Weakness and Fatigue in Cancer Patients Managing Pain With Opioids May Partly Be Caused by Endocrine Dysfunction

Gonadal function Significantly Affected

Opioids are commonly used as first-line therapy for cancer-related pain, and their long-term use is associated with a number of side effects which include physical dependence and nausea. Endocrine dysfunction is emerging as another consequence of the therapy, yet, it is seldom diagnosed in this patient population.1

Opioid therapy was shown to affect secretion of testosterone as well as the hypothalamic-pituitary axis, the latter effect being mediated by µ-opioid receptors.2,3,4 In a recent study published in Experimental and Therapeutic Medicine, researchers sought to determine whether cancer patients treated with opioid to manage their pain had higher prevalence of endocrinopathy.5

Data from 20 patients diagnosed with malignant tumors and cancer-associated pain, and treated at the Oncology Clinic at Akdeniz University Hospital, Antalya, Turkey between 2009 and 2013 (median follow-up of 9.4 months) were included in this retrospective study. Serum levels of free and total testosterone (65% men), FSH, LH and estradiol (35% women), as well as TSH, free thyroxine (fT4), prolactin, ACTH, cortisol and growth hormone (GH) were measured.

Study excluded patients with a history of pituitary tumors, hormone replacement therapy, and with other conditions and/or patients taking medications affecting the endocrine system or HPA axis. Patients who had chronic cancer-associated pain and were treated daily with a morphine equivalent daily dose (MEDD) ≥ 25 mg/dl for 1 month or longer were included in the study. The visual analog score (VAS) was used to measure pain, and was <2 for all study patients (i.e. mild to no pain).

Serum TSH levels were above and below normal range in 20% and 5% of the patients, respectively. 5.2% of patients had below normal fT4 serum levels. 15% and 40% of patients had below and higher than normal range respectively of serum cortisol concentration. Total serum testosterone and serum free testosterone were also affected in patients, with 68.7% and 57.1% respectively below the normal range. 30% and 45% of patients had serum FSH levels lower and higher than the normal range, respectively. Serum LH levels were also affected, with 30% of patients with lower than normal, and 40% with higher than normal range. 42.9% of patients had serum prolactin concentrations above normal values, and 25% and 12.5% of patients had lower and higher than normal range values of serum estradiol, respectively.

A logistic regression analysis showed no significant association between MEDD and levels of TSH, fT4, FSH, LH, ACTH, cortisol or prolactin, but revealed a link between MEDD and decreases in levels of total and free testosterone (p = .04 and .041, respectively). Higher MEDD was also linked with increases in prolactin levels (p =.083) and age (p ≤.001).

This study shows that gonadal function may be affected by opioid therapy in cancer patients; this may result in hyperprolactinemia. The authors conclude that symptoms of fatigue and weakness often observed in cancer patients may partly be due to adrenocortical insufficiency when concurrent with opioid therapy, and recommend screening for sex hormone deficiencies prior to and during opioid therapy.


1. Buss T, Leppert W. Opioid-induced endocrinopathy in cancer patients: an underestimated clinical problem. Adv Ther. 2014;31(2):153-67.

2. Adams ML, Sewing B, Forman JB, Meyer ER, Cicero TJ. Opioid-induced suppression of rat testicular function. J Pharmacol Exp Ther. 1993;266(1):323-8.

3. Vuong C, Van uum SH, O’dell LE, Lutfy K, Friedman TC. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev. 2010;31(1):98-132.

4. Ducat E, Ray B, Bart G, et al. Mu-opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic-pituitary-adrenal axis adrenocorticotropic hormone stress response to metyrapone. Addict Biol. 2013;18(2):325-31.

5. Merdin A, Merdin FA, Gündüz Ş, Bozcuk H, Coşkun HŞ. Opioid endocrinopathy: A clinical problem in patients with cancer pain. Exp Ther Med. 2016;11(5):1819-1822.

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