Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial

Nenke, Marni A.; Haylock, Clare L.; Rankin, Wayne; Inder, Warrick J.; Gagliardi, Lucia; Eldridge, Crystal; Rolan, Paul; Torpy, David J.

doi:10.1016/j.psyneuen.2015.03.015

Cited by 31 publications

(30 citation statements)

References 43 publications

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“…The converse of this relationship may also be true, as cortisol is a potent anti-inflammatory and SAI may cause worsening of inflammation contributing to pain. Nenke et al conducted a pilot randomized placebo-controlled trial of physiological cortisol replacement in patients taking opioids for chronic non-cancer pain demonstrating that physiological glucocorticoid replacement improved pain tolerance (11). This improvement suggests a component of symptoms such as pain intolerance may be attributed to hypocortisolism.…”

Section: Discussionmentioning

confidence: 99%

“…While the use of intrathecal opioids by continuous infusion has been well studied (10), few studies have examined the frequency of clinically significant secondary adrenal insufficiency (SAI) arising from oral or transdermal opioids. We have previously reported a reduced cortisol response to cold pain stimulus, but only 1 out of 10 participants in that study who underwent an ACTH 1-24 test had a sub-normal result (11). Another recent study undertook ACTH 1-24 tests on 48 participants on oral opioids and found a subnormal response in three (12).…”

Section: Introductionmentioning

confidence: 89%

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Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain

Lamprecht

Sorbello

Jang

et al. 2018

European Journal of Endocrinology

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ObjectiveTo evaluate pituitary function, sexual function and quality of life (QoL) in patients on oral or transdermal opioids.Design and methodsCross-sectional study comparing pituitary function, QoL and sexual function in people on long-term opioid therapy (n = 40) vs an age- and sex-matched control group (n = 25). Baseline pituitary function was assessed on blood samples collected prior to 0900 h. Further testing with corticotropin (250 µg IV) and metyrapone (30 mg/kg) stimulation tests was undertaken on participants with serum cortisol <250 nmol/L. Validated questionnaires completed to assess QoL, fatigue and sexual function.ResultsSecondary adrenal insufficiency (SAI) was identified on the basis of a failed stimulation test in 22.5% of opioid users vs no controls (P = 0.01). Opioid users with SAI had a higher median morphine-equivalent daily dose (MEDD),P = 0.037 – 50% with MEDD >200 mg and 0% with MEDD <60 mg had SAI. Among male participants, testosterone was inversely associated with BMI (P = 0.001) but not opioid use. A non-significant trend to low testosterone <8 nmol/L in male opioid users (11/24 opioid users vs 2/14 control,P = 0.08) suggests a small subgroup with opioid-induced androgen deficiency. Opioid users had greater fatigue, reduced quality of life in all subsections of the SF-36 and impaired sexual function in both males and females (all scoresP < 0.001 compared to controls).ConclusionLong-term opioid therapy was associated with dose-related SAI in over 20% of chronic pain patients and is associated with poor quality of life, fatigue and sexual dysfunction. Obesity confounds the interpretation of opioid-induced male androgen deficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain

Lamprecht

Sorbello

Jang

et al. 2018

European Journal of Endocrinology

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“…The accurate prevalence of adrenal insufficiency in these patients has not been clearly defined and chronic pain can be a major confounder (chronic The altered HPA axis function of opioid users improves or returns to normal after discontinuation or reduction in the dose of the drug (36,37,50,51,53,54), but the time interval of this has not been systematically studied. Interestingly, Nenke et al, in a pilot, randomized, doubleblind, placebo-controlled crossover study with 17 patients on long-term opioid therapy for chronic non-cancer pain and mild hypocortisolism (defined by a plasma cortisol response ≤350 nmol/L at 60 min following a cold pressor test), found that hydrocortisone therapy (10 mg/m 2 / day) led to improvement in vitality and pain tolerance compared to placebo (77).…”

Section: Hypothalamo-pituitary-adrenal Axismentioning

confidence: 99%

“…In summary, opioids exert inhibitory actions on the HPA axis by acting at various levels. Although it could be argued that hypocortisolism is an adaptive response to opioids, the reported cases of improvement of clinical manifestations resembling those of cortisol deficiency after glucocorticoid administration (52,53,74,77) and the description of Addisonian crises whilst on these agents (16,54) suggest that, at least in some patients, hypocortisolism is of clinical significance. Further studies are needed to define the prevalence of hypoadrenalism with different opioids at various regimes and routes, to establish the clinical significance and potential consequences/adverse outcomes of the biochemical findings (particularly if these reflect modest changes in the HPA axis) and to provide clear guidance on the reversibility and the time course of the hormonal changes following withdrawal or reduction of opioid dose.…”

Section: Hypothalamo-pituitary-adrenal Axismentioning

confidence: 99%

MECHANISMS OF ENDOCRINOLOGY: Endocrinology of opioids

Fountas

Chai

Kourkouti

et al. 2018

European Journal of Endocrinology

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The use of opioids has grown substantially over the past two decades reaching the dimensions of a global epidemic. These drugs have effects on multiple levels of the endocrine system through mechanisms which are still not fully elucidated, and awareness of their endocrine sequelae is vital for all specialists prescribing or managing patients on them. Hypogonadism is the most well recognised consequence of opioid use (prevalence 21-86%) which, however, may remain undiagnosed with potential adverse outcomes for the patients. Although less frequent, cortisol deficiency can be also found. Furthermore, there is negative impact on bone health (with reduced bone mineral density and increased fracture risk) and occasionally hyperprolactinaemia, whereas the clinical significance of alterations in other hormones remains to be clarified. Discontinuation or reduction of the opioid and, in cases of chronic pain, consideration of alternative therapies for pain relief are potential management options. Hormonal replacement, especially when the above measures are not practically feasible, needs to be considered. Further studies are needed to clearly establish the prevalence of hormonal abnormalities with various regimes, doses and routes of opioids and to address reliably the long-term benefits and risks of hormonal treatment in patients on opioids. Until evidence-based, safe and cost-effective clinical guidelines become available, periodical assessment of the gonadal and adrenal function (particularly when relevant clinical manifestations are present) and evaluation of the bone health status are advised.

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“…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 measurement was not clear), and 10% (1 of 10) did not reach the threshold cutoff (20 mg/dL) following a 1-mg corticotropin stimulation test. 23 More recently, 12% of patients (3 of 25) 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%.…”

Section: Epidemiologymentioning

confidence: 99%

Opioid-Induced Adrenal Insufficiency

Donegan

Bancos

2018

Mayo Clinic Proceedings

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The target audience for Mayo Clinic Proceedings is primarily internal medicine physicians and other clinicians who wish to advance their current knowledge of clinical medicine and who wish to stay abreast of advances in medical research. Statement of Need: General internists and primary care physicians must maintain an extensive knowledge base on a wide variety of topics covering all body systems as well as common and uncommon disorders. Mayo Clinic Proceedings aims to leverage the expertise of its authors to help physicians understand best practices in diagnosis and management of conditions encountered in the clinical setting. Accreditation Statement: In support of improving patient care, Mayo Clinic College of Medicine and Science is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team. Credit Statements: AMA: Mayo Clinic College of Medicine and Science designates this journalbased CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. MOC: Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 MOC point in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Learning Objectives: On completion of this article, you should be able to (1) review the pathophysiology of opioid-induced adrenal insufficiency, (2) evaluate a patient with suspected opioid-induced adrenal insufficiency, and (3) implement optimal treatment for opioid-induced adrenal insufficiency.

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Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial

Cited by 31 publications

References 43 publications

Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain

Secondary adrenal insufficiency and pituitary dysfunction in oral/transdermal opioid users with non-cancer pain

MECHANISMS OF ENDOCRINOLOGY: Endocrinology of opioids

Opioid-Induced Adrenal Insufficiency

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