Download a clinical problem in patients with cancer pain

OPIOID ENDOCRINOPATHY: A CLINICAL PROBLEM IN PATIENTS
WITH CANCER PAIN
Fatma Avci Merdin¹ , Alparslan Merdin¹, Seyda Gündüz² , Hasan Senol Coskun² , Hakan Bozcuk²
1: Akdeniz University Hospital, Department of Internal Medicine,Antalya,Turkey
2:Akdeniz University Hospital, Division of Oncology,Antalya,Turkey
Introduction
Chronic malignant pain is often managed using opioid medications. Side effects
of opioid treatment range from constipation, sedation, dizziness, fatigue, depression,
nausea, vomiting, respiratory depression, sexual dysfunction, anemia, physical
dependence.
There are several studies in the litareature, showing that opioids alter endocrine
functions1,2. Opioid induced endocrinopathy is one of the most common yet least often
diagnosed consequences of prolonged opioid theraphy, 3. It has been reported that
opioids decrease levels of gonadal sex hormones, growth hormone, cortisol and
dehydroepiandrosterone sulfate(DHEAS) 4,5. It is currently known that opioids have
detrimental effection on endocrine system including hypothalamic-pituitaryadrenal(HPA) axis 6,4. The mechanisms underlying this interference are unknown, but it
is possible that opioids inhibit HPA axis through µ-opiate receptor 7. Endogenous and
exogenous opioids also exert an inhibitory effect on GnRH 3.
Finally, opioids have been shown to increase pituitary release of prolactin in
preclinical studies, with secondary effects of decreasing testosteron secretion 8. In this
study, we planned to investigate the occurance of endocrine dysfunction in cancer pain
patients treated with opioids.
Method
The study included 20 patients who had cancer related pain. All data included
malignant tumors diagnosed and followed up at the Oncology Clinic of University
Hospital of Akdeniz between May 2009 and December 2013. Serum samples were
collected for free testestorone(for men), total testestorone(for men), follicle-stimulating
hormone(FSH), luteinizing hormone(LH), estradiol( for women), growth hormone(GH),
insuline like growth factor-1(IGF-1), serum free thyroxine(fT4), thyroid stimulating
hormone(TSH), prolactin, adrenocorticotropic hormone(ACTH), serum cortisole. The
blood samples were taken at 08:00 oclock in the morning. Patients with a history of
cranial radiation, cranial surgery, pituitary tumors, adrenal metastasis, brain metastasis,
anxiety, major depressive disorder, alcoholism, having an acute or chronic infection,
cachexia, obesity, uncontrolled pain management or hormone replacement therapy were
excluded, because these conditions might affect the HPA axis or endocrine system. In
addition, patients currently taking drugs that might interfere with pituitary function and
that might interfere with endocrine system such as magestrol acetate, continous steroid
usage over three weeks, tamoxifene, anastrozole, metoclopromide or psychiatric drugs
were not included in the study. The inclusion criteria were chronic cancer pain and
daily treatment with morphine equivalant daily dose(MEDD) of ≥25 mg/dL for at least 1
months. None of the patients in the current study were>80 years old.
Pain was measured with VAS( Visual analog score) score. All patients had
VAS score below 2. VAS score below 2 contained mild pain and no pain patients.
Obesity was classified according to BMI(Body Mass Index). Patients who had BMI over
30 were not included in the study. Patients who had ECOG(Eastern Cooperative
Oncology Group) score of > 2 were also not included in the study. We measured
procalcitonin and C-reactive peptide levels of patients to exclude infection. Daily opioid
use was recorded , and morphine equivalent daily dose(MEDD) was calculated using the
equianalgesic conversion table listed in the study of Cepeda et al about ‘’the
dosehpatterns in commercially insured subjects chronically exposed to opioids’’ at the
BMC Palliative Care Journal9.
Statistical analyses were performed using SPSS software version 20.0. The
variables were investigated using visual (histograms, probability plots) and analytical
methods (Kolmogorov-Simirnov/Shapiro-Wilk’s test) to determine whether they are
normally distributed (MEDD scores, level of ACTH, cortisole,prolactine, TSH, free T4,
FSH, LH, testosterone and free testosterone). Descriptive analysis were presented using
means and standard deviations for normally distributed variables. Independent predictors
were examined using logistic regression analysis.Variables with a P value of less than
0.05 (P<0.05) was considered as statistically significant.
References
1) Dev R, Hui D, Shalini D, Nooruddin Z, Yennurajalingam S, Fabbro E, Bruera E.
Association Between Serum Cortisol and Testestorone Levels, Opioid Theraphy, and
Symptom Distress in Patients with Advanced Cancer. J Pain Symp Man 2011;41:788-95.
2) Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, Kaur G, Bruera E. Symptomatic
hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer
2004 Feb 15;100(4):851-8.
3) Colameco S, Coren JS. Opioid-Induced Endocrinopathy. J Am Osteopath Assoc
2009 ;109 (1): 20-25
4) Abs R, Verhelst J, Maeyaert J, Van Buyten JP, Opsomer F, Adriaensen H, Verlooy J,
Van Havenbergh T, Smet M, Van Acker K. Endocrine Consequences of Long-Term
Intratecal Administration of Opioids. J Clin Endocrinol Metab 2000;85:2215-2222
5) Lee C, Ludwig S, Duerksen DR. Low-serum cortisol associated with opioid use:case
report and review of the literature. Endocrinologist. 2002;12:5-8.
6) Vuong C, Van Uum SH, O'Dell LE, Lutfy K, Friedman TC. The effects of opioids
and opioid analogs on animal and human endocrine systems. Endocrine Reviews 31 (1):
98-132
7) Elizabeth D, Brenda R, Gavin B, Yoshie U, Jack V, Ann H, Mary Jeanne K. Muopioid receptor A118G polymorphism in healthy volunteers affects hypothalamic–
pituitary–adrenal axis adrenocorticotropic hormone stress response to metyrapone.addict
biol 2013 march; 18(2):325
8) Adams ML, Sewing B, Forman JB, Meyer ER, Cicero TJ. Opioid-induced
suppression of rat testicular function. J Pharmacol Exp Ther 1993;266(1):323-8
9) Cepeda MS, Etropolski M, Weinstein R, Fife D, Boston R, Matcho A. Dosehpatterns
in commercially insured subjects chronically exposed to opioids: a large cohort study in
the United States. BMC Palliative Care 2010, 9:14;1464-72.
Results
In this study, we evaluated the data of 20 patients diagnosed with cancer and
followed- up at Akdeniz University Hospital between May 2009 and September 2013,
retrospectively. All patients had received opioid treatment at least 1 month for pain
management.
The median follow-up period was 9.4 months. The median age of the patients
was 50 years (ranging from 24 to 72). Of the patients, 65 % were male and 35 % were
female. Fifteen patients (75%) had metastasis. The demographic data of the patients are
summarized in Table 1.
The serum TSH levels (normal range: 0,2-4,2 μIU/mL) were above 4,2 μIU/mL
in 20% and below 0,2 μIU/mL in 5% of patients(Table 2). The serum free T4 levels
(normal range: 0,9-1,7 pg/mL ) were below 0,9 pg/mL in 5,2% and above 1,7 pg/mL in
none of the patients(Table 2). The serum cortisol concentrations (normal range: 4,3-22,4
ug/dl) were lower than normal in 15% of patients and higher than normal in 40% of
patients(Table 2). Serum total testosterone level (male normal range: 1,9-5,4 ng/ml;
female normal range: 0,06-0,8 ng/ml ) were lower in 68,7% and serum free testosterone
level (male normal range: 4,9-21,6 pg/mL; female normal range: 0-2,6 pg/ml) were
lower in 57,1% of patients(Table 2). Serum FSH level (male normal range: 1,5-12,4
mIU/mL; female normal range: 3,5-12,5 mIU/ml) were lower in 30% and higher in 45%
of patients. Serum LH level (male normal range: 1,7-8,6 mIU/mL; female: 2,4-12,6
mIU/mL) were lower in 30% and higher in 40% of patients. Serum growth hormone
concentrations were 94,8% within the normal values(normal range: 0-8 ng/ml). Serum
prolactine concentrations were 42,9% (normal range: 4,1-18,4 ng/mL) above the normal
values, but none of the patiets had concentrations below the normal values(Table 2).
Serum ACTH concentrations were 94,5% within the normal values(normal range: 0-65
pg/ml) (Table 2). Lastly serum estradiol levels (normal range: 24-195 pg/mL) were
lower in 25% and higher in 12,5% of patients(Table 2) (Table 2).
The median MEDD value was 180 (10-420). Independent predictors were
evaluated by using logistic regression analysis but we did not find any significant
relationships between MEDD and sex, level of ACTH, cortisole, prolactine, TSH, free
T4, FSH, LH. However, level of testosterone (P= 0.040) and level of free testosterone
(P= 0.041) is significantly affected by MEDD(Figure 1). This trial showed that when
MEDD scores increases, testosterone and free testosterone levels decreases (Figure 1).
On the otherhand, prolactin level was determined to be on a rising trend in increasing of
MEDD (P = 0.083). Lastly, MEDD is significantly affected by age (P= < 0.001) (Figure
2). Opioid analgesic need increases with age(Figure 2.
Conclusion
Opioids seem to induce a wide spectrum of endocrinopathies and hypogonadism
seems to be the most well-documented endocrinopathis adverse effect of opioid usage 1,2.
Although opioids’ affect on LH and subsequent sex hormone release is not completely
understood, opioids may alter the sex hormone-hypothalamic feedback process 3. Opioids may
also interfere with the pituitary release of LH and FSH 3. Lastly, opioids may have direct
negative effects on the testes resulting in decreased testosteron secretion and decreased
testicular interstitial fluid8. We found that opioid theraphy in patients with cancer may inhibit
gonadal function and may cause hyperprolactinemia. We found that testosteron levels decrease
with the increasing of MEDD. We did not find any statistically correlation between opioid
dosage and TSH, GH, FSH , LH, ACTH and cortisol. We showed a rising trend of prolactin
hormone level with increasing of MEDD.
We also found that opioid analgesic need çncreases with age. There is not much study
in the literatute about this area and further studies are needed to have an exact opinion about
this.
The signs and symptoms of hypogonadism include loss of libido, infertility,
depression, anxiety, fatigue, osteoporosis, loss of muscle strength and irregular menses. These
symptoms can also be seen in chronic cancer patients without any hypogonadism. Cancer
patients should be asked about any symptoms of sex hormone deficiency before starting opioid
treatment and should be followed-up regularly for hypogonadism during opioid treatment.
Besides it needs to be more researches to make a correct association between
hypocortisolism, decreased growth hormone, decreased TSH need and opioid usage.
Contact: Fatma Avci Merdin
Email: [email protected]
Ph: 0905327645402