CONCISE REVIEW FOR CLINICIANS

Opioid-Induced Adrenal Insufficiency

Diane Donegan, MB BCh, and Irina Bancos, MD
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From the Division of
Endocrinology, Diabetes
and Metabolism, Indiana
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Abstract

One in 10 Americans experience chronic pain. Although opioids do play a role in the management of pain, long-
term opioid use may lead to adverse effects. Endocrine-related adverse effects have been described but remain
poorly recognized. Opioid-induced adrenal insufficiency occurs because of suppression of hypothalamic-
pituitary-adrenal communication and may be challenging to diagnose but has been reported in 9% to 29% of
patients receiving long-term opiate therapy. Little data exist to guide case detection and patient management.
Treatment includes cessation of opiates (the inciting factor) if possible and glucocorticoid replacement.
ª 2018 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2018;93(7):937-944

Americans (11.2%) experience chronic pain,2

C
urrently, the United States is experi-
encing an opioid epidemic. Accord- opioids play a limited role in chronic pain
ing to the National Center for management. They are often associated with
Health Statistics, prescriptions for opioids adverse effects, some of which are well
increased 4-fold between 1999 and 2010 and recognized (constipation, sedation, and
are now one of the most commonly prescribed nausea), whereas others remain underappreci-
medications, with 3% to 4% of US adults ated, such as endocrine-related adverse effects,
receiving long-term opioid treatment.1 in particular opioid-induced adrenal insuffi-
Although an estimated 25.3 million adult ciency (OIAI).

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 MAYO CLINIC PROCEEDINGS

TABLE 1. Summary of the Literature Regarding Opioid-Induced Adrenal Insufficiency, Stratified by Opiatea
Opioid Reference, year No. of participants MOA Duration Dose (MEDD)b Effect on HPA
4
Morphine Allolio et al, 1987 6 Males and 1 Oral Single dose 30-mg slow release Reduction in cortisol
female (placebo- (124 vs 275 nmol/L),
controlled) corticotropin (1.2 vs
2.9 pmol/L), and
b-endorphin (28 vs
47 pmol/L) with
decreased peak
response to CRH
Palm et al,11 1997 5 (Double-blind, Oral 1 wk Day 1, 60 mg; day 2, Significant reduction in
randomized, 120 mg; day 3-7, cortisol and
placebo- 180 mg corticotropin (24 vs
controlled, 10 pg/mL) with
crossover) reduced response in
CRH stimulation (in
2 patients tested)
Abs et al,12 2000 73 Received Intrathecal Long-term Mean daily 4.8
3.2 mg Decreased urinary free
opioids and 20 (mean, (morphine, n¼68; cortisol (36 vs 50.7
chronic 26.6
16.3 hydromor-phone, mg/L) and a reduced
non-cancer mo) n¼5) peak cortisol after
painematched ITT (245.4 vs 300.8
controls mg/L)
Fentanyl Oltmanns et al,13 2005 1 (Case report) Patch 2y 480 mg Adrenal crisis with
reduced response to
CRH
Schimke et al,14 2009 1 (Case report) Patch 7 mo 180 mg Secondary adrenal
insufficiency with
failure of cortisol to
increase following
corticotropin
stimulation
Tramadol Debono et al,15 2011 1 (Case report) Oral 3y 15 mg Low basal cortisol (54
nmol/L) with failure
to reach peak with
corticotropin
stimulation test (537
nmol/L; peak >550
nmol/L)30
Methadone Gold et al,9 1980 4 (Placebo- Intravenous Single dose 20 mg Suppression of cortisol,
controlled mean decrease of
crossover) 76.9 ng/mL
(73.4%
2.8%
change)
Heroin Rasheed & Tareen,16 50 Heroin- Inhaled vapors 1-y history of Not stated Significantly reduced
1995 addicted males addiction cortisol levels in
and 25 male heroin addicts
control patients compared with
controls, although in
the normal
reference range
(12 vs 16.96 mg/dL;
reference range,
8-22 mg/dL)
Continued on next page

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OPIOID-INDUCED ADRENAL INSUFFICIENCY

TABLE 1. Continued
Opioid Reference, year No. of participants MOA Duration Dose (MEDD)b Effect on HPA
17
Mixed opioids Gibb et al, 2016 48 Patients with Oral: tramadol, Long-term (at Median, 68 mg 4 (8.3%) patients had a
chronic oxycodone, least 6 mo (40-153 mg) basal cortisol level of
noncancer pain morphine, or use) <100 nmol/L, 3 of
(25 female and dihydroco-deine whom had
23 male) Patch: fentanyl or inadequate response
buprenor-phine to corticotropin
stimulation test
Merdin et al,18 2016 20 Patients with Not specified Long-term (1 Median, 180 mg/ Serum cortisol level
chronic cancer- mo use) d (10-420 mg/d) was lower than the
associated pain normal reference
range in 3 patients
(15%) and higher
than normal range in
8 (40%) (reference
range, 4.3-22.4 mg/
dL). Corticotropin
level was normal in
17 of 18 patients
(94.5%) (reference
range, 0-65 pg/mL)
Rhodin et al,19 2010 39 Patients with Methadone and Long-term Mean in males treated Peak corticotropin
chronic slow-release (>1 y) with methadone, level following CRH
noncancer pain, morphine or 1596 mg; and in was higher in the
20 chronic non- oxycodone females. 1322 mg opioid-treated
cancer controls group than in
controls (73.7 IE/L vs
39.2 IE/l) with no
difference in basal or
peak cortisol level
a
ACTH ¼ adrenocorticotropic hormone; CRH ¼ corticotropin-releasing hormone; HPA ¼ hypothalamic-pituitary-adrenal axis; ITT ¼ insulin tolerance test; MEDD ¼
morphine equivalent daily dose; MOA ¼ mode of administration.
b
Oral MEDD obtained from the study or converted using Agency Medical Directors’ Group calculator at www.agencymeddirectors.wa.gov/files/dosingcalc.xl.

Symptoms of adrenal insufficiency include and k receptors. These G proteinecoupled

fatigue, nausea, vomiting, weight loss, dizzi-
ness, and muscular aches, many of which
overlap with or may compound symptoms
related to chronic pain syndrome. This issue
in turn may interfere with an opioid taper
and the ultimate goal of opioid cessation.
Given that most physicians will encounter
patients receiving long-term opioid treatment,
it is important to recognize OIAI because adre-
nal insufficiency is associated with increased
morbidity and possibly mortality and as such
patients need to be counseled appropriately
before opioid initiation.
PATHOPHYSIOLOGY
Opioids, endogenous and exogenous, exert their
effects through opioid receptors, primarily m, d,
receptors are located throughout the body
including the hypothalamus and the pituitary
gland. In studies in healthy volunteers, adminis-
tration of high doses of intravenous naloxone
(>10 mg), an opioid receptor antagonist with a
higher affinity for the m receptor, led to increased
cortisol levels and an augmented corticotropin
response to corticotropin-releasing hormone
(CRH) stimulation.3,4 Given that naloxone is
an opioid antagonist, this finding suggests that
endogenous opioids exert tonic inhibition on
the hypothalamic-pituitary-adrenal (HPA) axis.
In addition, in the acute setting, different opioids
with varying receptor affinitydeg, morphine
(m receptor agonist), met-enkephalin (d receptor
agonist), and nalorphine or pentazocine
(m antagonist and k receptor agonist)dcan

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Symptoms suggestive of OIAI:
8 am Cortisol*
ACTH*
DHEA-S*
8 am Cortisol <10 8 am Cortisol 5-10 8 am Cortisol >10
ACTH <10 ACTH <20 ACTH >20
DHEA-S <50 DHEA-S ~50 DHEA-S >50
Adrenal Proceed to No further testing in
insufficiency confirmatory testing the correct clinical
present eg, CST or ITT context
*Normal reference ranges: Cortisol: 7-25 mcg/dl, DHEA-S: 27-300 mcg/dl,
ACTH: 10-60 pmol/l
FIGURE. Suggested diagnostic flowchart for opioid-induced adrenal insuf-
ficiency (OIAI). CST ¼ cosyntropin stimulation test; DHEA-S ¼ dehydro-
epiandrosterone sulfate; ITT ¼ insulin tolerance test.
lead to HPA axis suppression. This result indi-
cates that the modulating effect may not be medi-
ated or solely mediated by the m receptor, but
perhaps d or k receptors may also be involved.5
Short-term Opioid Administration
The HPA response to the short-term adminis-
tration of opioids appears to differ between
animals and humans, making extrapolation of
findings challenging. A single intraperitoneal
injection of morphine in rodents is associated
with increased corticotropin and glucocorticoid
levels.6,7 Furthermore, the primary site of
opioid action on the HPA axis is thought to be
the hypothalamus. However, a positive dose-
dependent effect of endogenous and exogenous
opioid exposure on adrenal steroid synthesis
was seen in Wistar rats,8 suggesting that opioid
effects may in fact occur on multiple levels. In
contrast, a single dose of oral4 or intravenous5,9
opioid in humans resulted in suppression of the
HPA axis. The effect of opioids on adrenal
steroidogenesis in humans has not been
examined.
Long-term Opioid Administration
The effect of long-term administration of
opioids in rodents is variable, with adrenal
suppression seen with higher doses (2 mg/
kg per day vs 0.5 mg/d intraperitoneally),
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940 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
whereas rats given morphine at increasing
doses (10-100 mg/kg) subcutaneously twice
a day for 16 days were found to have elevated
basal corticosterone levels.10 The results of
most human studies (Table 1) suggest that
long-term administration of opioids (oral,
intravenous, or intrathecal) leads to suppres-
sion of the HPA axis.11,12,20 One study, how-
ever, reported a significant increased
corticotropin response to CRH stimulation
in patients treated with long-term opioid
therapy compared with controls, with no dif-
ference seen in basal cortisol or peak cortisol
levels following CRH administration between
the groups.19 Proposed mechanisms of re-
ported interindividual differences in results
include opioid receptor polymorphisms that
may alter opioid receptor affinity21 or genetic
variations in interleukin 1b (a stimulator of
corticotropin and CRH).22 Conversely, differ-
ences in study outcomes may be a conse-
quence of methodology or differences in
study population.
EPIDEMIOLOGY
The true prevalence, pathophysiology, optimal
investigation, and treatment outcome in OIAI
remain elusive. Available data are primarily
limited to small placebo-controlled trials,
retrospective studies, or case reports with
varying opioid formulations, frequency, and
modes of administration. In addition, investi-
gations for adrenal insufficiency have not
been consistent, making interpretation or
comparison of the available results difficult.
In a study examining the effects of long-
term intrathecal morphine or hydromorphone
therapy in 73 individuals, the prevalence of
OIAI was 9.2% based on a basal cortisol level
of less than 5 mg/dL (to convert to nmol/L,
multiply by 27.588), 15% based on an insulin
tolerance test, and 20% based on 24-hour
urinary free cortisol level below the reference
range (20-90 mg/24 h; to convert to nmol/24
h, multiply by 2.76).12 In another study of
17 patients receiving long-term treatment
with opioids (20 mg of morphine equivalent
daily doses [MEDDs] for >4 weeks), 29%
(5 of 17) had a basal cortisol level of less
than 5 mg/dL (the timing of cortisol measure-
ment was not clear), and 10% (1 of 10) did
not reach the threshold cutoff (20 mg/dL)
following a 1-mg corticotropin stimulation
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OPIOID-INDUCED ADRENAL INSUFFICIENCY

TABLE 2. Management of Opioid-Induced Adrenal Insufficiency

Management Instruction Consideration Alternative
Medication Hydrocortisone 15-25 mg/d in DHEA supplementation in women Dose-equivalent prednisone/
divided doses, eg, 10 mg on (25 mg/d) prednisolone
waking, 5 mg 6-8 h later
Education Sick day rule 1: Double your daily Annual check of IM corticosteroid Dexamethasone 4 mg,
glucocorticoid replacement expiration date methylprednisolone 40 mg
therapy in times of sickness
Sick day rule 2: Administer IM
corticosteroid in times of
sickness and inability to take
orally (if family or patient can
administer IM corticosteroids)
Corticosteroid card or written
adrenal insufficiency action plan
stating sick day rules
Medic alert bracelet or necklace
indicating the presence of
adrenal insufficiency
Emergency/adrenal crisis Administer 100 mg hydrocortisone Optimize education regarding sick Dexamethasone 4 mg,
IV/IM, IV hydration day rules to prevent adrenal methylprednisolone 40 mg
crisis
Procedure/operation Administer 100 mg hydrocortisone None Dexamethasone 4 mg,
IV/IM before procedure methylprednisolone 40 mg
followed by 200 mg/d IV until
able to eat and drink
DHEA ¼ dehydroepiandrosterone; IM ¼ intramuscular; IV ¼ intravenous.

test.23 More recently, 12% of patients (3 of 25) DIAGNOSIS

receiving different opioids with a median daily
opioid dose of 68 mg had negative findings on
a corticotropin stimulation test.17 Therefore,
the estimated prevalence of OIAI varies from
9% to 29%.
Several factors, such as increasing opioid
dose and longer duration of action, have been
identified as risk factors for the development
of opioid-induced androgen deficiency; howev-
er, risk factors for the development of OIAI have
not been identified or systematically studied.
Among those with chronic cancer pain
receiving 20 mg or more of MEDDs for 1 month
or longer, no association was found with MEDD
or patient sex and corticotropin or cortisol con-
centration.18 In opposition, a study involving
48 individuals with noncancer-associated pain
receiving long-term opioid therapy (median
MEDD, 68 mg) in whom morning cortisol con-
centrations were grouped into tertiles, lower
basal cortisol levels were associated with female
sex, increased body mass index, and younger
age.17
In a patient taking opiates who presents with
symptoms of adrenal insufficiency, baseline
cortisol and corticotropin measurement in
addition to synthetic corticotropin (cosyntro-
pin) stimulation testing (CST) is recommen-
ded.24 In OIAI, we expect to find a low
cortisol level along with a low or inappropri-
ately normal corticotropin concentration and
a failure to mount an appropriate cortisol
response after synthetic corticotropin adminis-
tration. Alternative causes of secondary
adrenal insufficiency, such as exogenous
glucocorticoid use or pituitary abnormalities,
should be considered before diagnosing OIAI
because management may be different.
Opioid-induced adrenal insufficiency occurs
primarily due to suppression of the HPA
axis, rather than suppression/destruction of
the adrenal cortex, and as such, mineralocorti-
coid deficiency does not occur. Dehydroepian-
drosterone sulfate (DHEA-S), a weak adrenal
androgen hormone produced by the zona
reticularis in response to corticotropin

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stimulation, levels will be low and can be used
as an indirect marker of low corticotropin
level.
Importantly, current tests to assess adrenal
insufficiency have limitations and must be
interpreted in the appropriate clinical context.
Not all patients with OIAI may have an
abnormal CST result. As illustrated by Ospina
et al,25 sensitivity of the 250-mg CST in sec-
ondary adrenal insufficiency is suboptimal
(64%; 95% CI, 52%-73%), with a likelihood
ratio for a negative result being only 0.39
(0.3-0.52). The CST is reliant on adrenal
cortex atrophy, which occurs in primary adre-
nal insufficiency or prolonged absence of
corticotropin. However, the onset of OIAI is
unknown, and some background cortico-
tropin may be present (partial secondary adre-
nal insufficiency) depending on the dose,
duration, and individual susceptibility to opi-
ates. This factor may explain the suboptimal
performance of the test. In this situation, the
administration of supraphysiologic synthetic
corticotropin may stimulate the adrenal cortex
enough to mount a cortisol response above the
cutoff considered diagnostic (18-20 mg/dL).
Although basal cortisol cutoffs utilized to
assess adrenal insufficiency vary institutionally
and given the limitations in diagnostic accu-
racy, the following diagnostic approach using
morning basal cortisol, corticotropin, and
DHEA-S levels initially, as outlined in the
Figure, can be considered. Among patients
referred for HPA axis assessment, a morning
(8-9 AM) basal cortisol level of greater than
10 mg/dL or less than 5 mg/dL predicted a suf-
ficient or insufficient response to the 250-mg
CST.26 Although the low-dose (1-mg) CST
could be considered, it is unclear if it would
provide any additional value over the 250-mg
CST, it contributes to technical difficulties
related to accurate dilution, and it is not uni-
versally available. A 24-hour urinary free
cortisol measurement does not perform well
in the assessment of adrenal insufficiency
and is not indicated. It is important, however,
to consider the overall hormonal assessment
when diagnosing OIAI because partial adrenal
deficiency may present with equivocal results
that should prompt further investigations.
Alternatively, when clinical suspicion for
OIAI is high and investigation results remain
equivocal, a therapeutic trial of physiologic
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942 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
glucocorticoid hormone replacement for a
few months can be considered and continued
if symptom improvement is sustained.
TREATMENT
Cortisol release, stimulated by corticotropin, is
regulated by the suprachiasmatic nucleus in
the hypothalamus and follows a circadian
rhythm. Therefore, in states of cortisol
deficiency, replacement is aimed at replicating
the physiologic cortisol profile to eliminate
symptoms associated with adrenal insufficiency
while avoiding the complications of excess
replacement. This process remains a challenge
with currently available oral glucocorticoid prep-
arations (Table 2). Hydrocortisone is the most
commonly used glucocorticoid. Endogenous
glucocorticoid production is estimated to be
between 5 and 10 mg/m.2,27 Hydrocortisone
doses ranging from 15 to 25 mg/d, given in
divided doses 2 to 3 times a day with the majority
given on waking (50%-66%) are typically
recommended. Alternative glucocorticoid prep-
arations with a longer half-life are available
(prednisone, prednisolone, and dexamethasone)
and may improve compliance but are more likely
to be associated with excess glucocorticoid
effects and greater suppression of endogenous
cortisol release.28 Adequacy of replacement is
based on symptomatic control because there is
no single reliable variable to assess optimal
dosing. Among those with secondary adrenal
insufficiency such as OIAI, mineralocorticoid
replacement is not required.
Adrenal androgens contribute minimally
to male androgen concentrations; however,
they contribute considerably to the female
androgen pool. Among long-term opioid
users, DHEA-S levels are reported to be lower
than in those who do not use opioids.29 Dehy-
droepiandrosterone sulfate supplementation
in both primary and secondary adrenal insuf-
ficiency has been examined with overall statis-
tically significant although clinically minimal
effect.30 None of the studies specifically exam-
ined DHEA-S supplementation in OIAI.
Although routine supplementation is not
recommended, a trial may be of use, especially
in younger women with low libido,
depressive symptoms, and decreased energy
who are receiving optimal glucocorticoid
replacement.31
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OPIOID-INDUCED ADRENAL INSUFFICIENCY
More recently, in an attempt to optimize
cortisol replacement, several methods of
cortisol delivery have been developed. Contin-
uous subcutaneous infusion of glucocorticoids
allows for finer dose alteration and
replication of the circadian rhythm. Alterna-
tively, new oral formulations using delayed
and sustained-release multiparticulate tablets
(Chronocort, Diurnal Group PLC) or immedi-
ate release with a sustained-release core
(Plenadren, Shire) to better resemble a physio-
logic profile have been developed but are
currently under study.31 It is worth noting
that the use of these novel agents has not
been investigated in the setting of OIAI.
In the event of adrenal crisis, characterized
by nausea, vomiting, myalgias, postural hypo-
tension, and eventually cardiovascular collapse,
prompt treatment with adequate hydration
(1 L of 0.9% saline over 1 hour followed by an
infusion based on patient needs) and parenteral
glucocorticoids (100 mg of intravenous hydro-
cortisone followed by 200 mg of hydrocortisone
per day) are essential.31 The best treatment for
adrenal crisis is prevention and requires educa-
tion of both physicians and patients. Patients
should be instructed to increase corticosteroids
in the event of stress (trauma, surgery, or major
psychological stress) and illness (typically dou-
ble or triple dose for 2-3 days) and if unable to
tolerate oral intake or if symptoms are severe,
intramuscular corticosteroids are required. In
addition, utility of a medic alert bracelet/necklace
or a corticosteroid card is helpful to inform
responders of the patient’s unique needs.
Limited data, based on case reports, suggest
that complete cessation of opioids leads to
reversal of OIAI (Table 1). The time to recovery
or the lowest opioid dose at which the HPA axis
recovers is unknown. Therefore, periodic
assessment of adrenal function once opioids
have been discontinued is recommended.
CONCLUSION
Available data from small heterogeneous
studies suggest that 9% to 29% of patients
receiving long-term treatment with opiates
have development of adrenal insufficiency.
However, predictors and the timing of the
OIAI onset are unclear. Given the widespread
use of narcotics in every field of medicine,
physicians should be aware of the potential
for endocrine-related adverse effects, in
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particular OIAI. We suggest careful consider-
ation of OIAI in any patient receiving long-
term opiate therapy who manifests symptoms
and signs suggestive of adrenal insufficiency.
Prospective large studies need to be designed
with the goals of elucidating factors associated
with OIAI, developing the best approach to
case detection of OIAI, and establishing an
appropriate management and monitoring
plan.
Abbreviations and Acronyms: CRH = corticotropin-
releasing hormone; CST = cosyntropin stimulation test;
DHEA-S = dehydroepiandrosterone sulfate; HPA = hypo-
thalamic-pituitary-adrenal; MEDD = morphine equivalent
daily dose; OIAI = opioid-induced adrenal insufficiency
Potential Competing Interests: Dr Bancos reports consul-
ting fees from Diurnal Group PLC for work not related to
this article. Dr Donegan reports no competing interests.
Correspondence: Address to Diane Donegan, MB BCh, Di-
vision of Endocrinology, Diabetes and Metabolism, Indiana
University, 550 N University Blvd, Ste 2180, Indianapolis,
IN 46202 (diadoneg@iu.edu).
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