Hypogonadism and Sexual Dysfunction in Male Cancer Survivors Receiving Chronic Opioid Therapy

Transcription

1 Vol. 26 No. 5 November 2003 Journal of Pain and Symptom Management 1055 Clinical Note Hypogonadism and Sexual Dysfunction in Male Cancer Survivors Receiving Chronic Opioid Therapy Arun Rajagopal, MD, Rena Vassilopoulou-Sellin, MD, J. Lynn Palmer, PhD, Guddi Kaur, RN, BSN, and Eduardo Bruera, MD Departments of Anesthesiology (A.R.), Endocrine Neoplasia and Hormonal Disorders (R.V.-S.), Palliative Care and Rehabilitation Medicine (J.L.P., G.K., E.B.), and Biostatistics (J.L.P.), University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA Abstract The purpose of this study was to determine the prevalence of central hypogonadism and sexual dysfunction in male cancer survivors exposed to chronic high-dose oral opioid therapy. We studied 20 male patients with cancer-related chronic pain who were disease-free for at least one year. All patients consumed at least 200 mg-equivalent of morphine on a daily basis for at least one year. Participants completed the Sexual Desire Inventory questionnaire and serum levels of testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were assessed. Serum testosterone levels were reduced in these patients. The median value was 140 ng/dl (normal ). There was no compensatory increase in FSH and LH. The median FSH level was 3.5 miu/ml (normal ). The median LH level was 2.1 miu/ml (normal ). The mean dyadic sexual desire score was (normal value, ). The mean solitary sexual desire score was (normal value, ). Our data suggest that chronic exposure to high-dose oral opioid therapy may result in marked central hypogonadism and sexual dysfunction. Given the increasing use of long-term opioid therapy for chronic pain syndromes, further investigation into these findings is warranted. J Pain Symptom Manage 2003;26: U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Hypogonadism, cancer pain, opioid, sexual dysfunction Introduction Many cancer survivors have chronic pain from their cancer or cancer-related treatment Address reprint requests to: Arun Rajagopal, MD, Section of Cancer Pain Management, Department of Anesthesiology, Box 42, U.T. M. D. Anderson Cancer Center,1515 Holcombe Blvd., Houston, TX 77030, USA. Accepted for publication: March 18, U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. and require opioid analgesics for extended periods of time. 1 In the non-cancer chronic pain population, there have been several articles in recent years documenting the development of marked central hypogonadism and sexual dysfunction in patients receiving intrathecal opioid therapy. 2 4 Although intrathecal opioid therapy for chronic pain syndromes is becoming more common, for the majority of patients the usual route of administration is the oral route. With recent policy initiatives underscoring the need for aggressive treatment of /03/$ see front matter doi: /s (03)

2 1056 Rajagopal et al. Vol. 26 No. 5 November 2003 pain, 5,6 coupled with increased direct-to-consumer advertising, 7 more consumers are requesting opioid therapy for their chronic pain syndromes. Sexual dysfunction is a common problem in cancer survivors. A number of causes have been suggested ranging from the effects of therapy, negative self-image from the debilitating effects of disease or surgery, and chronic fatigue, depression, or anxiety Unfortunately, sexual dysfunction is often unrecognized by the primary care provider and patients receive little information on how to deal with the problem. 8 It has also been shown that sexual problems relating to cancer treatment do not resolve with time. 8,10 Our clinic population includes a group of patients who have been free of cancer for a number of years but have relied on substantial doses of opioid therapy for chronic cancer-related pain syndromes. We hypothesized that these patients may also develop central hypogonadism and sexual dysfunction from disruption of the hypothalamic-pituitary-gonadal axis in a manner similar to non-cancer chronic pain patients exposed to intrathecal opioid therapy. In patients receiving intrathecal therapy, it is postulated that chronic administration of exogenous opioids interferes with the role of endogenous opioids on pituitary function. 4,12 The purpose of this initial study was to determine the prevalence of central hypogonadism and sexual dysfunction in the cancer survivor group exposed to high-dose oral opioid therapy. This question has not been previously studied in the cancer survivor group. Given the increasing role of the primary care setting in providing maintenance medications for cancer survivors with chronic pain, we report on our series of 20 patients who have consumed high doses of opioids for an extended period of time. Methods Patient Selection We identified 22 active male patients from our pain clinic population who matched all inclusion criteria. Twenty adult male patients with a mean age of 50.1 (range 34 77) agreed to participate in this cross-sectional survey. None had previously reported problems with sexual function. Their cancer status was no evidence of disease and all had chronic pain related to their cancer therapy for at least one year. All patients had been managed for at least one year on chronic opioid therapy at a morphineequivalent daily dose (MEDD) of at least 200 mg. Patients with pre-existing conditions that might affect the hypothalamic-pituitary-gonadal axis at the cranial level (e.g., cranial surgery, cranial irradiation, pituitary tumors, testosterone replacement therapy) were excluded from the study. Patients with pre-existing conditions that might affect the axis at the gonadal level (pelvic radiation, orchiectomy) were included in the study since these conditions should not affect the development of central hypogonadism. For all patients, the following demographic details were recorded: age, marital status, oncologic history, and current medications. The study was reviewed and approved by the Institutional Review Board. Informed consent was discussed with and obtained from all subjects. Sexual Desire Inventory (SDI) Questionnaire Sexual function was assessed using the Sexual Desire Inventory Questionnaire. 13 Assessing sexual dysfunction has always been difficult because of the confounding nature of assessing consummatory behavior with sexual desire. In addition, assessing sexual desire has been difficult because of the confounding nature of assessing dyadic desire (engaging in sexual activity with another person) with solitary desire (engaging in sexual behavior by oneself). Assuming that consummatory behavior necessarily follows some degree of sexual desire, we decided to assess only sexual desire as a basis for sexual function. The SDI questionnaire is a validated tool that specifically assesses sexual desire in the absence of consummatory behavior and specifically assesses dyadic vs. solitary desire. Normative data exists for 90 healthy college-age adults. 16 Serum Analysis The gonadal axis was evaluated by measuring single serum concentrations of total testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Eighteen out of the 20 samples were collected in a 4-hour window between 1000 and The remaining two were collected at 1700 and Although the free fraction of testosterone has been regarded as the biologically active molecule, we decided

3 Vol. 26 No. 5 November 2003 Hypogonadism and Sexual Dysfunction in Cancer Survivors 1057 to assess total testosterone because studies have shown that dissociation of protein-bound testosterone can occur within capillary beds so that the active fraction is larger than the free fraction. 14 In general, the biologically active fraction of testosterone is free testosterone plus the fraction bound to albumin. 14 We assumed a normal albumin in our patients since they were free of cancer and not undergoing any cancer-related therapy. In addition, although pulsatile secretion of FSH and LH has been recognized, we decided to assess single values because concentrations are usually within a limited range around a mean value. Accordingly, for patients with a subnormal testosterone we felt that a single value would be sufficient to distinguish between primary gonadal failure with expected increased LH and FSH and central hypogonadism (either hypothalamic or pituitary without elevated FSH/LH). Statistical Analysis Descriptive statistics are used to summarize the data. For the serum analyses, medians are reported instead of means as measures of central tendency since most variables did not have symmetric distributions. Although there is an age-related decline in testosterone levels, in general, testosterone levels are relatively constant between the ages of approximately 18 and 75, 15 an age range that includes all the patients in our study. After about age 75, there is a fairly rapid decline in circulating androgens. 15 As such, our institutional laboratory does not report age-related normal values. Thus, we did not use distributional statistics to report testosterone levels. In the case of the SDI scores, previously published scores for a cohort of healthy adults are reported as mean value; 16 thus, both median and mean values are reported for comparative purposes. Results Results are summarized in Tables 1 and 2. Eighteen out of 20 patients (90%) had low levels of testosterone. The median value of 140 ng/dl is more than 100 ng/dl lower than the low range of normal values. FSH and LH levels were not elevated; in fact, median values are clearly on the lower side of normal values. Dyadic and solitary sexual desire values were also reduced. Our group demonstrated a mean dyadic sexual desire score of and a mean solitary sexual desire score of Median values were lower (19.5 for dyadic and 0 for solitary), showing that more patients were at the lower levels. Twelve patients (60%) Table 1 Individual Patient Results Age Testosterone FSH LH Patient No. (yr) (ng/dl) (miu/ml) (miu/ml) Adjuvant Drugs N/A N/A Gabapentin 900 mg/day N/A N/A N/A Gabapentin 900 mg/day N/A N/A Amitriptyline 125 mg/day Gabapentin 3200 mg/day N/A Nortriptyline 5 mg/day N/A N/A N/A Gabapentin 1800 mg/day Paroxetine 20 mg/day N/A Gabapentin 1200 mg/day

4 1058 Rajagopal et al. Vol. 26 No. 5 November 2003 Table 2 Summary Results Median Range 25% patients 75% patients Normal Testosterone (ng/dl) FSH (miu/ml) LH (miu/ml) SDI (Dyadic) a SDI (Solitary) a a Based on reported data of 90 healthy adults. 16 reported a solitary sexual desire score of 0. Although this questionnaire has not been previously used in the cancer survivor population, a cohort of 90 healthy adults had a mean score of for dyadic sexual desire and for solitary sexual desire. 16 In Table 1, we report on adjuvant drugs that may affect sexual function such as antidepressants and anti-epileptics. Selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) are known to cause sexual dysfunction and recent scattered reports have suggested that gabapentin may also cause sexual difficulties. 17 Five out of 20 patients were taking gabapentin, 2 out of 20 were taking tricyclic antidepressants, and 1 out of 20 was taking paroxetine. Discussion Our results suggest that chronic oral opioid therapy may result in clinically significant central hypogonadism and sexual dysfunction. A great majority of our patients demonstrated a pattern of central hypogonadism with lownormal to markedly decreased levels of testosterone without the expected compensatory increase in FSH and LH. Our data are similar to previously published data on chronic administration of intrathecal opioids. 2 4 In these reports, patients receiving chronic intrathecal opioids developed marked central hypogonadism with decreased testosterone and low to low-normal FSH and LH. The role of endogenous opioid peptides in regulating gonadotrophin secretion has been described and reviewed. 12 It has been hypothesized that exogenous administration of intrathecal opioids may play a similar role. 4 Our data demonstrate that chronic usage of high doses of oral opioids may have a similar effect in neuroendocrine regulation as intrathecal opioids. The mechanism by which opioids affect hypothalamic-pituitary function is not clearly known. Since endogenous opioids regulate gonadotrophin secretion, there may be a direct effect of exogenous opioids on hypothalamic-pituitary function as well. However, studies have also shown that administration of morphine raises prolactin levels and it is known that increased prolactin levels can lead to hypotestosteronemia Thus, the mechanism of central hypogonadism in this group may be an indirect effect of hyperprolactinemia. The data from the SDI demonstrate markedly decreased sexual desire. Although a strong association between sexual desire and free testosterone levels has been shown in some studies, 21,22 there are also studies demonstrating little correlation between levels of testosterone and sexual desire, 23,24 thus underscoring the difficulty inherent in studying such a subjective entity. In addition, the reporting of sexual desire, even in an anonymous questionnaire, undoubtedly carries a large subjective bias. There are many variables that can contribute to sexual dysfunction in this population (effects of cancer treatment, loss of physical well-being, negative body image, drug interactions, etc.) and isolating chronic opioid therapy as an independent variable is not possible with our data. Two of our clinic patients (not included in this series because they were in the process of voluntarily discontinuing chronic opioid therapy) have reported a marked increase in sexual desire coincident with decreasing opioid therapy. Although our data shows a strong association between chronic opioid use and sexual dysfunction, we are unable to comment on a specific causal relationship between our group s decreased sexual desire and consumption of opioids. Although certain drugs are known to cause sexual dysfunction (e.g., SSRI and TCA), we cannot comment on any causality between our

5 Vol. 26 No. 5 November 2003 Hypogonadism and Sexual Dysfunction in Cancer Survivors 1059 patients consumption of these drugs and development of sexual side effects. Only a small number of our patients were consuming these drugs and we were unable to note an association between these drugs and their profound sexual dysfunction. Limitations Our study has limitations. This is an initial study in this group of patients. Although our data have validated our hypothesis that central hypogonadism and sexual dysfunction are a significant problem in this group of patients, this initial study did not consider a control group and thus is unable to demonstrate a causal relationship. Since the existence of this problem in cancer survivors was unknown prior to this study and was hypothesized based on data from patients receiving intraspinal opioids, our primary purpose was only in determining the prevalence of hypogonadism and not demonstrating causality. In order to definitively demonstrate causality, we would have to withhold opioid therapy in our patients and assess resumption of normal gonadal function over a period of time. Clearly, this would be unjustifiable from an ethical standpoint. In an ongoing study, our group is assessing the prevalence of central hypogonadism, sexual dysfunction, depression and fatigue in a cohort of cancer survivors not consuming opioids on a chronic basis. Our active group is also being assessed for depression and fatigue since these factors may also affect sexual function. Although such a study will not demonstrate causality per se, identifying normal gonadal and sexual function and decreased depression and fatigue in cancer survivors who are not taking chronic opioid therapy will strengthen our argument. Our choice of the SDI for evaluation of sexual desire was based on the belief that a central mechanism for hypogonadism would lead to reduced sexual desire. Although better comparison studies have been reported, especially with the pharmaceutical studies assessing sildenafil for patients with erectile dysfunction, 25,26 these reports largely tend to emphasize sexual function rather than desire. We believe that studies measuring sexual function, which assume the presence of a partner, may confound the assessment of whether opioids specifically affect interest in sexual function. The SDI questionnaire has been validated only in a population of young, college-age, healthy adults. Thus, a comparison between this group and our patient population is valid only to demonstrate the profound sexual dysfunction that exists in our population. Our ongoing study, which assesses cancer survivors not consuming opioids on a chronic basis, should offer a better comparison group. Although we excluded from our study patients whose hypothalamic-pituitary axis might be affected by prior conditions relating to their oncologic history (e.g., cranial radiation, pituitary tumors, cranial surgery), central hypogonadism has many causes. In this initial study, we did not attempt to identify causes unrelated to their oncologic history. Thus, it is possible that some of our patients had pre-existing hypogonadism unrelated to their chronic opioid history. Finally, in this selected group of high-dose opioid patients, our data cannot establish a dose-response effect between daily opioid dose and development of secondary hypogonadism. It is possible that this apparent hypogonadic state is induced only in patients receiving highdose therapy. A recent report demonstrated a lower prevalence of hypogonadism in patients receiving lower doses of opioids. 27 Future research should address this question. Conclusion Our data demonstrate that the prevalence of sexual dysfunction and central hypogonadism in this group of patients is very high and correlates with published data on the chronic pain patient receiving intrathecal opioids. Since chronically low levels of testosterone can lead to problems such as chronic anemia, decreased bone mass, muscle atrophy and even cognitive impairment, 28,29 our data suggest that testosterone replacement may be indicated in some patients receiving chronic opioid therapy. Future research in this area should include an assessment of concurrent fatigue and depression and the role of chronic opioid use in the female population since this group is additionally at higher risk of development of osteoporosis. Although overall concentration is lower in women, testosterone has an important physiological role in women and chronic hypogonadism from opioid use may lead to the same

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