Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome a combined cross-sectional and randomized clinical trial

Dag Sulheim, Even Fagermoen, Anette Winger, Anders Mikal Andersen, Kristin Godang, Fredrik Muller, Peter C. Rowe, J. Philip Saul, Eva Skovlund, Merete Glenne Oie, Vegard W. Bruun

Research output: Contribution to journalArticle

Abstract

Importance Chronic fatigue syndrome (CFS) is a disabling condition with unknown disease mechanisms and few treatment options. Objective To explore the pathophysiology of CFS and assess clonidine hydrochloride pharmacotherapy in adolescents with CFS by using a hypothesis that patients with CFS have enhanced sympathetic activity and that sympatho-inhibition by clonidine would improve symptoms and function. Design, Setting, and Participants Participants were enrolled from a single referral center recruiting nationwide in Norway. A referred sample of 176 adolescents with CFS was assessed for eligibility; 120 were included (34 males and 86 females; mean age, 15.4 years). A volunteer sample of 68 healthy adolescents serving as controls was included (22 males and 46 females; mean age, 15.1 years). The CSF patients and healthy controls were assessed cross-sectionally at baseline. Thereafter, patients with CFS were randomized 1:1 to treatment with low-dose clonidine or placebo for 9 weeks and monitored for 30 weeks; double-blinding was provided. Data were collected from March 2010 until October 2012 as part of the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial. Interventions Clonidine hydrochloride capsules (25 ?g or 50 ?g twice daily for body weight <35 kg or >35 kg, respectively) vs placebo capsules for 9 weeks. Main outcomes and measures Number of steps per day. Results At baseline, patients with CFS had a lower number of steps per day (P < .001), digit span backward score (P = .002), and urinary cortisol to creatinine ratio (P = .001), and a higher fatigue score (P < .001), heart rate responsiveness (P = .02), plasma norepinephrine level (P < .001), and serum C-reactive protein concentration (P = .04) compared with healthy controls. There were no significant differences regarding blood microbiology evaluation. During intervention, the clonidine group had a lower number of steps per day (mean difference, ?637 steps; P = .07), lower plasma norepinephrine level (mean difference, ?42 pg/mL; P = .01), and lower serum C-reactive protein concentration (mean ratio, 0.69; P = .02) compared with the CFS placebo group. conclusions and relevence Adolescent CFS is associated with enhanced sympathetic nervous activity, low-grade systemic inflammation, attenuated hypothalamus-pituitaryadrenal axis function, cognitive impairment, and large activity reduction, but not with common microorganisms. Low-dose clonidine attenuates sympathetic outflow and systemic inflammation in CFS but has a concomitant negative effect on physical activity; thus, sympathetic and inflammatory enhancement may be compensatory mechanisms. Low-dose clonidine is not clinically useful in CFS.

Original languageEnglish (US)
Pages (from-to)351-360
Number of pages10
JournalJAMA pediatrics
Volume168
Issue number4
DOIs
StatePublished - Apr 2014

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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    Sulheim, D., Fagermoen, E., Winger, A., Andersen, A. M., Godang, K., Muller, F., Rowe, P. C., Saul, J. P., Skovlund, E., Oie, M. G., & Bruun, V. W. (2014). Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome a combined cross-sectional and randomized clinical trial. JAMA pediatrics, 168(4), 351-360. https://doi.org/10.1001/jamapediatrics.2013.4647