title: Low-dose hydrocortisone replacement improves wellbeing and pain tolerance in chronic pain patients with opioid-induced hypocortisolemic responses. A pilot randomized, placebo-controlled trial.
abstract: Long-term opioid therapy has been associated with low cortisol levels due to central suppression of the hypothalamic-pituitary-adrenal axis. The implications of hypocortisolism on wellbeing have not been established. Our aim was to determine whether intervention with physiologic glucocorticoid replacement therapy improves wellbeing and analgesic responses in patients with chronic non-cancer pain on long-term opioid therapy with mild cortisol deficiency. We performed a pilot randomized, double-blind, placebo-controlled crossover study of oral hydrocortisone replacement therapy in 17 patients recruited from a Pain Clinic at a single tertiary center in Adelaide, Australia. Patients were receiving long-term opioid therapy (≥ 20 mg morphine equivalents per day for ≥ 4 weeks) for chronic non-cancer pain with mild hypocortisolism, as defined by a plasma cortisol response ≤ 350 nmol/L at 60 min following a cold pressor test. The crossover intervention included 28-day treatment with either 10mg/m(2)/day of oral hydrocortisone in three divided doses or placebo. Improvement in wellbeing was assessed using Version 2 of the Short Form-36 (SF-36v2), Brief Pain Inventory-Short Form, and Addison's disease quality of life questionnaires; improvement in analgesic response was assessed using cold pressor threshold and tolerance times. Following treatment with hydrocortisone, the bodily pain (P=0.042) and vitality (P=0.013) subscales of the SF-36v2 were significantly better than scores following treatment with placebo. There was also an improvement in pain interference on general activity (P=0.035), mood (P=0.03) and work (P=0.04) following hydrocortisone compared with placebo. This is the first randomized, double-blind placebo-controlled trial of glucocorticoid replacement in opioid users with chronic non-cancer pain and mild hypocortisolism. Our data suggest that physiologic hydrocortisone replacement produces improvements in vitality and pain experiences in this cohort compared with placebo.
  
  
  BACKGROUND
  Therapeutic Goods Administration Clinical Trials Notification Scheme (Drugs), Trial Number 2012/0476.
authors.affiliation: Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia. Electronic address: Marni.Nenke@health.sa.gov.au.
authors.forename: Marni A
authors.initials: MA
authors.lastname: Nenke
authors.affiliation: Northern Adelaide Geriatrics Service, Modbury Hospital, Modbury, Australia; School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Haylock
authors.affiliation: Chemical Pathology Directorate, SA Pathology, Adelaide, Australia.
authors.forename: Wayne
authors.initials: W
authors.lastname: Rankin
authors.affiliation: Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Woolloongabba, Australia.
authors.forename: Warrick J
authors.initials: WJ
authors.lastname: Inder
authors.affiliation: Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia; School of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Lucia
authors.initials: L
authors.lastname: Gagliardi
authors.affiliation: Pain and Anaesthesia Research Clinic, University of Adelaide, Adelaide, Australia.
authors.forename: Crystal
authors.initials: C
authors.lastname: Eldridge
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Rolan
authors.affiliation: Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Torpy
mesh_terms: D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D059350:Chronic Pain / Q000188:drug therapy / Q000523:psychology; D018592:Cross-Over Studies; D004311:Double-Blind Method; D020249:Hormone Replacement Therapy / Q000379:methods; D006854:Hydrocortisone / Q000009:adverse effects / Q000172:deficiency / Q000627:therapeutic use; D010147:Pain Measurement / Q000187:drug effects; D010865:Pilot Projects; D011788:Quality of Life; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D000893:Anti-Inflammatory Agents; D006854:Hydrocortisone
keywords: Chronic pain; Hydrocortisone replacement; Hypocortisolemia; Opioid