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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* term opioid treatment are not fully elucidated, and Background: The use of strong opioids for treatment of noncancer prospective randomized controlled studies for longer chronic pain has increased. However, strong evidence for sustained periods than for a few months are still lacking.5,6 pain relief and improved function is lacking. Controversy prevails, The outcome of long-term opioid treatment of chronic whether hormonal changes are induced by long-term treatment pain is often unsatisfactory owing to side effects, such as with opioids. The purpose of this study was to investigate the fatigue, sweating, sexual dysfunction, and emotional dis- occurrence of endocrine dysfunction in chronic pain patients onlong-term opioid treatment.
turbances, such as lethargy and mood changes. The reasonpostulated for this has been the effect of opioid drugs on Methods: A study group of 39 chronic pain patients treated with endocrine function as described by Abs et al in their work strong oral opioids for more than 1 year was compared with a with intrathecal opioids.7 Opioids have an influence on control group of 20 chronic pain patients without opioid treatment.
hormonal release at the hypothalamic-pituitary level Basic levels of prolactin and function of the hypothalamic- observed both in laboratory animals and in humans.8–10 pituitary-thyroid-, hypothalamic-pituitary-adrenal-axis, and hypo-thalamic-pituitary-growth-hormone - and hypothalamic-pituitary- In some studies, a decrease of pituitary hormone levels is gonadal-axis were measured. Quality-of-life and side effects were documented in relation to opioid treatment.7,11–13 These studies also indicate that hormone substitution can beindicated to treat symptoms, and, furthermore, that the Results: In the opioid-treated group, the patients had signs of options to decrease or stop the opioid treatment can reverse pituitary dysfunction affecting all axes. Significant differences were endocrine dysfunction. This is an important clinical issue shown in hypofunction of the hypothalamic-pituitary-gonadal -axis, hyperfunction of the hypothalamic-pituitary-adrenal -axis, for physicians treating chronic pain patients with opioids.
and higher prolactin levels in the opioid-treated group, compared At the Pain Clinic of Uppsala University Hospital, with the control group. The degree of pain was rated the same in Sweden, an increasing number of patients taking moderate both groups, but the opioid-treated group reported more side to high doses of oral strong opioids report symptoms that raised the question whether endocrine dysregulation couldbe induced by the opioid treatment. The purpose of this Conclusions: Long-term treatment of chronic pain with strong opioidscauses side effects that can be attributed to hormonal abnormalities exploratory case-control study was to investigate symptoms caused by opioid-induced inhibition of hypothalamic-pituitary and signs of endocrine dysfunction in chronic pain patients function. Hormone substitution can be indicated to treat symp- treated long-term with strong oral opioids and compare toms. Decreasing the opioid dose or stopping the opioid treatment these with a similar control group of pain patients not can reverse endocrine dysfunction. This needs to be recognized by treated with strong opioids. The secondary goal was to all practitioners treating chronic pain patients with opioids.
evaluate and compare quality of life (QoL) in both groups.
Key Words: oral opioid treatment, chronic pain, pituitarydysfunction, opioid endocrinopathy During 2002 to 2009, chronic pain patients treated long term with strong oral opioids were asked to participate in the Chronic pain is recognized as a common health problem study. The inclusion criteria were chronic noncancer pain, causing suffering and disability with socioeconomic daily treatment with strong oral opioids for more than a year, losses for the individual and society.1,2 Increasingly strong and age between 18 and 70. Exclusion criteria were sub- opioids are recommended for relieving severe pain not only stantial renal and liver dysfunction, or terminal disease.
in acute or cancer pain but also for long-lasting painful Uppsala University Ethics Committee accepted the study and disorders.3,4 However, the efficacy and side effects of long- 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 Received for publication September 21, 2009; revised December 14, insufficiency during the period of investigation. A control group of 20 patients without strong opioid treatment but From the Departments of *Surgical Sciences, Anesthesia; zMedical with the same age and gender distribution and chronic pain Sciences, Clinical Chemistry, University Hospital, Uppsala; and with similar duration and character were also recruited Centre 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.
Background factors, such as concomitant diseases, Reprints: Annica Rhodin, MD, Pain Center, University Hospital, medication, and the cause of pain were recorded from the SE 751 85 Uppsala, Sweden (e-mail: annika.persson.rhodin@ patients’ journals. Low back and musculoskeletal pain, Copyright r 2010 by Lippincott Williams & Wilkins failed back surgery, arthritis, visceral and neuropathic pains Clin J Pain  Volume 26, Number 5, June 2010 Clin J Pain  Volume 26, Number 5, June 2010 of corticotropin-releasing hormone (CRH). The mean value TABLE 1. Background Characteristics of Opioid Treated and between the values of À 15 min and 0 min were used in the figures and for comparison between the groups. Baseline values of dehydroepiandrosterone sulphate (DHEAS) wereobtained as an indication of adrenal function. DHEAS was analyzed both jointly and separately for male and female Somatotrop function was evaluated by measuring growth hormone (GH) at 0, 30, 60, and 90 minutes during the GnRH-TRH-CRH function test. Baseline values of IGF1 (insulin-like growth factor-1) and prolactin were Pituitary-thyroid function was evaluated measuring thyroid-stimulating hormone (TSH) À 15, 0, 30, 60, and 90 minutes after intravenous injection of 300 mg thyrotrophic-releasing hormone (TRH) as were baseline values of freethyroxin. The mean value of À 15 and 0 min measurements were diagnosed in both groups in similar proportions. The was used for figure and for comparison between the groups.
degree of pain, including the influence of pain on daily QoL regarding global health, physical, emotional, social, cognitive, and role (ability to work or study) The female patients had to be divided in groups function was evaluated with the EORTC-QLQ-C30 instru- according to age above and below 50 years owing to the ment.15 This instrument was originally developed to fact that only 2 of the 24 patients in the opioid-treated evaluate QoL in cancer patients but has been used also in group had normal menstruation. In the group of female patients, who were less than 50 years, 3 (45, 48, and 50 y of Degree of pain and the influence of pain on daily age) in the opioid group and none in the control were on activities, side effects, and symptoms, and reports of sexual estrogen replacement. Two patients, 55 and 61 years of age dysfunction was registered on a 4-grade scale used by the in the control group, were treated with estrogen.
EORTC-QLQ –C30 (version 2) form: none, a little, Most patients had been converted to methadone from moderate, and severe. Sexual disturbances were questioned other opioids, including parenteral formulations of strong in terms of libido and function, such as ability to have opioids. However, 4 patients were treated with 30 mg, erection and orgasm. Gynecomastia, galactorrhea, and menstrual irregularities were noted as reported by the slow-release oxycodone. These doses were transformed to methadone equivalents as described by Pereira et al.14 Themean methadone dose for male patients was 133 mg (40 to 320 mg), and 111 mg (30 to 230 mg) for female patients. The Hormonal analyses were performed at a routine control patients were treated with paracetamol, NSAID, Clinical Chemistry Laboratory at the University Hospital antidepressants, and antiepileptics for their pain. Inter- in Uppsala, Sweden. Samples were collected, centrifuged, mittent use of weak opioids was allowed in the control and stored frozen at minus 201C until analysis. The group, but none of the patients used these medications measurements were by established laboratory routine daily. In this group, 3 patients intermittently used codeine- methods on automated immunoassay systems (Architect paracetamol, 1 tramadol, and 1 dextropropoxyphen. None Ci8200s analyzer, Abbott, Abbot Park IL, USA, Auto- delfia, Wallac Oy, Turku, Finland, IMMULITE 2500;Siemens, Los Angeles CA, USA and Modular E170, Roche Diagnostics GmbH, Mannheim, Germany). The laboratory The pituitary-gonadal axis was investigated by mea- is accredited, and both internal and external quality suring serum estradiol in females and serum testosterone in assessment programs continuously controlled all methods.
males. It was not possible to determine the phase of themenstrual cycle, as most female patients in the opioid- treated group had amenorrhea or irregular menstruation.
SPSS 14Á0 and GRETL 1Á7Á0 were used for the data Amenorrhea was defined as the last period of menstruation analysis and statistics. Median differences for ordinal data being more than 1 year ago and menstrual irregularities as were measured by Mann-Whitney rank sum test and more than 3 months between the periods. Luteinizing Student t test for equality of means for continuous data.
hormone (LH) and follicle stimulating hormone (FSH) Results were judged significant if P<0.05 in a 2-sided test.
were measured at À 15, 0, 15, 30, 45, and 60 minutes after The area under curve of the hormonal changes in the intravenous injection of 100 mg of gonadotropin-releasing pituitary function test was computed in the SPSS system by hormone (GnRH). The mean value of the result from À 15 and 0 min was noted as baseline in the figures and forcomputing the baseline value for comparison between the groups. The results of male and female patients above 50years and female patients of 50 years and younger were Pituitary-Gonadal Axis and Sexual Function Main findings were the significant effects on the The pituitary- adrenal axis was investigated by pituitary-gonadal axis in the opioid-treated group com- measuring corticotropin (ACTH) and cortisol À 15, 0, 15, pared with the control group (Table 2). Lower levels of 30, 45, and 60 minutes after intravenous injection of 100 mg testosterone were found in the opioid group, mean Clin J Pain  Volume 26, Number 5, June 2010 TABLE 2. Function of Hypothalamic-Pituitary-Gonadal Axis 5.24 nmol/L as compared with mean 15.5 nmol in the control group P<0.001). Significantly lower values of LH The opioid group scored a peak ACTH of mean 0 and LH peak (P<0.01), FSH 0 (P<0.05), and FSH peak 73.7 IE/L and the control group mean 39.2 IE/L after (P = 0.053) in the pituitary function test were seen in the CRH-stimulation (P<0.05), and AUC for ACTH in the opioid-treated group of males (Table 2). Subnormal levels opioid group was also significantly larger (P<0.001) of testosterone in relation to age were seen in 12 of 15 (Table 3, Fig. 2). There was no difference between the opioid-treated males in comparison with 2 of 8 in the groups regarding cortisol measurements for AUC, cortisol control group (P<0.01). In the opioid-treated group 12 of 0, and cortisol peak after CRH-stimulation (Table 3).
15 males had significant sexual dysfunction, such as However, the number of patients that did not reach the decreased libido and impotence in comparison with 2 of required normal cortisol peak value of 550 IE/L was significantly higher (P<0.01) in the control group (14/20 In the female patients less than 50 years old the 70%) than in the opioid group (13/39 33%). There was no estradiol values were mean 208 pmol/L in the opioid-treated difference in DHEAS comparing the male groups, but a group compared with mean 510 pmol/L in the control significant lower mean value for DHEAS in the opioid- group (P<0.05), and mean 49.0 pmol/L in the opioid treated females 1.56 mmol/L compared with 2.71 mmol/L in group of over 50 years compared with mean 60.5 pmol in the control females (P<0.05). The number of patients with the control group. The LH peak of the female patients of subnormal DHEAS for age was 16 of 39 (43%) in the less than equal to 50 years was 17.6 IE/L in the opioid opioid-treated group and 1 of 20 (5%) in the control group 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 opioid-group and 60.7 in the control group. Furthermore, only 2females aged 50 and below were found to have normal Pituitary-growth Hormone-axis and Prolactin menstruation in the opioid-treated group, the rest had There was no difference in somatotrop function in amenorrhea or irregular periods and 1 had undergone GH-IGF1 axis measurement between the 2 groups.
hysterectomy. All the 6 females in the control group under Although IGF-1 was lower in the opioid-treated group, 50 years of age had normal menstruation. Sexual dysfunc- mean 118 mg/L compared with 127 mg/L in the controls, but tion was reported by 20 of the 24 opioid-treated females statistical significance could not be proved (Table 3). The and by 4 of the 12 females in the control group.
number of individuals not reaching normal levels of IGF1 The area under curve (AUC) for LH of the joint group for age was lower in the opioid group (17/39 43%) than in of males and females was mean 17.2 in the opioid-treated group in comparison with 50.5 in the control group Furthermore, 16 of the 39 opioid-treated patients had (P<0.05) (Table 2, Fig. 1). AUC for FSH of the joint supernormal prolactin levels, but there was none in the group of males and females was mean 13.8 in the opioid control group (P<0.001). Mean prolactin in the opioid group and mean 32.1 in the control group (P = 0.066) group was 25.1 mg/L and 8.88 mg/L in the control group (Table 2). Thirty-two of 39 (84%) opioid-treated patients (P<0.001) (Table 3). Three males and 4 females from the and 6 of 20 (32%) control patients (P<0.01) reported opioid-treated group reported of gynecomastia. Two of the Clin J Pain  Volume 26, Number 5, June 2010 TABLE 3. Function of Hypothalamic-Pituitary-Adrenal, Hypothalamic-Pituitary-GH-IGF1, and Hypothalamic-Pituitary-Thyroid Axes sedation, sweating, pruritus, dry mouth, and sexual dysfunc- The pituitary-thyroid function mean values did not tion were more prevalent in the opioid-treated group (Fig. 4).
differ between the groups (Table 3); however, in the opioid- Only 3 patients in the opioid-treated group had treated group, 5 cases of primary hypothyroidism, includ- no signs of endocrine dysfunction. These patients also ing subnormal values of free thyroxin were found. One had comparatively low daily doses of opioids: 30 mg of patient in the control group had a subnormal value of free methadone, 40 mg, and 120 mg of slow-release morphine.
thyroxin but normal reaction of TSH on TRH-stimulation.
In this study, characteristics of 39 opioid-treated QoL in the opioid-treated group was lower in chronic pain patients in comparison with 20 chronic pain comparison with the control group for physical (P<0.01), patients without strong opioid treatment were shown. The social (P<0.01), and emotional functioning (P<0.05) and opioid-treated group showed endocrine dysfunction mainly general evaluation for QoL (P<0.05) (Fig. 3). The degree in the form of hypofunction of the pituitary-gonadal axis of pain did not differ between the 2 groups (Fig. 4), but with sexual disturbance and menstrual irregularities. The side effects and symptoms, such as nausea, constipation, lower peak values LH and FSH, including the differences in FIGURE 1. Median LH after GnRH stimulation in opioid-treatedand control groups. The median value is used owing to skew FIGURE 2. Mean ACTH after CRH-stimulation in opioid-treated Clin J Pain  Volume 26, Number 5, June 2010 FIGURE 3. QoL EORTC-QLQ C-30 (version 2) in opioid-treated and control groups. High score indicates greater degree of function.
***P < 0.001, **P < 0.01, *P < 0.05.
the AUCs in the opioid group compared with the findings persons.22 This is congruent with our results. Many of our in the control group are suggesting an inhibitory effect of opioid-treated patients were treated on very high doses of the opioids on the hypothalamic-pituitary levels with opioids, including earlier treatment with parenteral pre- secondary effects on estradiol and testosterone levels. The parations of strong opioids, which could make them differences in estradiol measurements persist in the group of pharmacologically similar to heroin abusers. Hypofunc- females of less than 50 years, even if 3 of them in the opioid tional HPA-axis with suppression of ACTH and cortisol group were on estrogen replacement. The main findings in release have been diagnosed in chronic pain patients with earlier studies have been sexual dysfunction and low levels failed back surgery as presented by Geiss et al,23 and low of sex hormones in patients treated with intrathecal diurnal cortisol variability in patients with pain of lumbar opioids,7,17,18 high-dose oral opioids for cancer pain,19 oral disc herniation and severe disability.24 Thus, the findings of opioids,12,13 and methadone maintenance for heroin hyperfunction of HPA-axis in opioid-treated individuals addicts.20 This study corroborated those findings.
and hypofunction of HPA-axis in chronic pain patients in The opioid-treated group had signs of stimulation of these last 2 studies are in concordance with the results the pituitary-adrenal axis with higher levels of ACTH than the control group that seemed to have a suppressed cortisol DHEAS is a sensitive marker for adrenal insufficiency, response. Other studies provide evidence for opioid-induced and DHEAS diminishes more predictably and profoundly hypofunction of ACTH and cortisol release in opioid than cortisol levels.25,26 The lower levels of DHEAS in the treated patients, which is in contrast with our results.7,21 opioid-treated group of females were a clear sign of However, in 1 study of former heroin addicts treated with hypoadrenalism induced by opioids and are in concordance methadone, a similar pattern was seen with higher response with other studies. Low DHEAS can cause additional of ACTH after CRF-stimulation than in normal control sexual disturbance and fatigue in both sexes.25,27 Both FIGURE 4. Pain and side effects EORTC-QLQ C-30 (version 2) in opioid-treated and control groups. High score signifies greater severityof symptoms and side effects. ***P<0.001, **P<0.01, *P<0.05.
Clin J Pain  Volume 26, Number 5, June 2010 males (12 of 15) and females (20 of 24) in the opioid-treated the possibility of developing long-term side effects. It is group had sexual dysfunction. There is evidence of inhi- often easier to start treatment than to stop it. In view of the bition of adrenal androgen production as inferred by low risk of developing endocrine dysfunction, vigilance and values of DHEAS in patients treated with sustained action monitoring of symptoms are recommended. It is important opioids for pain, which is in agreement with our findings.25 to know and recognize symptoms that can signify endocrine The symptoms of fatigue and sexual dysfunction may disorders, such as fatigue, emotional distress, sweating, and respond to DHEAS replacement therapy.28,29 This is an sexual dysfunction. These symptoms are nonspecific and important clinical finding that may have practical con- can be interpreted in many ways. However, indications that sequences for improving the QoL of chronic pain patients.
point to opioid endocrinopathy should raise suspicion and Another important difference between the opioid- reason for starting a laboratory investigation. If endocrine treated and the control group was the levels of prolactin.
disturbance is determined, substitution treatment can All patients in the control group had normal prolactin benefit the well being of the patient, or the opioid dose levels, contrasting with the opioid-treated group, in which could be tapered. Opioid-induced pituitary dysfunction can 16 of 39 patients (42%) had supernormal values of be reversible when opioid doses are substantially reduced or prolactin. This could explain the painful gynecomastia stopped altogether, as is experienced in the follow-up of the spontaneously reported by 7 opioid-treated patients, 3 males and 4 females. Two females also had galactorrhea. Thereasons for high prolactin levels can be because of stress30 or a direct stimulatory effect of the opioid drug itself.31 Several individuals had signs of primary hypo- Long-term treatment of chronic pain with strong thyroidism with high TSH and low free thyroxin in the opioids cause side effects that can be attributed to opioid-treated group. In the control group, 1 patient had hormonal abnormalities caused by inhibition of hypotha- subnormal free thyroxin but normal TSH response. The lamic-pituitary function of the opioids. This problem needs primary hypothyroidism could be an incidental finding, and to be recognized and assessed by all practitioners treating the number of patients in our study group was not sufficiently high to prove significant differences. No otherstudies were found regarding opioids influencing the hypothalamic-pituitary-thyroid axes; so, our preliminary The authors thank Andreas Rosenbladh, PhD, and finding should induce further investigation.
Marja–Leena Ojutkangas, RN, for help with the statistical GH release was not fully investigated; the GHRH- work, Tony Wiklund and Katarina Ringstro¨m for skilled arginine testing was not done, as the method was not assistance in preparing the manuscript, and Inga-Lena available in the beginning of the study. However, the Sporrong, RN, and Gunhild O¨st, RN, for doing all the somatotrop factor IGF-1 was lower in the opioid-treated group mean 118 ( ± 59) mg/L compared with 127 ± 57 mg/Lin the controls, but statistical significance could not beproved. However, the number of opioid-treated patients with subnormal IGF-1 levels was greater than in the control 1. Breivik H, Collett B, Ventafridda V, et al. Survey of chronic group. Another study has also given evidence of an impact pain in Europe: prevalence, impact on daily life, and treatment.
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