Long-term opioid treatment and endocrine measures in patients with cancer-related pain: a systematic review

Introduction

The over-all prevalence of pain is 66% in patients with advanced cancer [1], which underpins a high demand for a sustained focus on improving pain management. The basis for cancer pain management is mainly pharmacological treatment, which includes opioids for moderate to severe pain [2]. Opioids are widely recommended due to their superior analgesic effect, multiple routes of administration, ease of titration and no dose-ceiling effect. Thus, opioid therapy is still the mainstay for achieving pain relief and to improve the quality of life for patients with cancer-related pain [3, 4]. However, opioids have well-known side effects such as constipation, nausea, vomiting, urinary retention and respiratory depression, and may have other long-term consequences such as development of tolerance, addiction, hyperalgesia, and alterations of the immune- and endocrine systems [5], [6], [7], [8], [9], [10], [11].

The effects of L-TOT on the endocrine system have been primarily investigated in chronic non-cancer pain patients. Studies have reported increased levels of prolactin (PRL) and suppression of the following endocrine measures: total testosterone (TT), luteinizing hormone (LH), follicular stimulating hormone (FSH), growth hormone (GH), cortisol, insulin like growth factor-1 (IGF-1), estradiol, progesterone, dehydroepiandrosterone (DHEA), adrenocorticotropic hormone (ACTH) and bone mineral density synthesis [11], [12], [13], [14], [15]. Most alterations described may be due to L-TOT inhibitory effects on the hypothalamic pituitary gonadal (HPG) axis involving opioid-induced androgen deficiency (OPIAD), which may result in sexual dysfunction, galactorrhea, amenorrhea, irregular menstrual cycle, infertility, and low libido, ultimately reducing the patients’ quality of life [6, 8, 11, 13, 15, 16].

There are few reviews, which indicated effect of opioids on the endocrine system. However, they have peculiar characteristics as mixed populations with cancer and non-cancer diseases [17] and some limitations as no description of systematic search, among of factors. A former systematic review has investigated L-TOT effects on the HPG-axis and the increased risk of hypogonadism in patients with cancer-related pain [18]; however, the review was conducted in 2013 and included rather few studies with methodological limitations, no evidence assessment-based grading and focus on only hormones from the HPG-axis. Thus, to our knowledge no systematic reviews assessing evidence of L-TOT effects on hormones produced by other hypothalamic pituitary axes, peripheral glands, and other biomarkers in patients with cancer-related pain are existing. Therefore, to answer the research question “In adult patients with cancer-related pain who are in L-TOT, what are the effects of opioids on the endocrine system?”, this systematic review was carried out with the aim to gather and investigate the evidence of effects of L-TOT on the endocrine system in patients with cancer-related pain.

Methods

This systematic review was elaborated based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) [19] and was registered at PROSPERO, ID-number: CRD42020213059 (https://www.crd.york.ac.uk/PROSPERO/).

Results

The systematic database search comprised 236 studies; 45 of them were duplicates.

Thus, 191 studies were screened, out of them 179 were excluded and 12 articles were selected for full reading. Eight articles from the database search were excluded due to other outcomes (n=5) and non-opioid interventions (n=3). 16 articles were found by hand-search, five of them were duplicates. Ten articles from the hand-search were excluded due to other interventions (n=4), other outcomes (n=3), other patient populations (n=2) and other design (n=1). Finally, five cross-sectional studies were included in this review (Figure 1). Two studies have retrieved information about laboratorial blood analyses and collected data retrospectively [16, 24]. One study had four patients in treatment with thyroxine, who were in the control group without opioid treatment (n=167) [25]. Thyroxine did not significantly seem to affect the group’s hormonal levels and accordingly the study was included in this review. Estradiol, TSH and fT₄ were analyzed [16, 25], but due to the very low number of patients with alterations (n=1), they were not mentioned in this section.

Figure 1:

Flow chart of the studies selected for inclusion.

Discussion

In this systematic review regarding effects of L-TOT on the endocrine system in patients with cancer-related pain we found suppression of hormones originating from the HPG-axis including lower levels of TT, fT, LH and FSH. Moreover, alterations in the HPA-axis were observed, which involved higher levels of cortisol, respectively.

In addition, this systematic review found that patients with cancer-related pain who showed signs and symptoms of central hypogonadism and sexual dysfunction related to L-TOT, which is in accordance with findings from other studies [28, 29]. However, the overall assessment of quality of evidence was very low.

It is well-known that the gonadotropic hormones are particularly affected by opioids via a feedback mechanism [30], which affects the gonadal status by an indirectly inhibition of gonadotropin-releasing hormone (GnRH) from hypothalamus [8, 11]. These mechanisms may probably have been in play causing the low concentrations of TT, fT, LH and FSH, which were found in the studies included in the present systematic review [16, 24], [25], [26], [27]. Further, opioids are also known to have a direct effect on the testes resulting in decreased TT and testicular interstitial fluid (TIF) [31]. This has also been observed in studies in other patient populations (chronic non-cancer pain and heroin addicted patients) in L-TOT [32, 33]. Hypogonadism can decrease bone density and mineral metabolism, and increase the risk of fractures [34, 35]. The increased risk of osteoporosis and fractures may be caused by inhibition of osteoblasts and osteocalcin synthesis via opioid receptors [6, 13, 36, 37]. Low TT levels may stimulate secretion of FSH and LH by a negative feedback loop; however, in this systematic review the opposite was observed (low levels of LH and FSH). An explanation for this finding may be that opioids bind to opioid receptors in the pituitary gland and reduce the secretion of LH and FSH. This reduction could also be due to opioid inhibition of the secretion of GnRH, which can decrease the secretion of LH and FSH and result in low TT and estradiol levels. Another explanation for our findings may be that PRL also plays a significant role in the regulation of the gonadal hormones. One of the included studies found increased levels of PRL in 42.9% of the patients (n=14) [16]. Opioid-induced hyperprolactinemia can decrease the pulsatile release of GnRH and decrease gonadal hormone levels (LH and FSH), which result in low levels of TT, which in turn may increase the risk of developing hypogonadism [38, 39].

In a study of the present review, an association between higher MEDDs and higher cortisol levels during L-TOT was reported [24]. The correlation between higher opioid doses and higher cortisol levels in patients with cancer-related pain, may be due to pain and/or stress caused by the cancer disease, which may result in hyperactivity of HPA causing increasing cortisol levels. The unchanged ACTH levels could possibly be due to the high cortisol levels in 40% of the patients (n=20), which may inhibit ACTH release by a negative feedback mechanism [16]. In contrast, the reverse effects have been seen in previous studies of opioid treated chronic non-cancer pain patients, in which low levels of ACTH and cortisol were found [40]. In chronic non-cancer pain patients in L-TOT a down-regulation of ACTH and cortisol and low levels of DHEAS [13, 40], may indicate opioid-induced adrenal insufficiency [6, 41]. Hormones derived from the HPA-axis play a significant role in the immune system. Previous studies found that L-TOT in patients with cancer was associated with higher levels of biomarkers of inflammation and infection [42]. L-TOT is known to suppress the immune system in patients with cancer and in chronic non-cancer patients – especially in those with adrenal insufficiency [9, 43], [44], [45]. Thus, the inflammatory response to the cancer disease and the resulting proinflammatory cytokines may affect the testes and result in suppression of TT, which may increase the risk of developing hypogonadism, anorexia, and even cancer-cachexia [13, 29]. Further, proinflammatory cytokines may stimulate aromatase activity in women and increase estradiol production [25]; however, no significant change in estradiol concentration was found during L-TOT in two of the studies of the present review [16, 25], which could possibly be due to the fact that the included female patients were postmenopausal women.

The exposure of endocrine system by L-TOT may be influenced by type of opioid, dose level and length of treatment. This systematic review could not assess effects of the different opioid types, doses, and length of treatment on the endocrine system, because this information was not available in all the included studies. Preclinical studies have shown that different types of opioids have differentiated effects on the endocrine system [8]. Thus, e.g., methadone intake might result in more suppression of TT compared to buprenorphine [46]. However, on the other hand methadone might result in less menstrual irregularity compared to other opioids [47]. In addition, previous studies have suggested that buprenorphine has less negative effect on the HPG-axis, which may make buprenorphine a better choice in terms of preserving TT level and sexual function [48], [49], [50].

According to the findings in the present review there may be some indications that opioid dose level may affect the endocrine system. Four studies found significant associations between opioid doses and hormone serum concentrations [16, 24, 25, 27]. Thus, high opioid doses were associated with low levels of hormones including TT, fT and LH, however, cortisol levels were high during high opioid dose therapy. Finally, length of L-TOT seemed to play a role as L-TOT duration of one year or more [27] compared to L-TOT duration of 1–2 months showed significantly lower sex- and gonadotropic hormone levels [16, 25]. To evaluate the risk/benefit ratio concerning the use of specific types of opioids in patients with cancer we need more knowledge about the endocrinological effects from clinical studies combined with assessment of disease stage, anticancer treatment, performance status, survival prognostics, etc.

Only two studies assessed patient reported clinical outcomes. They found low sexual desire in the patients with cancer in L-TOT [26, 27], which may be in accordance with findings in other populations demonstrating strong associations between low sexual desire and low TT [51, 52] and fT levels [53, 54]. A pilot study in patients with advanced cancer has also indicated that hypogonadism may be associated with symptoms including sexual dysfunction [28]. Both the symptoms and sexual dysfunction may substantially reduce patients’ quality of life.

Although the available literature is still sparse a strength of this systematic review is that it has included endocrine biomarkers from all hypothalamic pituitary axes. However, this systematic review also has some limitations. First, the different characteristics of the included studies make comparisons difficult (control groups/comparison methods, duration of L-TOT, variety of opioids, selection of outcomes, gender, and age of participants). Second, only few studies are available from existing literature. Third, all five included studies had a cross-sectional design resulting in lower quality of evidence and no reasoning of cause-effect relationship. Finally, some of the five studies had a high risk of bias due to small sample sizes, comparability and clinical reported outcomes including missing information about funding.

Conclusions

The findings of this systematic review suggest that L-TOT may affect the endocrine system including suppression of the HPG-axis and accordingly result in low levels of LH, FSH, TT and fT in patients with cancer-related pain on L-TOT. Sexual dysfunction and alterations on the HPA-axis including high levels of cortisol were also found. The studies have suggested an association between L-TOT and gonadal hypofunction, which was possibly correlated with high opioid dose level. However, the existing evidence is weak, and the overall quality is low. A future recommendation is to screen patients with cancer for sex hormone deficiency before and during L-TOT. Finally, further research to clarify the associations and investigate cause-effect relationship of L-TOT and endocrine system in patients with cancer-related pain is urgently needed.