Hydrocortisone Dose Influences Pain, Depressive Symptoms and Perceived Health in Adrenal Insufficiency: A Randomized Controlled Trial

Abstract

Background: There is a major lack of randomized controlled trials (RCTs) evaluating the effects of hydrocortisone (HC) substitution therapy in patients with secondary adrenal insufficiency. Therefore, we evaluated the effects of two different replacement doses of HC on health-related quality of life (HRQoL) in a RCT. Methods: This RCT with a double-blind cross-over design was performed at the University Medical Center Groningen. Forty-seven patients (29 men, age 51 ± 14 years, range 19-73 years) with secondary adrenal insufficiency participated. Patients received both a lower and a higher dose of HC (0.2-0.3 and 0.4-0.6 mg/kg body weight/day) for 10 weeks in random order. HRQoL was assessed with a daily mood and symptom checklist (Patient Health Questionnaire-15 [PHQ-15], Generalized Anxiety Disorder-7 [GAD-7], Patient Health Questionnaire-9 [PHQ-9]) and with questionnaires assessing general well-being (RAND 36-Item Health Survey [RAND-36]), mood (Hospital Anxiety and Depression Scale [HADS]) and fatigue (Multidimensional Fatigue Inventory-20 [MFI-20]). ClinicalTrials.gov identifier: NCT01546922. Results: Patients receiving the higher dose of HC reported significantly fewer symptoms of depression (p = 0.016 and p = 0.045 for HADS and PHQ-9, respectively), less general and mental fatigue (p = 0.004 and p = 0.003, respectively, both MFI-20), increased motivation (p = 0.021, MFI-20), better physical functioning (p = 0.041), better general health (p = 0.013) and more vitality (p = 0.025) (all RAND-36). In addition, while on the higher dose, fewer somatic symptoms (p = 0.022) and less pain (p < 0.001) (both PHQ-15) were experienced. Conclusions: On the higher dose of HC, patients reported a better HRQoL on various domains as compared to the lower dose of HC. The fact that a higher dose of HC may improve patient well-being should be taken into consideration when individualizing the HC substitution dose.

Somatosensory function in patients with secondary adrenal insufficiency treated with two different doses of hydrocortisone—Results from a randomized controlled trial

“…Despite the previously observed difference in subjective pain reports as assessed by daily diaries comparing both doses of HC [14], sensory changes supportive for HC induced alteration of mechanical function could not be established in this study. Therefore, previously found altered subjective pain due to a low dose of HC in SAI patients is not caused by different somatosensory functioning in response to mechanical stimuli.…”

“…Our results indicate that the dose of HC has no impact on mechanical pain perception in patients with SAI, even though a difference in subjectively experienced pain symptoms was reported previously by the same patient group [14]. …”

“…However, it is unknown whether these two substitution doses also influence somatosensory function. This study is part of a recently conducted randomized double blind cross-over study which assessed the effect of two different doses of HC on cognition [13], health related quality of life [14], blood pressure [15], pharmacokinetics and somatosensory functioning. Sensory function was assessed using parts of the German Research Network on Neuropathic Pain (DFNS) Quantitative Sensory Testing (QST) battery which assesses the perceptual response to systematically applied and quantifiable sensory stimuli [16,17].…”

Decreased physical activity, reduced QoL and presence of debilitating fatigue in patients with Addison's disease

“…This emphasizes the very important role of mineralocorticoid replacement; apparently, mineralocorticoid replacement is required for quality of life and the little mineralocorticoid effects of glucocorticoids are not sufficient. Potentially, the decreased QoL in these patients can be connected to the mineralocorticoid receptors in the brain, which also interact with glucocorticoids . In patients on a thrice‐daily regime, we found higher fatigue and lower SF‐36 scores (RP, VT, PCS scores).…”

Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study

“…By contrast, 10 weeks of treatment with higher doses of hydrocortisone was shown to improve health-related QoL vs lower doses in a recent randomized, double-blind crossover trial in 47 patients with secondary AI (37). In the 3-month comparison with hydrocortisone TID, DR-HC significantly improved total scores and several domain scores on the FIS and the PGWB questionnaire despite an average 20% reduction in cortisol exposure (22).…”