Chronic fatigue syndrome (CFS) is a disabling condition with unknown disease mechanisms
and few treatment options.
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
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.
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.
Number of steps per day.
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.
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
clinicaltrials.gov Identifier: NCT01040429.