Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency


  • Gary Eichenbaum, PhD
  • Karin Göhler, MD
  • Mila Etropolski, MD
  • Ilona Steigerwald, MD, PhD
  • Joseph Pergolizzi, MD
  • Myoung Kim, PhD, MA
  • Gary Vorsanger, PhD, MD



OPIAD, tapentadol, opioid, adverse event, hormone


Objectives: Opioid-induced androgen deficiency (OPIAD) affects patients treated with opioid analgesics. The norepinephrine reuptake inhibitor (NRI) and μ-opioid receptor (MOR) agonist activities of tapentadol may result in tapentadol having less effect on serum androgen concentrations than analgesics acting through the MOR alone, such as morphine and oxycodone. The objectives of this publication are to 1) evaluate the effects of tapentadol (NUCYNTA and NUCYNTA extended release [ER]) on sex hormone concentrations in healthy male volunteers (vs placebo and morphine) and patients with osteoarthritis (vs placebo and oxycodone), and 2) present a mechanistic hypothesis explaining how the combined MOR agonist and NRI activities of tapentadol may result in less impact on androgen concentrations.

Methods: Three clinical studies were conducted: study 1 (single-dose comparison study vs morphine in healthy volunteers), study 2 (single-dose-escalation study in healthy volunteers without an active comparator), and study 3 (multiple-dose study vs oxycodone in patients with osteoarthritis). Studies 1 and 2 were conducted at medical research centers in Germany and the United Kingdom; study 3 was conducted at primary and secondary care centers and medical research centers in the United States. All three studies were randomized, double blind, and placebo controlled. Concentrations of testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH; study 3 only) were evaluated at 6 and 24 hours postdose in studies 1 and 2, respectively, and at varying time points postdose in study 3.

Results: In study 1, mean serum total testosterone concentrations in healthy male volunteers were similar at baseline for all treatment periods; 6 hours after dosing, mean concentrations were comparable between placebo (8.6 nmol/L) and tapentadol immediate release (IR; 43 mg, 8.8 nmol/L; 86 mg, 9.3 nmol/L), but were lower following administration of morphine IR 30 mg (5.4 nmol/L). In study 2, there were no or minimal changes in testosterone in the therapeutic dose range with tapentadol IR (75-100 mg), and there was a modest decrease that appeared to level off in the supratherapeutic range (125-175 mg); mean testosterone and LH concentrations with all doses remained within normal ranges (testosterone, 4.56-28.2 nmol/L; LH, 2.9-4.6 U/L). In study 3, the decrease in the mean [standard deviation] testosterone concentration from baseline to endpoint for male patients receiving tapentadol ER (100 mg, 1.9 [0.71] nmol/L; 200 mg, 2.1 [0.93] nmol/L) was numerically smaller compared to oxycodone CR (20 mg, 2.7 [0.93] nmol/L), but higher compared to placebo (0.3 [1.62] nmol/L).

Conclusions: These results suggest that tapentadol, which has combined MOR and NRI activities, may have a lower impact on sex hormone concentrations than pure opioid analgesics, such as morphine or oxycodone. The data and mechanistic rationale presented herein provide a justification for conducting additional hypothesis testing studies, and are not intended to be used as a basis for clinical decision making. Future studies may help elucidate whether the observed trends are clinically significant and would translate into a reduced incidence of OPIAD.

Author Biographies

Gary Eichenbaum, PhD

Janssen Research & Development, LLC, Raritan, New Jersey.

Karin Göhler, MD

Global Clinical Pharmacology, Grünenthal GmbH, Aachen, Germany.

Mila Etropolski, MD

Janssen Research & Development, LLC, Raritan, New Jersey.

Ilona Steigerwald, MD, PhD

Medical Affairs Europe & Australia, Grünenthal GmbH, Aachen, Germany.


Joseph Pergolizzi, MD

Naples Anesthesia and Pain Associates, Naples, Florida.

Myoung Kim, PhD, MA

Janssen Scientific Affairs, LLC, Raritan, New Jersey.

Gary Vorsanger, PhD, MD

Janssen Scientific Affairs, LLC, Raritan, New Jersey.


Smith HS, Elliott JA: Opioid-induced androgen deficiency (OPIAD). Pain Physician. 2012; 15(3 suppl): ES145-ES156.

Colameco S, Coren JS: Opioid-induced endocrinopathy. J Am Osteopath Assoc. 2009; 109(1): 20-25.

Diver MJ, Imtiaz KE, Ahmad AM, et al.: Diurnal rhythms of serum total, free and bioavailable testosterone and of SHBG in middle-aged men compared with those in young men. Clin Endocrinol (Oxf). 2003; 58(6): 710-717.

Daniell HW: Hypogonadism in men consuming sustainedaction oral opioids. J Pain. 2002; 3(5): 377-384.

Manchikanti L, Fellows B, Singh V: Understanding psychological aspects of chronic pain in interventional pain management. Pain Physician. 2002; 5(1): 57-82.

De Maddalena C, Bellini M, Berra M, et al.: Opioid-induced hypogonadism: Why and how to treat it. Pain Physician. 2012; 15(3 suppl): ES111-ES118.

Aloisi AM, Aurilio C, Bachiocco V, et al.: Endocrine consequences of opioid therapy. Psychoneuroendocrinology. 2009; 34(suppl 1): S162-S168.

Mazer N, Chapman C, Daniell H, et al.: Opioids in non-cancer pain: Opioid induced androgen deficiency in men (OPIAD): An estimate of the potential patient population in the U.S. and Canada. J Pain. 2004; 5(3 suppl): S73; abstract 857.

Fraser LA, Morrison D, Morley-Forster P, et al.: Oral opioids for chronic non-cancer pain: Higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009; 117(1): 38-43.

Daniell HW: Opioid endocrinopathy in women consuming prescribed sustained-action opioids for control of nonmalignant pain. J Pain. 2008; 9(1): 28-36.

Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al.: Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer. 2004; 100(4): 851-858.

Mendelson JH, Mello NK: Plasma testosterone levels during chronic heroin use and protracted abstinence. A study of Hong Kong addicts. Clin Pharmacol Ther. 1975; 17(5): 529-533.

Woody G, Mclellan AT, O’Brien C, et al.: Hormone secretion in methadone-dependent and abstinent patients. NIDA Res Monogr. 1988; 81: 216-223.

Tennant F: Physiologic, endocrine, an inflammation status after 10 years of high dose opioid treatment. J Pain. 2013; 14(4 suppl): S3; abstract 111.

Vuong C, Van Uum SH, O’Dell LE, et al.: The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010; 31(1): 98-132.

Katz N, Mazer NA: The impact of opioids on the endocrine system. Clin J Pain. 2009; 25(2): 170-175.

Sadeghi M, Tzschentke TM, Christie MJ: Mu-opioid receptor activation and noradrenaline transport inhibition by tapentadol in rat single locus coeruleus neurons. Br J Pharmacol. 2015; 172(2): 460-468.

Tzschentke TM, Christoph T, Kögel B, et al.: (−)-(1R,2R)-3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): A novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther. 2007; 323(1): 265-276.

Gabilondo AM, Meana JJ, Barturen F, et al.: Mu-opioid receptor and alpha 2-adrenoceptor agonist binding sites in the postmortem brain of heroin addicts. Psychopharmacology (Berl). 1994; 115(1-2): 135-140.

Garcia-Sevilla JA, Ugedo L, Ulibarri I, et al.: Platelet alpha 2-adrenoceptors in heroin addicts during withdrawal and after treatment with clonidine. Eur J Pharmacol. 1985; 114(3): 365-374.

Kienbaum P, Heuter T, Michel MC, et al.: Chronic mu-opioid receptor stimulation in humans decreases muscle sympathetic nerve activity. Circulation. 2001; 103(6): 850-855.

Herbison AE: Noradrenergic regulation of cyclic GnRH secretion. Rev Reprod. 1997; 2(1): 1-6.

Nicoletti I, Filipponi P, Fedeli L, et al.: Progesterone positive feedback on gonadotropin release in estrogen-primed postmenopausal women: Central nervous system and pituitary as possible sites of action. J Clin Endocrinol Metab. 1981; 53(1): 135-138.

Schule C, Baghai T, Schmidbauer S, et al.: Reboxetine acutely stimulates cortisol, ACTH, growth hormone and prolactin secretion in healthy male subjects. Psychoneuroendocrinology. 2004; 29(2): 185-200.

Terasawa E, Krook C, Hei DL, et al.: Norepinephrine is a possible neurotransmitter stimulating pulsatile release of luteinizing hormone-releasing hormone in the rhesus monkey. Endocrinology. 1988; 123(4): 1808-1816.

Hoy SM: Tapentadol extended release: In adults with chronic pain. Drugs. 2012; 72(3): 375-393.

Nucynta® ER (tapentadol) extended-release oral tablets C-II [package insert]. Raritan, NJ: Janssen Pharmaceuticals, Inc., 2014.

Schroder W, Tzschentke TM, Terlinden R, et al.: Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. J Pharmacol Exp Ther. 2011; 337(1): 312-320.

Daniels S, Casson E, Stegmann JU, et al.: A randomized, double-blind, placebo-controlled phase 3 study of the relative efficacy and tolerability of tapentadol IR and oxycodone IR for acute pain. Curr Med Res Opin. 2009; 25(6): 1551-1561.

Hartrick C, Van Hove I, Stegmann J-U, et al.: Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: A 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin Ther. 2009; 31(2): 260-271.

Gálvez R, Schäfer M, Hans G, et al.: Tapentadol prolonged release versus strong opioids for severe, chronic low back pain: Results of an open-label, phase IIIb study. Adv Ther. 2013; 30(3): 229-259.

Afilalo M, Etropolski MS, Kuperwasser B, et al.: Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: A randomized, double-blind, placebo- and active-controlled phase III study. Clin Drug Investig. 2010; 30(8): 489-505.

Buynak R, Shapiro DY, Okamoto A, et al.: Efficacy and safety of tapentadol extended release for the management of chronic low back pain: Results of a prospective, randomized, double-blind, placebo- and active-controlled phase III study. Expert Opin Pharmacother. 2010; 11(11): 1787-1804.

Lange B, Kuperwasser B, Okamoto A, et al.: Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. Adv Ther. 2010; 27(6): 381-399.

Wild JE, Grond S, Kuperwasser B, et al.: Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Pract. 2010; 10(5):416-427.

Kress HG, Koch ED, Kosturski H, et al.: Tapentadol prolonged release for managing moderate to severe, chronic malignant tumor-related pain. Pain Physician. 2014; 17: 329-343.

Raffa RB, Buschmann H, Christoph T, et al.: Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother. 2012; 13(10): 1437-1449.

Nucynta® (tapentadol) immediate-release oral tablets [package insert]. Raritan, NJ: Ortho-McNeil-Janssen Pharmaceuticals, Inc., 2011.

Mendelson JH, Meyer RE, Ellingboe J, et al.: Effects of heroin and methadone on plasma cortisol and testosterone. J Pharmacol Exp Ther. 1975; 195(2): 296-302.

Rubinstein AL, Carpenter DM, Minkoff JR: Hypogonadism in men with chronic pain linked to the use of long-acting rather than short-acting opioids. Clin J Pain. 2013; 29(10): 840-845.

Braunstein GD, Reitz RE, Buch A, et al.: Testosterone reference ranges in normally cycling healthy premenopausal

women. J Sex Med. 2011; 8(10): 2924-2934.

Spratt DI, O’Dea LS, Schoenfeld D, et al.: Neuroendocrinegonadal axis in men: Frequent sampling of LH, FSH, and testosterone. Am J Physiol. 1988; 254(5 Pt 1): E658-E666.

Pau KY, Lee CJ, Cowles A, et al.: Possible involvement of norepinephrine transporter activity in the pulsatility of hypothalamic gonadotropin-releasing hormone release: Influence of the gonad. J Neuroendocrinol. 1998; 10(1): 21-29.

Veldhuis JD, Rogol AD, Williams FA, et al.: Do alpha-adrenergic mechanisms regulate spontaneous or opiate-modulated pulsatile luteinizing hormone secretion in man? J Clin Endocrinol Metab. 1983; 57(6): 1292-1296.

Kaufman JM, Vermeulen A: Lack of effect of the alphaadrenergic agonist clonidine on pulsatile luteinizing hormone secretion in a double blind study in men. J Clin Endocrinol Metab. 1989; 68(1): 219-222.

Dudas B, Merchenthaler I: Catecholaminergic axons innervate LH-releasing hormone immunoreactive neurons of the human diencephalon. J Clin Endocrinol Metab. 2001; 86(11): 5620-5626.



How to Cite

Eichenbaum, PhD, G., Göhler, MD, K., Etropolski, MD, M., Steigerwald, MD, PhD, I., Pergolizzi, MD, J., Kim, PhD, MA, M., & Vorsanger, PhD, MD, G. (2015). Does tapentadol affect sex hormone concentrations differently from morphine and oxycodone? An initial assessment and possible implications for opioid-induced androgen deficiency. Journal of Opioid Management, 11(3), 211–227.