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


METHODS
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.


METHODS
Clonidine hydrochloride capsules (25 µg or 50 µg twice daily for body weight <35 kg or >35 kg, respectively) vs placebo capsules for 9 weeks.


METHODS
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
Adolescent CFS is associated with enhanced sympathetic nervous activity, low-grade systemic inflammation, attenuated hypothalamus-pituitary-adrenal 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.


BACKGROUND
clinicaltrials.gov Identifier: NCT01040429.
Department of Paediatrics, Oslo University Hospital, Oslo, Norway2Department of Paediatrics, Lillehammer County Hospital, Lillehammer, Norway.
Dag
D
Sulheim
Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway4Department of Anesthesiology and Critical Care, Oslo University Hospital, Oslo, Norway.
Even
E
Fagermoen
Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway5Institute of Nursing Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway.
Anette
A
Winger
Department of Pharmacology, Oslo University Hospital, Oslo, Norway.
Anders Mikal
AM
Andersen
Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital Rikshospitalet, Oslo, Norway.
Kristin
K
Godang
Department of Microbiology, Oslo University Hospital, Oslo, Norway.
Fredrik
F
Müller
Department of Pediatrics, the Johns Hopkins University School of Medicine, Baltimore, Maryland.
Peter C
PC
Rowe
Department of Pediatrics, Medical University of South Carolina, Charleston.
J Philip
JP
Saul
School of Pharmacy, University of Oslo, Oslo, Norway12Norwegian Institute of Public Health, Oslo, Norway.
Eva
E
Skovlund
Department of Psychology, University of Oslo, Oslo, Norway14Innlandet Hospital Trust, Lillehammer, Norway.
Merete Glenne
MG
Øie
Department of Paediatrics, Oslo University Hospital, Oslo, Norway15Division of Medicine and Laboratory Sciences, Medical Faculty, University of Oslo, Oslo, Norway16Department of Paediatrics, Akershus University Hospital, Nordbyhagen, Norway.
Vegard Bruun
VB
Wyller
D000293:Adolescent; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage* / Q000009:adverse effects; D002097:C-Reactive Protein / Q000378:metabolism; D003000:Clonidine / Q000008:administration & dosage* / Q000009:adverse effects; D003404:Creatinine / Q000652:urine; D003430:Cross-Sectional Studies; D004311:Double-Blind Method; D015673:Fatigue Syndrome, Chronic / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D008297:Male; D009638:Norepinephrine / Q000097:blood; D009664:Norway; D013564:Sympathetic Nervous System / Q000502:physiology; D016896:Treatment Outcome
D058647:Adrenergic alpha-2 Receptor Agonists; D002097:C-Reactive Protein; D003404:Creatinine; D003000:Clonidine; D006854:Hydrocortisone; D009638:Norepinephrine