Title: Adrenal insufficiency in patients on long-term opioid analgesia
Short title: Adrenal insufficiency and opioid analgesia
Authors:
Dr Fraser W Gibb1
Dr Alexandra Stewart2
Prof Brian R Walker1
Prof Mark W J Strachan1
Affiliation:
1. Edinburgh Centre for Endocrinology and Diabetes, NHS Lothian and
University of Edinburgh
2. Department of Anaesthetics, Royal Infirmary of Edinburgh
Correspondence:
Dr Fraser W Gibb
Edinburgh Centre for Endocrinology and Diabetes
Royal Infirmary of Edinburgh
Edinburgh
EH16 6AG
United Kingdom
Email: [email protected]
Keywords: Cortisol, adrenal, opioid, morphine
Disclosure: nothing to declare
Word count: 1933
Acknowledgements: This project was supported by a grant from the Edinburgh
and Lothians Health Foundation. We are grateful to the CORtisol NETwork
(CORNET) consortium for making available cortisol data from population-based
cohorts.
ABSTRACT
Objective:
Opioid analgesia has been implicated as a cause of secondary adrenal
insufficiency but little is known of the prevalence of this potentially serious
adverse effect in patients with chronic pain.
Design:
Cross-sectional study of chronic pain patients on long-term opioid analgesia.
Patients:
Patients attending tertiary chronic pain clinics at the Western General Hospital,
Edinburgh, treated with long-term opioid analgesia (n=48) with no recent
exposure to exogenous glucocorticoids.
Results:
4 patients (8.3%) had basal morning plasma cortisol concentrations below 100
nmol/L, of whom 3 failed to achieve a satisfactory cortisol response to
exogenous ACTH1-24 stimulation (peak cortisol >430 nmol/L). Basal cortisol was
positively associated with age (R = 0.398, p = 0.005) and negatively associated
with BMI (R = -0.435, p = 0.002).
Conclusions:
Suppression of the hypothalamic-pituitary-adrenal axis is present in a clinically
significant proportion of chronic pain patients treated with opioid analgesia.
Studies of larger populations should be conducted to better define the
prevalence and potential clinical consequences of adrenal insufficiency in this
context.
Introduction:
The use of long-term opioid analgesia is increasingly common, rising by
approximately 10% from 2003 until 2013 in England, when over 6.4 million
prescriptions were issued for morphine sulphate, buprenorphine and oxycodone
annually1. Compared with nonsteroidal anti-inflammatory drugs, opioid
analgesics may be associated with a higher risk of mortality in older individuals2,
although mechanisms underlying this association remain unclear. In recent
years a number of case reports have described cortisol deficiency in patients
treated with a variety of opioid analgesics, both oral3 and transdermal4. Opioids
affect the circadian rhythm of the hypothalamic-pituitary-adrenal (HPA) axis5
and reduce the effect of exogenous CRH upon ACTH and cortisol release6.
The suppressive effects of opioids upon the hypothalamic-pituitary-gonadal axis
have been well characterized, with hypogonadism present in 75% of male and
21% of female chronic pain patients treated with opioids7. However, the
prevalence of adrenal insufficiency has not been systematically assessed, except
in chronic intra-thecal opioid administration, where it is estimated to occur in
approximately 15% of patients8. We investigated the prevalence of cortisol
insufficiency in opioid-treated patients, attending a tertiary chronic pain clinic,
and whether this was associated with typical clinical manifestations of cortisol
insufficiency, such as hypotension and weight loss.
Methods:
Potential participants were identified from the electronic records of patients
attending chronic pain clinics at the Western General Hospital, Edinburgh.
Patients were eligible for inclusion if treated for at least 6 months with opioid
analgesics in the setting of chronic non-cancer pain. Patients with disease of the
HPA axis, current glucocorticoid therapy (by any route) or glucocorticoid
therapy within the preceding 3 months were excluded. 236 patients were
contacted by letter to participate in the study, with 48 ultimately taking part. Of
the 236 contacted, 8 patients were excluded from the study due to
current/recent glucocorticoid use and 4 were excluded due to recent
discontinuation of opioid medication. There were no significant differences in
age (54 [IQR 45 – 62] vs. 49 [42 – 59] years, p = 0.084) or gender representation
between those taking part and those who did not (17.6% of women and 24.5% of
invited men took part, p = 0.248). Ethical approval was granted by the South
East Scotland Ethics Committee and written informed consent obtained from all
participants.
Participants attended the clinical research facility at 8am and completed the SF-
36 health questionnaire. Basic anthropometric measurements were obtained
(weight and height) and body fat assessed using an Omron BF306 bioimpedance
device. Both erect and supine blood pressure and heart rate were measured
using an Omron 705IT automatic blood pressure monitor. Blood sampling was
performed immediately before and 30 min after IM administration of 250
micrograms of ACTH1-24 (Synacthen®). Cortisol was measured by Abbott
Architect Immunoassay, with a stimulated cortisol >430 nmol/L regarded as
normal, in keeping with locally established normative data. When patients
failed to achieve a sufficient cortisol response to ACTH stimulation, full anterior
pituitary function testing was performed in line with standard clinical care
including, if appropriate, pituitary MRI.
Normative data for morning cortisol were obtained from two European
population-based cohorts: CROATIA-Korcula (n=964) and ORCADES (n=1019) 9.
Cortisol was measured by immunoassay from samples taken between 0700h and
1100h. In addition, mean and standard deviation data were provided by Abbott
Laboratories (personal communication) from morning cortisol values (sampled
before 10 am) used to produce the Architect immunoassay reference range (n =
150). These data were used to create z-scores to permit direct comparison with
results obtained in the current study.
Dose of opioid is presented as a morphine sulphate (MST) dose equivalent as
described in the British National Formulary10. Correlations are presented as
Pearson correlation coefficients. Continuous variables were compared by
Kruskal-Wallis test. Data are presented as median (interquartile range). P value
<0.05 was regarded as significant for all analyses.
Results:
Demographics and opioid treatment
The median age of participants was 53.5 years (45.4 – 62.4). 25 participants
were female and 23 were male. Median BMI in the cohort was 31.2 kg/m2 (26.4
– 37.4). The median daily opioid dose was 68 mg (40 – 153) as determined by
morphine sulphate equivalent dose. A variety of opioid medications were
prescribed, as detailed in figure 1, with tramadol and dihydrocodeine treated
patients receiving significantly lower MST-equivalent doses.
Plasma cortisol
Cortisol at baseline and 30 min after ACTH1-24 stimulation is shown in figure 2.
8am cortisol was less than 100 nmol/L in 4 patients (8.3%). This represents
values below a z-score for the Abbott assay of -1.6. For comparison, only 1.1% of
unselected participants from the combined ORCADES / CROATIA-Korcula
population-based cohorts (n=1983) had morning cortisol values below the
equivalent threshold (z-score of -1.6). Three patients failed to achieve an
appropriate cortisol response to ACTH stimulation; all were female, aged
between 36 - 39 years, obese (BMI > 30mg/kg2), and with basal plasma cortisol
<100 nmol/L. When limiting this analysis to the 33 patients on high-dose opioid
analgesia (excluding tramadol and dihydrocodeine), approximately 10% of those
assessed had an initial suboptimal cortisol response to ACTH.
Clinical characteristics of the cohort are presented in table 1 and quality of life
questionnaire data in table 2, stratified by tertiles of basal cortisol. Lower basal
cortisol was associated with younger age (R = -0.435, p = 0.002) and higher BMI
(R = -0.435, p = 0.002) (figure 3), but not with other indices of glucocorticoid
action such as blood pressure and not with opioid dose. Lower basal cortisol
was associated with somewhat poorer quality of life scores (table 2). No
significant associations were observed between these variables and ACTH-
stimulated cortisol concentration (not shown).
Further investigation in patients with glucocorticoid insufficiency
Patient 1: A 39-year-old woman (BMI 37.9 kg/m2) treated with a fentanyl patch
(75 gμ /hour) and oramorph (5mg as required) [MST daily equivalent
185mg/day] for fibromyalgia. She had no additional co-morbidities. Initial
synacthen test showed a basal morning cortisol of 84 nmol/L rising to 270
nmol/L. Repeat synacthen tests showed borderline results 69 to 431 nmol/L
and 147 to 412 nmol/L. Morning ACTH was 11 ng/L (reference range 7 – 63
ng/L) and prolactin and IGF-1 were within the reference ranges. Mild subclinical
primary hypothyroidism was noted with a TSH of 13.5 mU/L and a free T4 of 11
pmol/L. She was receiving oral combined estrogen/progesterone replacement
therapy. Pituitary MRI was normal. She reported modest symptomatic
improvement following commencement of hydrocortisone (10mg am and 5 mg
pm), specifically with improvement in lethargy.
Patient 2: A 37-year-old woman (BMI 31.5 kg/m2) treated with MST (60mg
daily) and sevredol (40mg as required) [MST equivalent 100mg/day] for
neuropathic scar pain. She had no additional co-morbidities. Initial synacthen
test showed a basal morning cortisol of 91 nmol/L rising to 385 nmol/L. Repeat
synacthen tests showed borderline results 180 to 437 nmol/L and 257 to 375
nmol/L. Morning ACTH was 13 ng/L and prolactin, IGF-1 and thyroid function
were within the reference ranges. She had been amenorrhoeic for approximately
one year, following commencement of a depot contraceptive. Pituitary MRI was
normal. She reported symptomatic improvement following commencement of
hydrocortisone (10mg am and 5 mg pm), specifically with improvement in
fatigue, although this effect waned after approximately 6 months.
Patient 3: A 36-year-old woman (BMI 37.7 kg/m2) treated with a fentanyl patch
(75 gμ /hour) and dihydrocodeine (240mg daily) [MST daily equivalent
222mg/day] for chronic abdominal pain. She had no additional co-morbidities.
Initial synacthen test showed a basal morning cortisol of 64 nmol/L rising to 424
nmol/L. A repeat synacthen test was unequivocally normal (446 rising to 590
nmol/L) with an associated early morning ACTH of 37 ng/L. Full anterior
pituitary function testing was also normal and, in view of this, no further
investigations or treatment were considered.
Discussion:
In this series of opioid-treated chronic pain clinic patients, low morning cortisol
was more common than would be expected with reference to large population-
based studies. Similarly, 3 of 33 patients receiving high dose opioid failed to
mount an appropriate cortisol response to ACTH stimulation. In view of the
widespread use of opioid analgesia in chronic pain, a large number of patients
may be at risk of hypocortisolaemia.
Case reports3,4 and small case series11 have reported significant effects of opioid
analgesia upon the hypothalamic-pituitary-adrenal axis, although the prevalence
of adrenal insufficiency in this context has not been documented previously.
Prospective evaluation of plasma cortisol concentration in a series of 8 chronic
pain patients, following commencement of oral opioids, demonstrated significant
(possibly subnormal) reductions in morning cortisol, although ACTH-stimulated
cortisol was normal in all those investigated11. The circadian rhythm of ACTH
secretion is blunted in heroin addicts with lower morning concentrations
observed than in healthy controls12 and concomitantly lower morning plasma
cortisol, with attenuation of the expected late evening nadir13. Perhaps contrary
to expectations, opioid treated chronic pain patients were found to have elevated
hair cortisol levels when compared to healthy controls14. Elevated hair cortisol, a
measure of long-term systemic cortisol exposure, may however reflect changes
related to chronic pain rather than opioid therapy. Chronic pain has also been
associated with disruption of the diurnal rhythm of cortisol15, low morning
cortisol and enhanced reactivity of the HPA axis to stimulation16. Opioids may
have direct effects upon adrenal glucocorticoid production, based on previous
studies in rodents. In rat adrenal cell culture experiments, administration of
opioid peptides resulted in corticosterone production, which was diminished by
naloxone17. In vivo, morphine potentiated and naloxone inhibited corticosterone
production in hypophysectomised rats18. If similar mechanisms exist in humans,
a pattern of low morning cortisol, blunted ACTH-stimulated cortisol and loss of
diurnal rhythm could occur during chronic opioid exposure.
Demonstrably lower quality of life has been reported in chronic pain patients19
and cortisol insufficiency may compound this in opioid-treated patients, perhaps
mediated at a CNS level or in relation to attenuated anti-inflammatory
mechanisms. We were, however, unable to detect any significant association
between basal or stimulated cortisol and quality of life measures. The observed
relationship between basal cortisol and role limitation secondary to emotional
problems is of questionable significance. However, given the relatively small size
of this cohort, our findings do not necessarily exclude such relationships. In
older individuals, opioid analgesia has been associated with a higher mortality
risk than in matched patients treated with NSAIDs2. The mechanisms through
which opioids may exert such an effect remain obscure, although it would be of
significant interest to investigate the potential role of perturbations in the
hypothalamic-pituitary axes.
It is open to question whether biochemically modest cortisol deficiency is
associated with clinically meaningful symptoms or adverse outcomes, but it is
conceivable that during acute illness such patients may be at risk. When patients
with mild opioid-related adrenal insufficiency are identified, it is not clear
whether they benefit from glucocorticoid replacement. The current study was
not designed to address this question, although the two patients commenced on
hydrocortisone did report subjective improvement in their level of well-being.
The small size of the study limits the assessment of risk factors for
adrenocortical insufficiency and is inadequately powered to confirm dose-
response or drug-specific relationships with opioid exposure. Failure to mount
an appropriate cortisol response was limited to female patients who were
younger and with higher BMI than the cohort average. Sexual dimorphism has
been demonstrated in the propensity to develop opioid-induced hypogonadism7.
Further work is required to better establish the prevalence of cortisol deficiency
in patients receiving high dose long-term opioid therapy, as well as the clinical
relevance of modestly suboptimal cortisol response to ACTH-stimulation in this
context. Nonetheless, on the basis of the data presented in this study, we
suggest it reasonable to consider measuring an early morning plasma cortisol in
patients receiving long-term, high-dose opioids, with consideration of further
endocrine evaluation in those with a result less than 100 nmol/L.
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Figures
Figure 1: Regular opioid medication and median dose of opioid within each group (presented as equivalent daily dose of morphine sulphate [mg]).
Figure 2: Synacthen test results in study participants (n=48). Pearson R = 0.677 (p <0.001). Dotted line represent threshold for satisfactory cortisol response to ACTH-stimulation (>430 nmol/L).
Figure 3: Relationship of basal cortisol with (A) age (Pearson R = 0.398, p = 0.005) and (B) BMI (Pearson R = -0.435, p = 0.002).
Table 1: Clinical characteristics of patients stratified by tertiles of basal cortisol. Presented as median (IQR) and compared by Kruskal-Wallis test.
Morning cortisol tertilesTertile 1 Tertile 2 Tertile 3 p
Morning cortisol (nmol/L)
173 (106 – 237)
318 (271 - 343)
438 (384 - 466)
Stimulated cortisol (nmol/L)
490 (443 - 544)
596 (526 – 642)
619 (594 - 638)
Cortisol increment (nmol/L)
321 (273 - 372)
289 (241 - 332)
169 (137 - 225)
Age (years) 50.7 (40.5 - 54)
57.8 (48.2 – 64.8)
61.1 (49.5 – 68.2)
0.017
Gender F 9 / M 7 F 8 / M 8 F 8 / M 8Weight (kg) 90.9 (80.8 –
107.5)101.9 (87.5 – 115.3)
72.3 (67.7 – 91.8)
0.007
BMI (kg/m2) 32.4 (29.5 – 36.7)
31.5 (29.5 – 39.2)
26.0 (23.3 – 32.6)
0.008
Body fat (%) 39.2 (31.0 – 40.6)
32.3 (30.3 – 40.3)
33.6 (26.2 – 39.2)
NS
SBP supine (mmHg) 130 (120 - 136)
136 (125 - 158)
140 (126 - 157)
NS
DBP supine (mmHg) 75 (67 - 81) 84 (76 - 89) 78 (74 - 90) NSSBP erect (mmHg) 124 (117 -
132)135 (121 - 146)
136 (126 - 144)
NS
DBP erect (mmHg) 83 (73 - 86) 88 (76 - 104) 81 (77 – 89) NS SBP (mmHg)Δ 4 (-2 - 8) 7 (-3 - 12) 5 (-6 - 13) NS DBP (mmHg)Δ -8 (-11 - -2) -6 (-11 - -2) -3 (-8 - -2) NS
MST dose equivalent (mg/day)
95 (40 - 166) 75 (30 - 124) 60 (42 - 140) NS
Table 2: Results of SF-36 questionnaire stratified by tertiles of basal cortisol and presented as median (IQR).
Morning cortisol tertilesTertile 1 Tertile 2 Tertile 3 p
Physical functioning 20 (18 – 35) 15 (10 – 30) 20 (13 - 63) NSRole limitations due 0 (0 – 13) 0 (0 – 0) 0 (0 – 38) NS
to physical healthRole limitation due to emotional problems
0 (0 – 50) 0 (0 – 33) 33 (33 – 100) 0.047
Energy / fatigue 30 (15 – 43) 15 (8 – 25) 25 (15 – 33) NSEmotional well-being
56 (32 – 66) 52 (42 – 54) 68 (48 – 78) NS
Social functioning 19 (13 – 56) 25 (0 – 56) 38 (25 – 56) NSPain 23 (10 – 23) 23 (10 – 23) 23 (10 – 27) NSGeneral health 28 (15 – 45) 30 (15 – 33) 40 (20 – 45) NS
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