Tuesday, February 4, 2014

Low-dose clonidine is not clinically useful in CFS


Original Investigation | February 03, 2014

Disease Mechanisms and Clonidine Treatment in Adolescent Chronic
Fatigue Syndrome:  A Combined Cross-sectional and Randomized Clinical

Dag Sulheim, MD1,2; Even Fagermoen, MD3,4; Anette Winger, RN, MA3,5;
Anders Mikal Andersen, BSc6; Kristin Godang, BSc7; Fredrik Müller, MD,
PhD8; Peter C. Rowe, MD, PhD9; J. Philip Saul, MD10; Eva Skovlund,
PhD11,12; Merete Glenne Øie, PhD13,14; Vegard Bruun Wyller, MD,

JAMA Pediatr. Published online February 03, 2014.


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

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 µg or 50 µg 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 Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT01040429

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