna TJ. The low-dose ACTH test does not provide a useful assessment of the hypothalamic-pituitary-adrenal axis in secondary adrenal insufficiency. Clinical Endocrinology 2002;56:533–539.CrossRefPubMedGoogle Scholar
  29. 29.
    Orth DN, Jackson RV, DeCherney GS, et al. Effect of synthetic ovine corticotropin-releasing factor dose response of plasma adrenocorticotropin and cortisol. J Clin Invest 1983;71:587–595.PubMedCrossRefGoogle Scholar
  30. 30.
    Schulte HM, Chrousos GP, Avgerinos P, et al. The cortico-tropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency. J Clin Endocrinol Metab 1984;58(6):1064–1067.PubMedGoogle Scholar
  31. 31.
    Schlaghecke R, Kornely E, Santen RT, Ridderskamp P. The effect of long-term glucocorticoid therapy on pituitary-adrenal responses to exogenous corticotropin-releasing hormone. N Engl J Med 1992;326(4):226–230.PubMedCrossRefGoogle Scholar
  32. 32.
    Delitala G, Trainer P, Oliva O, Fanciulli G, Grossman A. Opioid peptide and alpha-adrenoceptor pathways in the regulation of the pituitary-adrenal axis in man. J Endocrinol 1994;141:163–168.PubMedCrossRefGoogle Scholar
  33. 33.
    Zis AP, Haskett RF, Albala AA, Carroll BJ. Morphine inhibits cortisol and stimulates prolactin secretion in man. Psychoneuroendocrinology 1984;9(4):423–427.CrossRefPubMedGoogle Scholar
  34. 34.
    Inder W, Ellis M, Evans M, Donald R. A comparison of the naloxone test with ovine CRH and insulin hypoglycemia in the evaluation of the hypothalamic-pituitary-adrenal axis in normal man. Clin Endocrinol 1995;43:425–431.CrossRefGoogle Scholar
  35. 35.
    McAllister A, McCance D, Hadden D, et al. A comparison of the naloxone test with the insulin stress test in patients following transphenoidal surgery. Clin Endocrinol 1999;50:261–265.CrossRefGoogle Scholar
  36. 36.
    Product Information: REVEX (R), nalmefene. New Providence, NJ: Baxter Pharmaceutical Products, 1999.Google Scholar
  37. 37.
    Michel ME, Bolger G, Weissman BA. Binding of a new opiate antagonist, nalmefene, to rat brain membranes. Methods Find Exp Clin Pharmacol 1985;7:175–177.PubMedGoogle Scholar
  38. 38.
    Erturk E, Jaffe C, Barkan A. Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test. J Clin Endocrinol Metab 1998;83:2350–2354.CrossRefPubMedGoogle Scholar
  39. 39.
    Kaplan J, Marx J, Calabro J, et al. Double-blind, randomized study of nalmefene and naloxone in emergency department patients with suspected narcotic overdose. Ann Emerg Med 1999;34:42–50.CrossRefPubMedGoogle Scholar
  40. 40.
    Mason B, Ritvo E, Morgan R, et al. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res. 1994;18(5):1162–1167.PubMedCrossRefGoogle Scholar
  41. 41.
    Ward R, Lawrence R, Hawkins R, DiChiara S, Biegner A, Vacchiano C. The use of nalmefene for intrathecal opioid-associated nausea in postpartum patients. AANA J 2002;70(1):57–60.PubMedGoogle Scholar
  42. 42.
    Clark W, Raps E, Tong D, Kelly R. Cervene (nalmefene) in acute ischemic stroke: final results of a phase III efficacy study. Stroke 2000;31:1234–1239.PubMedGoogle Scholar
  43. 43.
    Mason B, Salvato F, Williams L, Rivto E, Cutler R. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 1999;56(8):719–724.PubMedCrossRefGoogle Scholar
  44. 44.
    McArthur J, Turnbull B, Pehrson J, et al. Nalmefene enhances LH secretion in a proportion of oligo-amenorrheic athletes. Acta Endocrinologica 1993;128:325–333.PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  • Eliza B Geer
    • 1
  • Rita E Landman
    • 1
  • Sharon L Wardlaw
    • 1
  • Irene M Conwell
    • 1
  • Pamela U. Freda
    • 1
    • 2
  1. 1.Department of MedicineColumbia University College of Physicians and SurgeonsNew York
  2. 2.Department of MedicineColumbia College of Physicians and SurgeonsNew York

Personalised recommendations