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The Impact Of Long-term Opioid Treatment On Endocrine Parameters

The Impact Of Long-term Opioid Treatment On Endocrine Parameters

The injudicious use of opioids has always been a significant concern for health practitioners. It is due to the propensity of users to develop a dependence on these medications and the debilitating adverse effects associated with extended use of opioids. New research gratifies these worries and shows the impact of long-term opioid use on the endocrine function of patients with chronic non-cancer pain.

The Background of the Study

Experts from the Copenhagen University Hospital, Denmark, have linked long-term opioid treatment to deranged endocrine parameters in chronic non-cancer pain patients in their outstanding research published in the European Journal of Pain [1]. Previous evidence-based studies have revealed a significant rise in chronic non-cancer cases and a rapid growth of opioid use in Europe in recent years, necessitating this index study [2] [3]. Notably, prior studies had failed to elucidate the potential adverse effects and long-term consequences of extended use of opioids on patients, particularly in chronic non-cancer (CNCP) patients. This knowledge gap could lead to misinformation among patients and medical practitioners and affect patient management and treatment outcomes. Ultimately, it could result in poorer health and quality of life for patients.

Even though few human studies have been done on this topic, animal studies show that opiates cause short-term and chronic alterations in endocrine parameters [4]. Typically, these modifications can be peripherally mediated by direct effects on endocrine glands or centrally mediated by the hypothalamic-pituitary pathways. The proposed mechanism is that opioids attach to specific opioid receptors, mainly in the hypothalamus, interfering with the pulsatile release of hormones. Also, 0pioids bind to opioid receptors in the pituitary gland, testis, and ovaries, modulating gonadal activity. Additionally, these animal studies revealed that opioids bind to receptors in the zona reticularis of the adrenal cortex (the part of the adrenal cortex responsible for producing dehydroepiandrosterone (DHEA) — a precursor hormone for testosterone and estrogen), altering the adrenal steroidogenesis and indirectly causing hypogonadism.

In corroboration, studies on patients with acute and cancer-related pain who used opioids or abused heroin indicated that more than half of the men treated with opioids developed hypogonadism [5]. These studies also showed low growth hormone (GH) secretion levels and adrenal insufficiency in cancer patients who use opioids for extended periods. Also, some experts have hypothesized that long-term opioid intake can modulate glucocorticoids and reduce insulin blood levels.

Given the above reasons and, crucially, a dearth of studies on the effects of long-term use of opioids in managing non-cancer pain cases, the researchers aimed to discover if this practice has endocrine consequences.


The Study Method

This cross-sectional comparative study was conducted from 2014 to 2021 at the Multidisciplinary Pain Center at the Copenhagen University Hospital, Denmark. The researchers recruited 259 patients with chronic non-cancer pain for at least six (6) months for the study [1]. The participants were between 18 and 59 years old, educated, and regular outpatients of the Multidisciplinary Pain Center.

The participants were subsequently allocated to two (2) different groups; an opioid group and a control group. The participants in the opioid group had a continuous morphine daily dose of at least 30 milligrams (mg) for four (4) weeks or more. In contrast, the control group had no opioids for at least four (4) weeks. The participants in the opioid group were further divided into a high-dose opioids sub-group (Participants in this subgroup received more than 90 milligrams of morphine daily) and low dose opioids sub-group (participants who belonged to this sub-group got less than 90 milligrams daily dose of morphine) [1].

Patients currently on or who had taken hormonal, anti-hormonal, and other drugs that could impact the endocrine function in the last six months were excluded from the study. Also, individuals who had taken adjuvant analgesics, hypnotics, and benzodiazepines in the 4 weeks before the study were excluded. Additionally, pregnant, lactating patients with active cancers, liver, renal or endocrine conditions were excluded from the study [1].

The researchers obtained data concerning the participants’ bio-demographics, pain features, opioid therapy, and other relevant information from their health records at the Multidisciplinary Pain Center. The researchers ensured that blood samples from the study participants were taken at a fixed time, between 9.45 am to 12.45 pm, to ensure the homogeneity of the endocrine measures being assessed. The patients were also fasted. The hormones considered include cortisol, thyroid stimulating hormone (TSH), thyroxine, Insulin-like growth factor (IGF-1), prolactin, 17- hydroxyprogesterone, dehydroepiandrosterone (DHEAS), androstenedione, sex hormone-binding globulin (SHBG) and total testosterone.

In addition, the first 20 patients in each group underwent a 30-minute adrenocorticotropic hormone (ACTH) test to evaluate adrenocortical function as part of an exploratory sub-study. After obtaining a blood sample from the patient for other measurements, synthetic ACTH was administered directly into the patient’s bloodstream. After 30 minutes, a second cortisol blood sample was drawn. The normal adrenocortical function was defined as a plasma cortisol concentration of 420 nmol/L or more after stimulation. Afterward, general blood samples were taken to assess the participants’ hematology, infectious parameters, and kidney and liver function.



Concerning the statistical analysis of the study, the Wilcoxon two-sample test and the chi-square test were used to analyze numerical data and categorical data, respectively. Age, body mass index (BMI), alcohol consumption, and tobacco use were all accounted for using unpaired multiple regression analysis since they were either significantly different across groups or were known to affect the outcome parameters. Afterward, the researchers compared the findings for the opioid and control groups, also the high-dose opioid sub-group and low-dose opioid sub-group.



Only 82 patients of the 259 individuals found eligible for the study participated, as 124 patients were excluded and 53 patients declined participation. Thirty-eight (38) patients were allocated to the opioid group, while forty-four (44) patients were included in the control group.

The study revealed the following findings concerning the endocrine parameters assessed.

  • Cortisol: There were no statistically significant differences in cortisol levels between the control and opioid groups, as the spot cortisol levels in both groups were at the upper end of the usual range for clock time.
  • ACTH: All participants exhibited a normal response to ACTH stimulation, with no peak cortisol levels below the cut-off value of 420 nmol/L 30 minutes after stimulation. Consequently, none had adrenal insufficiency. The peak cortisol levels following ACTH administration differed significantly between the two groups. Patients in the control group had more significant peak cortisol responses to stimulation than patients on long-term opioid therapy. Furthermore, there were no significant differences in cortisol levels between high and low opioid dose sub-groups. Due to the limited sample size, the researchers didn’t analyze the relationship between opioid dosage and the results of the ATCH stimulation test.
  • Androgens: Male patients on long-term opioid therapy (L- TOT) had decreased levels of total testosterone (TT), free testosterone (fT), dehydroepiandrosterone (DHEAS), and an increased blood level of sex hormone-binding globulin SHBG compared to male controls. However, there was no difference in TT, fT, SHBG, DHEAS, 17-hydroxyprogesterone, or androstenedione levels in pre- or postmenopausal women on long-term opioid treatment (L- TOT) compared to controls. Also, there was no significant change in TT or fT between male CNCP patients on high- and low-dose opioids. The findings showed significantly lower fT blood levels in premenopausal women receiving high doses of opioids than women on low-dose opioids.
  • Prolactin: Patients receiving long-term opioid therapy had significantly higher prolactin blood levels than the participants in the control group
  • Thyroid Stimulating Hormone (TSH): The results revealed no significant difference in TSH levels between groups.
  • Insulin-like Growth Factor 1 (IGF-1): IGF-1 levels were significantly lower in the opioid group than in the control group. Furthermore, the results suggested a correlation between low IGF-1 levels and increased opioid doses.



The results of this exploratory study showed that L- TOT was significantly linked to lower fT in men and lower IGF- 1 SDS, moderately associated with lower TT and lower IGF- 1, and weakly linked to lower DHEAS and higher SHBG in men, as well as a raised prolactin blood levels and reduced cortisol response to the ACTH stimulation test. The study also showed a substantial correlation between Opioid dosage and IGF-1 levels [1].

Importantly, this study suggests that long-term opioid therapy raises patients’ risk of developing hypogonadism. Although there is very little research on long-term opioid therapy, available evidence corroborates the findings of this study as most of the studies point towards low luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), free testosterone (fT), estradiol, and dehydroepiandrosterone (DHEAS)  as a consequence of long-term opioid treatment (L-TOT) [6], [7]. Consequently, reduced libido, erectile dysfunction, irregular menstruation, and infertility are all potential complications of long-term opioid treatment.

In addition, hypogonadism may contribute to increased pain perception and the development of hyperalgesia, according to data from a single randomized controlled trial examining the effects of testosterone replacement therapy. It is significant because it implies that long-term analgesia with opioids could result in a reduced pain threshold for the patient, necessitating more pain relief or an increase in daily opioid doses. Ultimately, it could increase patients’ risk of experiencing other possible complications of opioid treatment.

Furthermore, this study’s findings indicate that patients on long-term opioids risk developing a hyperglycemic state and its attending complications as reduced insulin-like growth factor-1 is associated with reduced insulin blood levels.

The study revealed that the opioid group had a higher BMI and prolactin blood level. Prolactin stimulates adipogenesis and inhibits lipolysis, resulting in increased fat tissue. It implies that individuals on prolonged opioid treatments are likely to gain excess weight or become obese.


Limitations of the Study

This research has specific limitations that should be taken into account. They include:

  • The study’s cross-sectional design limits its ability to draw causal conclusions with certainty.
  • The study’s small sample size prevented an assessment of the variations in the effects of different opioids. It may be significant since opioids bind to many receptors with varied efficacies.
  • In addition, the ACTH stimulation test was only performed in a small subgroup due to logistical constraints.
  • Furthermore, the number of outcomes investigated in this study increases the likelihood of random results.



This study substantially adds to the pool of knowledge on the probable consequences of extended use of opioids on the endocrine function of patients with chronic non-cancer pain. However, more research is required to grasp the impact of long-term opioid treatment on patients’ overall health.



  1. Diasso, P. D. K., Abou-Kassem, D., Nielsen, S. D., Main, K. M., Sjøgren, P., & Kurita, G. P. (2023). Long-term opioid treatment and endocrine measures in chronic non-cancer pain patients. European Journal of Pain (London, England).
  2. Hamina, A., Hjellvik, V., Handal, M., Odsbu, I., Clausen, T., & Skurtveit, S. (2022). Describing long-term opioid use utilizing Nordic prescription registers-A Norwegian example. Basic & clinical pharmacology & toxicology, 130(4), 481–491.
  3. Ekholm, O., Diasso, P. D. K., Davidsen, M., Kurita, G. P., & Sjøgren, P. (2022). Increasing prevalence of chronic non-cancer pain in Denmark from 2000 to 2017: A population-based survey. European journal of pain (London, England), 26(3), 624–633.
  4. Vuong, C., Van Uum, S. H., O’Dell, L. E., Lutfy, K., & Friedman, T. C. (2010). The effects of opioids and opioid analogs on animal and human endocrine systems. Endocrine reviews, 31(1), 98–132.
  5. de Vries, F., Bruin, M., Lobatto, D. J., Dekkers, O. M., Schoones, J. W., van Furth, W. R., Pereira, A. M., Karavitaki, N., Biermasz, N. R., & Zamanipoor Najafabadi, A. H. (2020). Opioids and Their Endocrine Effects: A Systematic Review and Meta-analysis. The Journal of clinical endocrinology and metabolism, 105(3), 1020–1029.
  6. Valverde-Filho, J., da Cunha Neto, M. B., Fonoff, E. T., Meirelles, E.deS., & Teixeira, M. J. (2015). Chronic spinal and oral morphine-induced neuroendocrine and metabolic changes in noncancer pain patients. Pain medicine (Malden, Mass.), 16(4), 715–725.
  7. Wong, D., Gray, D. P., Simmonds, M., Rashiq, S., Sobolev, I., & Morrish, D. W. (2011). Opioid analgesics suppress male gonadal function but opioid use in males and females does not correlate with symptoms of sexual dysfunction. Pain research & management, 16(5), 311–316.
  8. Basaria, S., Travison, T. G., Alford, D., Knapp, P. E., Teeter, K., Cahalan, C., Eder, R., Lakshman, K., Bachman, E., Mensing, G., Martel, M. O., Le, D., Stroh, H., Bhasin, S., Wasan, A. D., & Edwards, R. R. (2015). Effects of testosterone replacement in men with opioid-induced androgen deficiency: a randomized controlled trial. Pain, 156(2), 280–288.




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