Chronic pain is recognized as a common health problem

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1 ORIGINAL ARTICLE Opioid Endocrinopathy: A Clinical Problem in Patients With Chronic Pain and Long-term Oral Opioid Treatment Annica Rhodin, MD,*w Mats Stridsberg, MD, PhD,z and Torsten Gordh, MD, PhD* Background: The use of strong opioids for treatment of noncancer chronic pain has increased. However, strong evidence for sustained pain relief and improved is lacking. Controversy prevails, whether hormonal changes are induced by long-term treatment with opioids. The purpose of this study was to investigate the occurrence of endocrine dys in chronic pain patients on long-term opioid treatment. Methods: A study group of 39 chronic pain patients treated with strong oral opioids for more than 1 year was compared with a control group of 20 chronic pain patients without opioid treatment. Basic levels of prolactin and of the hypothalamicpituitary-thyroid-, hypothalamic-pituitary-adrenal-axis, and hypothalamic-pituitary-growth-hormone - and hypothalamic-pituitarygonadal-axis were measured. Quality-of-life and side effects were estimated with EORTC-QLQ-C30. Results: In the opioid-treated group, the patients had signs of pituitary dys affecting all axes. Significant differences were shown in hypo of the hypothalamic-pituitary-gonadal - axis, hyper of the hypothalamic-pituitary-adrenal -axis, and higher prolactin levels in the opioid-treated group, compared with the control group. The degree of pain was rated the same in both groups, but the opioid-treated group reported more side effects and lower quality of life. Conclusions: Long-term treatment of chronic pain with strong opioids causes side effects that can be attributed to hormonal abnormalities caused by opioid-induced inhibition of hypothalamic-pituitary. Hormone substitution can be indicated to treat symptoms. Decreasing the opioid dose or stopping the opioid treatment can reverse endocrine dys. This needs to be recognized by all practitioners treating chronic pain patients with opioids. Key Words: oral opioid treatment, chronic pain, pituitary dys, opioid endocrinopathy (Clin J Pain 2010;26: ) Received for publication September 21, 2009; revised December 14, 2009; accepted December 20, From the Departments of *Surgical Sciences, Anesthesia; zmedical Sciences, Clinical Chemistry, University Hospital, Uppsala; and wcentre for Clinical Research, Central Hospital, Va stera s, Sweden. This work was financed jointly by the Departments of Anesthesia, Orthopedics, and Psychiatry, University Hospital of Uppsala. Reprints: Annica Rhodin, MD, Pain Center, University Hospital, SE Uppsala, Sweden ( annika.persson.rhodin@ akademiska.se). Copyright r 2010 by Lippincott Williams & Wilkins Chronic pain is recognized as a common health problem causing suffering and disability with socioeconomic losses for the individual and society. 1,2 Increasingly strong opioids are recommended for relieving severe pain not only in acute or cancer pain but also for long-lasting painful disorders. 3,4 However, the efficacy and side effects of longterm opioid treatment are not fully elucidated, and prospective randomized controlled studies for longer periods than for a few months are still lacking. 5,6 The outcome of long-term opioid treatment of chronic pain is often unsatisfactory owing to side effects, such as fatigue, sweating, sexual dys, and emotional disturbances, such as lethargy and mood changes. The reason postulated for this has been the effect of opioid drugs on endocrine as described by Abs et al in their work with intrathecal opioids. 7 Opioids have an influence on hormonal release at the hypothalamic-pituitary level observed both in laboratory animals and in humans In some studies, a decrease of pituitary hormone levels is documented in relation to opioid treatment. 7,11 13 These studies also indicate that hormone substitution can be indicated to treat symptoms, and, furthermore, that the options to decrease or stop the opioid treatment can reverse endocrine dys. This is an important clinical issue for physicians treating chronic pain patients with opioids. At the Pain Clinic of Uppsala University Hospital, Sweden, an increasing number of patients taking moderate to high doses of oral strong opioids report symptoms that raised the question whether endocrine dysregulation could be induced by the opioid treatment. The purpose of this exploratory case-control study was to investigate symptoms and signs of endocrine dys in chronic pain patients treated long-term with strong oral opioids and compare these with a similar control group of pain patients not treated with strong opioids. The secondary goal was to evaluate and compare quality of life (QoL) in both groups. MATERIALS AND METHODS Participants/Patients During 2002 to 2009, chronic pain patients treated long term with strong oral opioids were asked to participate in the study. The inclusion criteria were chronic noncancer pain, daily treatment with strong oral opioids for more than a year, andagebetween18and70.exclusioncriteriaweresubstantial renal and liver dys, or terminal disease. Uppsala University Ethics Committee accepted the study and written informed consent was obtained from each patient. Forty opioid-treated pain patients entered the study: 1 patient was excluded owing to development of renal insufficiency during the period of investigation. A control group of 20 patients without strong opioid treatment but with the same age and gender distribution and chronic pain with similar duration and character were also recruited (Table 1). Background factors, such as concomitant diseases, medication, and the cause of pain were recorded from the patients journals. Low back and musculoskeletal pain, failed back surgery, arthritis, visceral and neuropathic pains Clin J Pain Volume 26, Number 5, June 2010

2 Clin J Pain Volume 26, Number 5, June 2010 Opioid Endocrinopathy TABLE 1. Background Characteristics of Opioid Treated and Control Groups Opioid Group Control Group Number Gender (M/F) 15/24 8/12 Mean age (range) 48 (32-63) 49 (32-63) Mean years with pain (range) 13 (4-30) 12 (4-23) Causes of pain Lumbago 15 7 Musculoskeletal 10 7 Neuropathic 6 4 Visceral 6 1 Arthritis 1 1 Headache 1 0 were diagnosed in both groups in similar proportions. The degree of pain, including the influence of pain on daily activities, was recorded. The female patients had to be divided in groups according to age above and below 50 years owing to the fact that only 2 of the 24 patients in the opioid-treated group had normal menstruation. In the group of female patients, who were less than 50 years, 3 (45, 48, and 50 y of age) in the opioid group and none in the control were on estrogen replacement. Two patients, 55 and 61 years of age in the control group, were treated with estrogen. Most patients had been converted to methadone from other opioids, including parenteral formulations of strong opioids. However, 4 patients were treated with 30 mg, 120 mg, 140-mg slow-release morphine, and 200 mg slow-release oxycodone. These doses were transformed to methadone equivalents as described by Pereira et al. 14 The mean methadone dose for male patients was 133 mg (40 to 320 mg), and 111 mg (30 to 230 mg) for female patients. The control patients were treated with paracetamol, NSAID, antidepressants, and antiepileptics for their pain. Intermittent use of weak opioids was allowed in the control group, but none of the patients used these medications daily. In this group, 3 patients intermittently used codeineparacetamol, 1 tramadol, and 1 dextropropoxyphen. None of the patients used oral steroids. Endocrine Function Investigations The pituitary-gonadal axis was investigated by measuring serum estradiol in females and serum testosterone in males. It was not possible to determine the phase of the menstrual cycle, as most female patients in the opioidtreated group had amenorrhea or irregular menstruation. Amenorrhea was defined as the last period of menstruation being more than 1 year ago and menstrual irregularities as more than 3 months between the periods. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured at 15, 0, 15, 30, 45, and 60 minutes after intravenous injection of 100 mg of gonadotropin-releasing hormone (GnRH). The mean value of the result from 15 and 0 min was noted as baseline in the figures and for computing the baseline value for comparison between the groups. The results of male and female patients above 50 years and female patients of 50 years and younger were analyzed in separate groups. The pituitary- adrenal axis was investigated by measuring corticotropin (ACTH) and cortisol 15, 0, 15, 30, 45, and 60 minutes after intravenous injection of 100 mg of corticotropin-releasing hormone (CRH). The mean value between the values of 15 min and 0 min were used in the figures and for comparison between the groups. Baseline values of dehydroepiandrosterone sulphate (DHEAS) were obtained as an indication of adrenal. DHEAS was analyzed both jointly and separately for male and female patients. Somatotrop was evaluated by measuring growth hormone (GH) at 0, 30, 60, and 90 minutes during the GnRH-TRH-CRH test. Baseline values of IGF1 (insulin-like growth factor-1) and prolactin were measured. Pituitary-thyroid was evaluated measuring thyroid-stimulating hormone (TSH) 15, 0, 30, 60, and 90 minutes after intravenous injection of 300 mg thyrotrophicreleasing hormone (TRH) as were baseline values of free thyroxin. The mean value of 15 and 0 min measurements was used for figure and for comparison between the groups. QoL regarding global health, physical, emotional, social, cognitive, and role (ability to work or study) was evaluated with the EORTC-QLQ-C30 instrument. 15 This instrument was originally developed to evaluate QoL in cancer patients but has been used also in noncancer pain patients. 16 Degree of pain and the influence of pain on daily activities, side effects, and symptoms, and reports of sexual dys was registered on a 4-grade scale used by the EORTC-QLQ C30 (version 2) form: none, a little, moderate, and severe. Sexual disturbances were questioned in terms of libido and, such as ability to have erection and orgasm. Gynecomastia, galactorrhea, and menstrual irregularities were noted as reported by the patients. Assays Hormonal analyses were performed at a routine Clinical Chemistry Laboratory at the University Hospital in Uppsala, Sweden. Samples were collected, centrifuged, and stored frozen at minus 201C until analysis. The measurements were by established laboratory routine methods on automated immunoassay systems (Architect Ci8200s analyzer, Abbott, Abbot Park IL, USA, Autodelfia, Wallac Oy, Turku, Finland, IMMULITE 2500; Siemens, Los Angeles CA, USA and Modular E170, Roche Diagnostics GmbH, Mannheim, Germany). The laboratory is accredited, and both internal and external quality assessment programs continuously controlled all methods. Statistical Analysis SPSS 140 and GRETL 170 were used for the data analysis and statistics. Median differences for ordinal data were measured by Mann-Whitney rank sum test and Student t test for equality of means for continuous data. Results were judged significant if P<0.05 in a 2-sided test. The area under curve of the hormonal changes in the pituitary test was computed in the SPSS system by the trapezoid rule. RESULTS Pituitary-Gonadal Axis and Sexual Function Main findings were the significant effects on the pituitary-gonadal axis in the opioid-treated group compared with the control group (Table 2). Lower levels of testosterone were found in the opioid group, mean r 2010 Lippincott Williams & Wilkins 375

3 Rhodin et al Clin J Pain Volume 26, Number 5, June 2010 TABLE 2. Function of Hypothalamic-Pituitary-Gonadal Axis Opioid Group Control Group Reference Ranges SEM SEM P Pituitary-gonadal axis N = 39 N = 20 LH AUC after GnRh FSH AUC after GnRh Males N = 15 N = 8 Testosterone (nmol/l) LH 0 (IE/L) LH peak after GnRH (IE/L) FSH 0 (IE/L) FSH peak after GnRH (IE/L) Females r 50 years N = 16 N = 6 Estradiol (pmol/l) LH 0 (IE/L) ns LH peak after GnRH (IE/L) FSH 0 (IE/L) ns FSH peak after GnRH (IE/L) ,5 ns Females >50 y N = 8 N = 6 Estradiol (pmol/l) ns LH0 (IE/L) ns LH peak (IE/L) , ns FSH 0 (IE/L) ns FSH peak (IE/L) nmol/l as compared with mean 15.5 nmol in the control group P<0.001). Significantly lower values of LH 0 and LH peak (P<0.01), FSH 0 (P<0.05), and FSH peak (P = 0.053) in the pituitary test were seen in the opioid-treated group of males (Table 2). Subnormal levels of testosterone in relation to age were seen in 12 of 15 opioid-treated males in comparison with 2 of 8 in the control group (P<0.01). In the opioid-treated group 12 of 15 males had significant sexual dys, such as decreased libido and impotence in comparison with 2 of the 8 males in the control group. In the female patients less than 50 years old the estradiol values were mean 208 pmol/l in the opioid-treated group compared with mean 510 pmol/l in the control group (P<0.05), and mean 49.0 pmol/l in the opioid group of over 50 years compared with mean 60.5 pmol in the control group. The LH peak of the female patients of less than equal to 50 years was 17.6 IE/L in the opioid group compared with 38.3 IE/L in the females of the control group (P<0.01). For the females over 50 years old, basal FSH differed (P<0.05): 25.7 IE/L in the opioidgroup and 60.7 in the control group. Furthermore, only 2 females aged 50 and below were found to have normal menstruation in the opioid-treated group, the rest had amenorrhea or irregular periods and 1 had undergone hysterectomy. All the 6 females in the control group under 50 years of age had normal menstruation. Sexual dys was reported by 20 of the 24 opioid-treated females and by 4 of the 12 females in the control group. The area under curve (AUC) for LH of the joint group of males and females was mean 17.2 in the opioid-treated group in comparison with 50.5 in the control group (P<0.05) (Table 2, Fig. 1). AUC for FSH of the joint group of males and females was mean 13.8 in the opioid group and mean 32.1 in the control group (P = 0.066) (Table 2). Thirty-two of 39 (84%) opioid-treated patients and 6 of 20 (32%) control patients (P<0.01) reported sexual dys. Pituitary-Adrenal Axis The opioid group scored a peak ACTH of mean 73.7 IE/L and the control group mean 39.2 IE/L after CRH-stimulation (P<0.05), and AUC for ACTH in the opioid group was also significantly larger (P<0.001) (Table 3, Fig. 2). There was no difference between the groups regarding cortisol measurements for AUC, cortisol 0, and cortisol peak after CRH-stimulation (Table 3). However, the number of patients that did not reach the required normal cortisol peak value of 550 IE/L was significantly higher (P<0.01) in the control group (14/20 70%) than in the opioid group (13/39 33%). There was no difference in DHEAS comparing the male groups, but a significant lower mean value for DHEAS in the opioidtreated females 1.56 mmol/l compared with 2.71 mmol/l in the control females (P<0.05). The number of patients with subnormal DHEAS for age was 16 of 39 (43%) in the opioid-treated group and 1 of 20 (5%) in the control group (P<0.05). Pituitary-growth Hormone-axis and Prolactin There was no difference in somatotrop in GH-IGF1 axis measurement between the 2 groups. Although IGF-1 was lower in the opioid-treated group, mean 118 mg/l compared with 127 mg/l in the controls, but statistical significance could not be proved (Table 3). The number of individuals not reaching normal levels of IGF1 for age was lower in the opioid group (17/39 43%) than in the control group (5/20 25%). Furthermore, 16 of the 39 opioid-treated patients had supernormal prolactin levels, but there was none in the control group (P<0.001). Mean prolactin in the opioid group was 25.1 mg/l and 8.88 mg/l in the control group (P<0.001) (Table 3). Three males and 4 females from the opioid-treated group reported of gynecomastia. Two of the females also had galactorrhea r 2010 Lippincott Williams & Wilkins

4 Clin J Pain Volume 26, Number 5, June 2010 Opioid Endocrinopathy TABLE 3. Function of Hypothalamic-Pituitary-Adrenal, Hypothalamic-Pituitary-GH-IGF1, and Hypothalamic-Pituitary-Thyroid Axes Opioid Group Control Group Reference Ranges n = 39 SEM n = 20 SEM P Pituitary-adrenal axis ACTH 0 (ng/l) < ns ACTH peak after CRH Cortisol 0 (nmol/l) ns Cortisol peak after CRH ns ACTH AUC after CRH Cortisol AUC after CRH DHEAS males (mmol/l) ns DHEAS females (mmol/l) GH-IGF1-axis GH 0 (mie/l) ns GH peak ns IGF1 (mg/l) ns Prolactin (mg/l) < Pituitary-thyroid axis TSH 0 (mie/l) ns TSH max after TRH ns TSH AUC after TRH ns Free thyroxin (pmol/l) ns Pituitary-Thyroid Axis The pituitary-thyroid mean values did not differ between the groups (Table 3); however, in the opioidtreated group, 5 cases of primary hypothyroidism, including subnormal values of free thyroxin were found. One patient in the control group had a subnormal value of free thyroxin but normal reaction of TSH on TRH-stimulation. QoL, Symptoms, and Side Effects QoL in the opioid-treated group was lower in comparison with the control group for physical (P<0.01), social (P<0.01), and emotional ing (P<0.05) and general evaluation for QoL (P<0.05) (Fig. 3). The degree of pain did not differ between the 2 groups (Fig. 4), but side effects and symptoms, such as nausea, constipation, sedation, sweating, pruritus, dry mouth, and sexual dys were more prevalent in the opioid-treated group (Fig. 4). Only 3 patients in the opioid-treated group had no signs of endocrine dys. These patients also had comparatively low daily doses of opioids: 30 mg of methadone, 40 mg, and 120 mg of slow-release morphine. DISCUSSION In this study, characteristics of 39 opioid-treated chronic pain patients in comparison with 20 chronic pain patients without strong opioid treatment were shown. The opioid-treated group showed endocrine dys mainly in the form of hypo of the pituitary-gonadal axis with sexual disturbance and menstrual irregularities. The lower peak values LH and FSH, including the differences in FIGURE 1. Median LH after GnRH stimulation in opioid-treated and control groups. The median value is used owing to skew distribution. FIGURE 2. Mean ACTH after CRH-stimulation in opioid-treated and control groups. r 2010 Lippincott Williams & Wilkins 377

5 Rhodin et al Clin J Pain Volume 26, Number 5, June QoL Function scores * 0 physical role social cognitive emotional quality of life opioid group control FIGURE 3. QoL EORTC-QLQ C-30 (version 2) in opioid-treated and control groups. High score indicates greater degree of. *P < 0.001, P < 0.01, *P < the AUCs in the opioid group compared with the findings in the control group are suggesting an inhibitory effect of the opioids on the hypothalamic-pituitary levels with secondary effects on estradiol and testosterone levels. The differences in estradiol measurements persist in the group of females of less than 50 years, even if 3 of them in the opioid group were on estrogen replacement. The main findings in earlier studies have been sexual dys and low levels of sex hormones in patients treated with intrathecal opioids, 7,17,18 high-dose oral opioids for cancer pain, 19 oral opioids, 12,13 and methadone maintenance for heroin addicts. 20 This study corroborated those findings. The opioid-treated group had signs of stimulation of the pituitary-adrenal axis with higher levels of ACTH than the control group that seemed to have a suppressed cortisol response. Other studies provide evidence for opioid-induced hypo of ACTH and cortisol release in opioid treated patients, which is in contrast with our results. 7,21 However, in 1 study of former heroin addicts treated with methadone, a similar pattern was seen with higher response of ACTH after CRF-stimulation than in normal control persons. 22 This is congruent with our results. Many of our opioid-treated patients were treated on very high doses of opioids, including earlier treatment with parenteral preparations of strong opioids, which could make them pharmacologically similar to heroin abusers. Hypoal HPA-axis with suppression of ACTH and cortisol release have been diagnosed in chronic pain patients with failed back surgery as presented by Geiss et al, 23 and low diurnal cortisol variability in patients with pain of lumbar disc herniation and severe disability. 24 Thus, the findings of hyper of HPA-axis in opioid-treated individuals and hypo of HPA-axis in chronic pain patients in these last 2 studies are in concordance with the results presented here. DHEAS is a sensitive marker for adrenal insufficiency, and DHEAS diminishes more predictably and profoundly than cortisol levels. 25,26 The lower levels of DHEAS in the opioid-treated group of females were a clear sign of hypoadrenalism induced by opioids and are in concordance with other studies. Low DHEAS can cause additional sexual disturbance and fatigue in both sexes. 25,27 Both Symptom scores Pain and side effects * * * * * 0 pain constipation nausea sedation fatigue insomnia sweating sexual dys dry mouth pruritus opioid group control FIGURE 4. Pain and side effects EORTC-QLQ C-30 (version 2) in opioid-treated and control groups. High score signifies greater severity of symptoms and side effects. *P<0.001, P<0.01, *P< r 2010 Lippincott Williams & Wilkins

6 Clin J Pain Volume 26, Number 5, June 2010 Opioid Endocrinopathy males (12 of 15) and females (20 of 24) in the opioid-treated group had sexual dys. There is evidence of inhibition of adrenal androgen production as inferred by low values of DHEAS in patients treated with sustained action opioids for pain, which is in agreement with our findings. 25 The symptoms of fatigue and sexual dys may respond to DHEAS replacement therapy. 28,29 This is an important clinical finding that may have practical consequences for improving the QoL of chronic pain patients. Another important difference between the opioidtreated and the control group was the levels of prolactin. All patients in the control group had normal prolactin levels, contrasting with the opioid-treated group, in which 16 of 39 patients (42%) had supernormal values of prolactin. This could explain the painful gynecomastia spontaneously reported by 7 opioid-treated patients, 3 males and 4 females. Two females also had galactorrhea. The reasons for high prolactin levels can be because of stress 30 or a direct stimulatory effect of the opioid drug itself. 31 Several individuals had signs of primary hypothyroidism with high TSH and low free thyroxin in the opioid-treated group. In the control group, 1 patient had subnormal free thyroxin but normal TSH response. The primary hypothyroidism could be an incidental finding, and the number of patients in our study group was not sufficiently high to prove significant differences. No other studies were found regarding opioids influencing the hypothalamic-pituitary-thyroid axes; so, our preliminary finding should induce further investigation. GH release was not fully investigated; the GHRHarginine testing was not done, as the method was not available in the beginning of the study. However, the somatotrop factor IGF-1 was lower in the opioid-treated group mean 118 ( ± 59) mg/l compared with 127 ± 57 mg/l in the controls, but statistical significance could not be proved. However, the number of opioid-treated patients with subnormal IGF-1 levels was greater than in the control group. Another study has also given evidence of an impact of opioid treatment on the GH-IGF1 axis with risk of developing loss of energy, decreased muscle strength, and abnormal body composition; 7 this is in agreement with our findings. The low QoL in the opioid group can, in part, be explained by classical side effects from opioid treatment, such as constipation, nausea, and sedation, but also from the symptoms of endocrine dys, such as low physical and emotional, sweating, and sexual dys. These differences were seen in our patients, whereas there surprisingly was no difference regarding pain. The opioid-treated group probably reported more severe pain from the beginning than the control group did, but their pain has been moderated with comparatively high doses of strong opioids. Despite of this fact, the patients with opioid treatment still reported substantial pain. Other investigators also describe insufficient analgesia and poor QoL in patients treated with opioids. 32,33 Endocrine dys or opioid endocrinopathy can be suggested as 1 contributing reason for poor outcome of long-term opioid treatment. Thus, the important question, whether longterm opioid treatment is a good solution to relieving chronic pain, can be raised. Conversely, satisfactory and sustained analgesia with moderate dosing of opioids, including improved and QoL, is also reported. 34,35 Before beginning opioid treatment, the physician needs to evaluate the risk-benefit ratio of pain relief versus the possibility of developing long-term side effects. It is often easier to start treatment than to stop it. In view of the risk of developing endocrine dys, vigilance and monitoring of symptoms are recommended. It is important to know and recognize symptoms that can signify endocrine disorders, such as fatigue, emotional distress, sweating, and sexual dys. These symptoms are nonspecific and can be interpreted in many ways. However, indications that point to opioid endocrinopathy should raise suspicion and reason for starting a laboratory investigation. If endocrine disturbance is determined, substitution treatment can benefit the well being of the patient, or the opioid dose could be tapered. Opioid-induced pituitary dys can be reversible when opioid doses are substantially reduced or stopped altogether, as is experienced in the follow-up of the patients in this study. CONCLUSION Long-term treatment of chronic pain with strong opioids cause side effects that can be attributed to hormonal abnormalities caused by inhibition of hypothalamic-pituitary of the opioids. This problem needs to be recognized and assessed by all practitioners treating chronic pain patients with opioids. 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