Adv Ther (2014) 31:153–167 DOI 10.1007/s12325-014-0096-x

REVIEW

Opioid-Induced Endocrinopathy in Cancer Patients: An Underestimated Clinical Problem Tomasz Buss • Wojciech Leppert

To view enhanced content go to www.advancesintherapy.com Received: December 2, 2013 / Published online: February 5, 2014 Ó Springer Healthcare 2014

ABSTRACT

importance. Conversely, this problem may be

The

and

less relevant for patients in active cancer treatment or in the advanced stage of

exogenous opioids on the endocrine system

disease. This article presents the available

has been known for many years. With the increased use of opioids in chronic pain

research on the effects of opioids on the endocrine system and the clinical

treatment, the research focuses mainly on their effects on the endocrine system in

consequences resulting from opioid use in cancer patients. Clinicians who use opioids

patients with chronic non-malignant pain.

in clinical practice should be aware of the

Despite the wide dissemination of cancer, there has been little research on the possible

existence of the endocrine symptoms of opioid therapy. There is still a need for more research

effects of opioids on the endocrine system in cancer patients. For the growing number of

in this area to maintain the best possible quality of life for cancer patients treated with

cancer survivors and patients in long-term

opioid analgesics.

impact

of

both

endogenous

remission who take opioids, other aspects of endocrine disorders caused or exacerbated by opioids

will

have

practical

and

clinical

Keywords: Cancer;

Endocrinopathy;

Hormones; Opioids; Quality of life Electronic supplementary material The online version of this article (doi:10.1007/s12325-014-0096-x) contains supplementary material, which is available to authorized users.

INTRODUCTION The

T. Buss Department of Palliative Medicine, Medical University of Gdansk, Gdansk, Poland W. Leppert (&) Chair and Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland e-mail: [email protected]

impact

of

both

endogenous

and

exogenous opioids on the endocrine system has been known and studied for many years now. The earliest studies on the effects of opioids and their antagonists on the various endocrine axes were carried out on small groups of healthy subjects or opiate addicts.

Adv Ther (2014) 31:153–167

154

These studies were rather theoretical in nature and related to the interaction between opioids and serum hormone levels in humans and rodents. Later, studies were conducted in more selected groups of patients with infertility, often in the course of polycystic ovary syndrome

(PCOS)

and

obese

or

diabetic

patients. Currently, due to the increasing use of opioids in chronic pain treatment, the research focuses mainly on the effects of opioids on the endocrine system in patients with chronic non-malignant pain. Despite the wide dissemination of cancer, there is almost no research on the possible effects of opioids on the endocrine system in cancer patients. It is known that cancer patients are a diverse group, even in terms of the stage of the disease. Thus, for the growing number of cancer survivors and patients in long-term remission who need to take opioids, other aspects of endocrine

HOW OPIOIDS INFLUENCE THE ENDOCRINE SYSTEM Four groups of endogenous opioids have been described by researchers: enkephalins, dynorphins,

beta-endorphins,

and

endomorphins. Opioid peptides have been identified in the peripheral and central nervous systems, e.g., brainstem, hypothalamus, spinal cord [1]. They exert action by binding specific receptors located in the brain and throughout the human body, including endocrine organs such as the adrenal glands and the gonads [1]. Three classes of opioids receptors have been well recognized: mu, delta, and kappa [2]. Other receptors that have also been described include nociception/ orphanin FQ receptor, zeta, lambda, and epsilon [2]. Both endogenous and exogenous opioids can bind more than one type of an opioid receptor [2]. Endogenous opioids appear

disorders caused or exacerbated by opioids will have greater practical and clinical importance

to be primarily involved in the regulation of gonadotropins and adrenocorticotropin

than for patients in active cancer treatment or

hormone (ACTH) release [2]. Beta-endorphins modulate gonadotropin-releasing hormone

in the advanced stage of disease. Some of them, i.e., adrenal crisis and hypoglycemia, can lead

(GnRH) pulse amplitude and interaction with

to a premature death of the patient if not diagnosed and treated. This report presents the

adrenergic neurotransmission [3]. Exogenous opioids, like morphine, fentanyl, or

available research on the effects of opioids on

oxycodone, exert their analgesic action mainly through the mu-opioid receptor [4]. The effects

the endocrine system. The problems resulting from opioid use that can occur in cancer

of acute and chronic opioid use on the

patients have also been described. The main aim of the report is to increase awareness of

endocrine system are summarized in Table 1.

clinicians

Effect on Somatotropic Axis

of

the

existence

of

endocrine

symptoms of opioid therapy and to highlight the need for more research in this area to maintain the best possible quality of life for cancer patients. The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

No studies on the effect of opioids on somatotropic axis in cancer patients have been found. A small number of studies have been conducted in healthy volunteers, addicts, or in acromegalic subjects [5–9]. In healthy individuals, acute administration of opioids results in an increase of the growth hormone

Adv Ther (2014) 31:153–167

155

Table 1 Effects of acute and chronic opioid use on the endocrine system in humans—modified from Vuong et al. [4] Hormone

Growth hormone

Acute opioid Chronic administration opioid administration :

;/$ a

Moreover, impact

differences

of

were

endogenous

noted

opioids

in

the

on

GH

secretion depending on the age [4]. The hypothesis that beta-endorphins affect the GH response to GH-releasing hormone (GHRH) in prepubertal children, but not in pubertal children has been raised [10].

Prolactin

:/(:$;)

:/$

Thyroid-stimulating hormone

:/;b

$

Effect on Lactotropic Axis

Adrenocorticotropin hormone

;

;/$/:c

Acute

Luteinizing hormone

;;

;;

Follicle-stimulating hormone

$

$

Estradiol

;;

;/$

Testosterone

;;

;;

opioid analgesia showed normal PRL level [7], while the PRL level was elevated in

Arginine vasopressin

:/;

:/;

heroin addicts [13] and opium smokers [14].

:, stimulation; ;, inhibition; $, no change a Buprenorphine at low, medium, and high doses [17] b Severely stressed patients [19] c Methadone [30]

morphine

administration

increases

serum prolactin (PRL) levels in healthy men [11] as well as in postmenopausal women [12]. The results of the studies on the influence of chronic opioid administration on PRL level are conflicting. Studies in patients on chronic

The reason for such situation is not known. The influence of stressful social environment and malnutrition has been raised as co-factors in these patients [7]. The data suggest that opiates stimulate PRL release in men by acting through dopaminergic mechanisms [11]. Beta-

(GH) secretion [5]. The chronic usage of opioids appears to be more complex. There is evidence

endorphins inhibit dopamine release from the

of GH deficiency in approximately 30% of

median eminence and thus increase PRL level [15]. The effect of opioids on plasma PRL

addicts [6] as well as in patients on long-term intrathecal opioids [7]. Conversely, no

levels varies according to the phase of the menstrual cycle indicating a role of sex

significant differences in GH response to the glucagon stimulation test or in the insulin-like

steroids [16]. The opioid-induced PRL release

growth factor 1 (IGF-1) levels compared to a

appears to be mediated by hypothalamic factors rather than via direct action on the

control group in patients with orally administered opioids have been shown [8].

pituitary [4]. It is enhanced by serotoninergic pathways but reduced by dopaminergic

The potential role of opioid dosing is also unclear. Higher doses of morphine were

pathways [15].

required to stimulate GH secretion in normal

Both, the kind and the affinity of the receptors as well as the kind of opioid used

subjects than in patients with active acromegaly [9]. Other probable factors associated with GH

may play a role in PRL secretion. The hypothesis that buprenorphine could

release after opioids are composition, and insulin

interfere

gender, body resistance [4].

with

two

different

but

inter-

dependent receptors has been raised [17]. The

Adv Ther (2014) 31:153–167

156

effects of various doses of buprenorphine on

Effect on Hypothalamic–Pituitary–

serum PRL levels were studied by Amoroso

Adrenal (HPA) Axis

et al. [17]. Buprenorphine at low doses (3–30 lg/kg) increased PRL level [17]. Medium doses (100–300 lg/kg) did not change PRL level while at larger doses (1,000–3,000 lg/kg) the

levels

of

PRL

decreased

[17].

The

explanation of this fact is that buprenorphine at low doses acts at one (high affinity) site and increases PRL level, but at higher doses interacts with a second site (low affinity) and decreases

PRL

secretion

[17].

When

buprenorphine activates the lower affinity site, the interaction with this receptor counteracts and reverses the effects of high affinity site [17].

The mechanism of opioid action on the HPA axis, as well as the place of action of opioids within it, has not been clearly established. Rittmaster et al. [23] indicated that opioid peptides inhibit the pituitary gland response to corticotropin-releasing hormone (CRH) and induce the decrease of ACTH and cortisol in plasma. Most likely, the kappa-opioid receptor is involved in this regulation [24, 25]. Additionally, mean basal morning cortisol level in heroin addicts was lower than in the control group [26]. The disturbances in the circadian rhythm of cortisol by means of decreased evening cortisol reduction were

Effect on Hypothalamus–Pituitary–

found [26]. On the other hand, a single dose

Thyroid (HPT) Axis

of a slow-release oral morphine suppressed ACTH and cortisol production both at baseline

The effect of opioids on the HPT axis has been

and after CRH stimulation [27]. The evidence of central hypoadrenalism after intrathecal

noticed by researchers. The increase of thyroidstimulating hormone (TSH) levels after

opioids due to chronic non-malignant pain

morphine administration in healthy volunteers has been observed by Devilla et al.

was shown by Abs et al. [7]. Moreover, some case reports described secondary adrenal

[18] in contrast to TSH suppression after

insufficiency in patients on fentanyl patches [28] and during treatment with

morphine administration in severely stressed patients [19]. On the other hand, TSH and free

hydromorphone [29]. However, in methadone

thyroxin levels were normal during chronic oral opioid treatment in subjects with chronic pain

addicts, Pullan et al. [30] found normal basal cortisol levels. Basal ACTH levels were

compared to a control group [8]. The effect of

significantly elevated by 60%, which suggest a possible compensated primary hypoadrenalism

opioids can be modulated by thyroid disorders [20]. There is also a suggestion that endogenous

[30]. Fallo et al. [31] suggest that zona

opioids do not modulate TSH in hypothyroid patients [20]. The site of opioids action on the

fasciculata of the adrenal gland is probably the site of action for opioids. In men, a decrease of

HPT axis appears to be at the hypothalamus,

adrenal androgen dehydroepiandrosterone sulfate (DHEAS) during opioids administration

with little direct effect at the pituitary [21]. Kappa-opioid receptors are probably the

for

non-malignant

pain

was

observed,

primary receptors involved in mediating the action of opioids on TSH [21]. Freire-Garabal

suggesting that opioids may alter adrenal function [32]. In an animal model, Krazinski

et al. [22] demonstrated the presence of opioid-

et al. [33] showed that endogenous opioids may participate in modulation of adrenocortical

binding sites in the thyroid tissue.

Adv Ther (2014) 31:153–167

157

steroid genesis. Mu-opioid receptor agonists

direct effects at the gonadal level. Opioids have

appear to stimulate cortisol secretion and

suppressive effects on sexual behavior which

kappa agonists inhibit aldosterone release in pigs [33]. Studies conducted in opioid-addicted

appear to be mediated primarily via activation of mu and delta opioid receptors in gonads [38].

patients indicated both a suppressive effect of heroin on the HPA axis in heroin-dependent

The decrease in the LH level in healthy men [38] as well as in premenopausal women [7] on long-

patients compared to placebo and healthy

term intrathecal opioids has been observed,

controls, and normalized HPA axis response to regular heroin doses compared with healthy

whereas the FSH level has not been or has been only minimally affected. There is a

controls [34, 35]. Walter et al. [34] conclude this fact that regular opioid administration protects

suspicion that the suppression of LH may be less profound when opioids are administered

addicts from endocrine stress response. A study

orally or transdermally rather than intrathecally

by Zhang et al. [35] confirmed reduced function of the HPA axis in chronic opioid dependence

[7, 39]. In addition, the effect of opioids on HPG axis may also depend on the level of circulating

and noticed that opioid withdrawal may decrease the response of the pituitary to CRH

sex steroids during the menstrual cycle [41]. The effect on LH occurs primarily by

and increase the adrenal response to ACTH.

inhibiting

Effect on Hypothalamic–Pituitary–

although opioids also decrease the negative feedback of sex steroids on pituitary LH

hypothalamic

GnRH

secretion,

Gonadal (HPG) Axis

secretion [36]. In turn, sex steroid hormones are required for and have major modulating

The problem of the negative impact of opioids on gonadal status has been studied more

effects on the sensitivity of the HPG axis to opioids and their antagonists [36]. The

extensively in different patients’ population, including cancer patients [36]. Conducted

sensitivity to opioids appears to be higher in men than in women [39]. Furthermore, opioid

studies indicate that opioids, regardless of the administration route, are associated with high prevalence of hypogonadism named opioid-

Table 2 Symptoms of hypogonadism [85]

associated androgen deficiency (OPIAD) [36–47]. This syndrome is characterized by low

Loss of libido

levels of certain gonadotropins [i.e., luteinizing

Infertility

hormone (LH), follicle-stimulating hormone (FSH)] which lead to insufficient sex hormone

Depression and anxiety

production and has a significant negative influence on the quality of life of opioid users

Fatigue or tiredness

Erectile dysfunction

Decreased muscle mass and strength

[36]. Symptoms of hypogonadism are presented

Hot flashes and night sweats

in Table 2. Opioids are hypothesized to cause a decline

Amenorrhea, irregular menses, galactorrhea

in testosterone (TT) levels by alteration in normal gonadotropin pulse patterns or changes in the response of anterior pituitary to GnRH [37]. In addition, there may be also

Osteoporosis and fractures Paina Decreased opioid effecta a

Potential symptoms of hypogonadism

Adv Ther (2014) 31:153–167

158

antagonist naltrexone may induce ovulation in

appeared after 7–15 days of treatment but did

women with PCOS and result in conception by

not sustain after naltrexone discontinuation

LH surge [40]. Both endogenous and exogenous opioids have an effect on the female menstrual

[44]. Fabbri et al. [44] suggest central level of action of naltrexone rather than peripheral. The

cycle [41]. Exogenous opioids, like morphine, have a more drastic effect on this cycle [41].

antagonist did not increase TT or LH levels [44]. In males with pancreatic cancer, opioid usage

Long-term intrathecal opioid administration

was

an

independent

determinant

of

low

may result in irregularities in menstruation and lead to a decline in LH, FSH, estradiol,

calculated free testosterone (cFT) and total TT levels, and hypogonadism, which in turn was

and progesterone levels, thus affecting menstruation [7]. Daniell et al. [41] have

associated with shortened survival [45]. Daily opioid dose correlated inversely with TT, cFT,

documented cessation of menstruation shortly

and LH [45]. Secondary hypogonadism has been

after beginning treatment with oral transdermal, sustained-release opioids.

and The

also observed in cancer survivors [46]. The type of opioid may play a role in the degree of

authors also noted a significant decrease in adrenal androgen production, suggesting

hypogonadism. Studies performed in patients treated with buprenorphine for opioid

that opioids may also play a role in regulating

dependence revealed lower frequency of sexual

sexual libido via androgens [41]. In men, hypogonadism was present in 89% of the

dysfunction and significantly higher TT levels than in patients on methadone [47]. Endocrine

treated with oral opioids like methadone [42]. The decreased levels of estradiol,

effects of opioids in OPIAD are shown in Table 3.

dihydrotestosterone, LH, and FSH were observed [42]. Similar data have been obtained

Effect on Bone Mineral Density

by Fraser et al. [39].

and Fracture Risk

Chronic opioid use in males for pain control or on account of heroin, morphine, or

In epidemiological study conducted on Danish

methadone addiction leads to symptoms of delayed ejaculation, erectile dysfunction, and

population by Vestergaard et al. [48], opioid use has been associated with the increase of

significant decreases in sexual libido [42, 43].

osteoporotic fractures. The authors suggested that the main reason for that fact is the change

Administration of opioid antagonists such as naltrexone can improve symptoms of hypogonadism [44]. The effect of the drug

in postural balance or an increased proneness to accidents [48]. The increase in fracture risk was

Table 3 The site of action and endocrine effects of opioid analgesics in OPIAD Site of action

Endocrine effect

Hypothalamus

Decreased hypothalamic GnRH pulse pattern

Pituitary gland

Decreased LH and possibly FSH secretion

Adrenal glands

Decreased adrenal androgens release (DHEAS and testosterone)

Gonads

Decreased estradiol and progesterone secretion (in women) or testicular testosterone (in men)

DHEAS dehydroepiandrosterone sulfate, FSH follicle-stimulating hormone, GnRH gonadotropin-releasing hormone, OPIAD opioid-associated androgen deficiency

Adv Ther (2014) 31:153–167

159

seen already at very low opioid doses [48]. The

undergoing surgery, intravenous or epidural

authors suggest that the duration of opioid

morphine raised AVP levels [59]. In humans,

administration was too short to produce changes in the bone structure [48]. The

mu-opioid receptors are more likely involved in modulating AVP [4].

increase in fracture risk was higher with shorter time interval since the last use of

Effect on Carbohydrates Metabolism

opiates [48]. In this study [48], there was no distinction between cancer and non-cancer subjects. This observation confirms Carbone’s

Existing data on the relationship between

et al. [49] study as they also noticed that an increased risk for lower extremity fractures is

conflicting. Endogenous plasma opioids levels are altered in patients with diabetes, especially

associated with higher doses of opioid used.

as far as beta-endorphin is concerned [60]. Endorphins influence the autonomic response

Conversely, in other studies, bone mineral density for opioids users was lower than for

opioids

and

glucose

metabolism

are

to hypoglycemia via opioid receptor activation

non-users [50, 51]. Reduced bone mineral density may be an effect of hypogonadism [52]

[60]. Leu et al. [61] indicated that hypoglycemia-associated autonomic failure

or inhibition of osteoblasts and osteocalcin

(HAAF), which increases the risk of severe hypoglycemia, can be prevented by opioid

synthesis via opioid receptors [53]. Additionally, low serum osteocalcin levels

receptor

blockade

in

diabetic

patients.

have been noticed in pregnant heroin users and their newborns [54]. It confirms the direct

Additionally, increased enkephalins level may inhibit insulin secretion and delay glucose

effect of opioids on bones in humans on chronic opioids [54]. In an animal model,

absorption [62]. In terms of exogenous opioids, Giugliano

Chrastil

[63] suggested that heroin addicts do not respond correctly to insulin signals. Moreover,

et

al.

[55]

identified

that

administration of opioids may lead to weaker callus and impede callus maturation.

naloxone, an opioid antagonist, can restore

Effect on Arginine Vasopressin (AVP)

insulin secretion in some subjects with diabetes mellitus [63]. The higher and delayed

Research on the influence of exogenous opioids

peak in insulin levels after glucose load in heroin addicts suggest an insulin resistance in

on AVP secretion is difficult to conduct due to

these patients, thereby implicating a higher

the adverse effects of opioids like hypotension and nausea, which can both stimulate AVP

prevalence population

release [56]. On the basis of available studies, the effect of opioids on AVP is inconsistent and

hemoglobin levels were similar in heroin addicts and controls [65]. In patients with

may depend on the type of opioid used. The

chronic pain treated with intrathecal opioids,

increase in AVP secretion was observed after fentanyl or sufentanyl administration in

there were no differences in plasma glucose levels compared to controls [7]. The study

surgical patients [56] and in healthy volunteers [57]. Conversely, after morphine

conducted by Li et al. [66] has found no increased risk of diabetes mellitus in adults

administration, the decrease in AVP release

with non-cancer pain exposed to opioids. In

was

males, insulin resistance and the risk for

noticed

[58].

However,

in

children

of

glucose disorders [64]. However,

in this glycated

Adv Ther (2014) 31:153–167

160

diabetes mellitus can be associated with opioid-

on daily functioning, long-term complications,

induced

i.e.,

hypogonadism

[66].

Testosterone

the

influence

on

the

immune

and

replacement may improve insulin resistance [67]. There are some case reports concerning

reproductive systems, are also significant [71]. In contrast, in patients in the final stages of

hypoglycemia during opioid administration, for example, propoxyphene in renal failure patients

cancer, the most important aim of palliative and supportive care is to maintain as long as

[68] and methadone [69]. Moryl et al. [69], in a

possible the best possible mobility and overall

retrospective study, documented hypoglycemic episodes associated with methadone dose

quality of life. For all cancer patients, survival is of crucial importance.

increase in 22% of cancer patients with uncontrolled pain. Another problem is

The problem of the influence of opioids on GH release may play a different role in adult

analgesia and plasma glucose level. Higher

cancer patients than in children with neoplastic

doses of morphine were needed for sufficient pain control in postoperative pain in patients

disease. The application of opioids may impede the GH response to GHRH, especially in

with diabetes mellitus [70].

prepubertal children [10]. Therefore, opioid use may have greater consequences in young children than in adults. The primary function of

SYMPTOMS THAT RESULT FROM OPIOID-INDUCED ENDOCRINOPATHY AND THEIR INFLUENCE ON THE QUALITY OF LIFE IN CANCER PATIENTS As mentioned above, there is little evidence evaluating the effect of opioids on endocrine

GH is the promotion of a linear growth [7]. Other metabolic effects, like the increase of protein and acceleration of the transcription and translation of mRNA, are mediated via IGF-1 [5]. In addition, GH tends to decrease protein catabolism by mobilizing fat as a more efficient fuel source [6]. GH also affects carbohydrate

system in cancer patients. Only a few studies on

metabolism [71]. In excess, it produces GHinduced insulin resistance, glucose intolerance

the impact of opioids on the HPG axis and carbohydrate metabolism exist in this group of

and secondary hyperinsulinism [71]. If an increased GH secretion by an opioid is

patients [45, 46, 69]. It is known that opioids interfere with almost all hormonal axes and

suspected, the acceleration of carcinogenesis

already

especially in cancer patients may be considered [71]. Another aspect is the influence on body

existing hormonal problems [4]. Due to the increasing number of cancer patients and an

composition. Theoretically, this would be a positive effect because, as follows from the

increase in the consumption of opioids [36], there is a need to address the potential

definition of cancer cachexia, the loss of

their

attachment

could

aggravate

endocrine complications arising under their

muscle mass and muscle protein is observed in cancer patients [72]. The deterioration of

influence. The most important problems, in our opinion, associated with opioid

glycemic control due to the impact of GH may cause difficulties in analgesia. There have been

administration in cancer patients are listed in Table 4. For a growing number of cancer

reports of the need to increase the dose of

survivors and patients in long-term remission who need to take opioids, besides their impact

morphine in postoperative pain in diabetic patients [70]. However, there are no studies of this problem in patients with cancer.

Adv Ther (2014) 31:153–167

161

Table 4 Possible effects of opioid administration on the endocrine system in cancer patients

selection of the appropriate dose of thyroxin for

Stature disturbances (in children)

cause erroneous diagnosis of hyperthyroidism [73]. In addition, the reduction in the analgesic

Impaired carbohydrates metabolism: hypoglycemia, glucose intolerance, insulin resistance

the treatment of hypothyroidism as well as

effect of morphine and oxycodone has been described while increasing the dose of thyroxin

Hypogonadism

in hypothyroid patients [73]. It is known that in

Acceleration of carcinogenesis

the course of acute or chronic severe disease (such as cancer), euthyroid sick syndrome or

Overall survival

otherwise named non-thyroidal illness syndrome (NTIS) may be observed [74]. This

Body composition changes Changes in food intake

syndrome refers to patients with no known

Increased risk of fractures and osteoporosis

history of thyroid disorders. The laboratory parameters of NTIS usually include low serum

Changes in cortisol level (Addisonian crisis) Altered response to analgesic treatment

triiodothyronine T3, normal or low levels of thyroxin T4, and normal or low serum levels of TSH [74]. Opioids are seen as one of the causes

Opioid-induced

hyperprolactinemia

can

affect cancer patients’ quality of life, especially

of the reduced secretion of TRH and thus TSH. This can lead to a misdiagnosis of

in younger patients or/and with active sexual life. In women, it may induce decreased libido,

hyperthyroidism. The question of whether NTIS is a protective adaptation of the

galactorrhea, amenorrhea, and infertility, and in men it may induce erectile disorders [38].

organism to disease or maladaptation has remained unanswered [74].

Due to increasing somatic or psychiatric

The inhibitory effects of opioids on the

disorders in advanced cancer patients, drugs that act through the dopaminergic and

HPA axis may have significant implications for cancer patients. Inclusion of opioids,

serotoninergic pathways are often used [3]. Classic examples of the antagonists of

especially when the reduction or withdrawal of steroids used during cancer treatment can

dopamine

cause

are

haloperidol

and

life-threatening

adrenal

crisis

[74].

metoclopramide. The addition of an opioid to that treatment may cause greater increased

Furthermore, the loperamide drug widely used in the treatment of diarrhea, when used

secretion of PRL [14]. Antidepressants from the class of serotonin reuptake inhibitors can also

together with opioids, may potentiate the HPA axis suppression. Ambrosi et al. [75] showed

produce

especially

that loperamide has central effect on HPA axis

together with opioids [16]. Thus, combining certain drugs with opioids may exacerbate

and significantly decreases ACTH levels in patients with Addison’s disease. On the other

hypogonadism induced by the excess of PRL. The effects of opioids on HPT may hamper

hand, loperamide did not change ACTH and cortisol levels in patients with Cushing

both the treatment of patients with previously diagnosed thyroid disorder and differential

syndrome,

increased

PRL

levels,

whereas

it

did

suppress

these

diagnosis. Changes in the TSH levels during

levels in normal volunteers [76]. Moreover, cancer and its treatment is an extremely

opioid treatment may produce difficulties in the

stressful situation in patients’ lives. Activity

Adv Ther (2014) 31:153–167

162

of HPA axis (serum cortisol level) and plasma

Insulin resistance and hypoglycemia seem to

epinephrine level significantly clustered with

be the most important effects [72]. Opioid-

depression, pain, and fatigue in advanced breast cancer patients [77]. In patients with

induced insulin resistance may have an impact on the development of certain

chronic stress, an increased level glucocorticosteroids is observed even

of if

tumors, like uterine cancer; thus, reducing insulin resistance may inhibit carcinogenesis.

opioids are added to the treatment [77]. In

Nevadunsky et al. [83] revealed that diabetic

the face of this information, there may be a risk of adrenal insufficiency being less

patients with non-endometrial tumors who used metformin had lower risk of death than

expressed. There is a lack of information on the risk of developing adrenal insufficiency

women with endometrial cancer who did not use metformin. These data suggest that

after opioid administration in cancer patients,

metformin

a problem that requires more research. One of the most extensively studied effects

therapy for non-endometrial tumors [83]. The usefulness of metformin in reducing

of opioids on endocrine system in cancer patients is a hypogonadism termed OPIAD. In

the adverse effects of opioids in cancer patients should be examined. Furthermore,

the main, OPIAD in males can result in anemia,

unrecognized

decreased libido, decreased muscle mass, depression, erectile dysfunction, fatigue,

death [71]; therefore, blood glucose should be checked during opioid treatment.

vasomotor instability, hot flushes, reduced growth of facial hair, weight gain, and

Opioid effects on the risk of fractures and osteoporosis are other very important

infertility, while in females it can result in menstrual irregularities and infertility. It can

problems in cancer patients. Fracture of the femoral neck in patients with cancer may

promote osteoporosis and increase the risk of

lead

fractures [36]. Hypogonadism as a result of opioid usage can lead to depression [78]. It is

complications along with the significant deterioration in the quality of life [48]. The

also a potential contributor to muscle wasting [79]. Additionally, Garcia et al. [80]

question of whether shortened male survival associated with opioid use is a direct result

demonstrated that plasma levels of free and

of medication or simply a reflection of the

bioavailable TT correlated inversely with IL-6. This suggests a potential interplay between

fact that opioids are often prescribed to frailer hypogonadal patients with stronger

proinflammatory cytokines and HPG axis. Proinflammatory cytokines act directly on the

inflammatory responses still remains unanswered. However, there are studies

testicles

enhance

showing that opioid-induced TT decrease

hypogonadism [81]. Based on these facts, it can be concluded that these endocrine changes

may be associated with shortened survival of pancreatic cancer patients [45]. Opioid

may increase cancer cachexia. It is also suggested that opioids may influence

usage, even at high doses, had no effect on survival among advanced cancer patients in

to

suppress

TT

and

to

might

the

be

useful

hypoglycemia

premature

as

can

death

adjuvant

lead

due

to

to

hypothalamic areas governing food intake [82].

a hospice setting [84]. Therefore, the impact

Another aspect of the effect of opioids is their influence on carbohydrate metabolism.

of opioids depends on the stage of the disease.

Adv Ther (2014) 31:153–167

163

Management of Opioid-Induced Endocrinopathy An important problem in patients with cancer on opioids is the difficulty of separating opioid-

Table 5 The proposal to monitor the following blood parameters in the case of presumptive opioid-induced endocrinopathy in cancer depending on patients’ condition Serum glucose

induced endocrinopathies from both, cancer and cancer treatment-related complications.

Luteinizing hormone, follicle-stimulating hormone, estradiol, progesterone (in women)

Some possible effects are listed in Table 4.

Testosterone (in men)

Every disturbance in physical or mental status can affect stature velocity in children [10]. Thus,

Dehydroepiandrosterone sulfate

the cancer itself can lead to such disorders in addition to the medication used in the process of treatment. Oncology therapy, the cancer itself, and symptomatic

the opioids treatment

used may

in the induce

Adrenocorticotropin hormone, cortisol level, serum sodium, and potassium or cortisol in the daily urine collection Vitamin D, serum calcium

hypogonadism [36]. In some cases, negative effects may be reversible [35]; therefore, it is

OPIAD is detected, physicians should consider the following options (in this order): (1) non-

necessary to conduct appropriate differential

opioid pain management; (2) opioid rotation;

diagnosis. Opioid rotation to buprenorphine can reduce some effects of hypogonadism [17].

and (3) sex hormone replacement therapy [85]. Depending on patient physical condition,

Carbohydrate metabolism impairment may result from the nature of the cancer like

cancer progression, or expected survival time, we propose to monitor the blood and/or urine

insulinoma that produces hypoglycemia or

parameters in cancer patients with opioid

opioid-induced endocrinopathy [82]. Fracture risk and osteoporosis can be an effect of bone

treatment (Table 5). When disturbances in carbohydrate metabolism are observed,

metastases and deterioration of physical status in the course of cancer or primary and

metformin should be taken into consideration to possibly reduce opioid adverse effects or as an

secondary osteoporosis [49]. Opioids may lead

adjuvant therapy in some tumors.

to the latter [48]. The same is true as far as the level of released cortisol is concerned [7]. The

CONCLUSION

above-mentioned assumptions arise from the available literature on the influence of opioids on

endocrine

system

and

need

to

be

investigated in cancer patients more extensively. They are clinically important and have a significant impact on the quality, and probably the length, of life of cancer patients.

Physicians are usually aware of the adverse effects of opioids, such as respiratory depression, delirium, or constipation, but the possible endocrine complications in opioid users are often misdiagnosed and overlooked.

Unfortunately, there are no standards on the

The interaction between opioids and the endocrine system may result in potentially

management of the presumptive opioidinduced endocrinopathy. Only, in the case of

life-threatening effects and significantly reduce patients’ quality of life. However, despite the

OPIAD some proposals of monitoring and treatment have been published [36, 85]. If

wide prevalence of cancer, there are almost no good studies on this aspect. To improve

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164

detection of opioid-induced endocrinopathy

7.

Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab. 2000;85:2215–22.

8.

Merza Z, Edwards N, Walters SJ, Newell-Price J, Ross RJ. Patients with chronic pain and abnormal pituitary function require investigation. Lancet. 2003;361:2203–4.

9.

Bhansali A, Velayutham P, Sialy R, Sethi B. Effect of opiates on growth hormone secretion in acromegaly. Horm Metab Res. 2005;37:425–7.

and recognize how opioids affect endocrine system, more studies should be conducted.

ACKNOWLEDGMENTS No funding or sponsorship was received for this study or publication of this article. All named authors meet the ICMJE criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Conflict of interest. T. Buss and W. Leppert declare no conflict of interest. Compliance

with ethics guidelines. The

analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.

10. Pugliese MT, Abdenur J, Fort P, Lifshitz F. The relationship between beta-endorphin and the growth hormone (GH) response to GH releasing hormone in prepubertal children. Endocr Res. 1992;18:41–50. 11. Delitala G, Grossman A, Besser GM. The participation of hypothalamic dopamine in morphine-induced prolactin release in man. Clin Endocrinol (Oxf). 1983;19:437–44. 12. Hemmings R, Fox G, Tolis G. Effect of morphine on the hypothalamic-pituitary axis in postmenopausal women. Fertil Steril. 1982;37:389–91. 13. Ragni G, De Lauretis L, Bestetti O, Sghedoni D, Gambaro V. Gonadal function in male heroin and methadone addicts. Int J Androl. 1988;11:93–100. 14. Moshtaghi-Kashanian GR, Esmaeeli F, Dabiri S. Enhanced prolactin levels in opium smokers. Addict Biol. 2005;10:345–9.

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