TY - JOUR
T1 - Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome a combined cross-sectional and randomized clinical trial
AU - Sulheim, Dag
AU - Fagermoen, Even
AU - Winger, Anette
AU - Andersen, Anders Mikal
AU - Godang, Kristin
AU - Muller, Fredrik
AU - Rowe, Peter C.
AU - Saul, J. Philip
AU - Skovlund, Eva
AU - Oie, Merete Glenne
AU - Bruun, Vegard W.
PY - 2014/4
Y1 - 2014/4
N2 - 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.
AB - 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.
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U2 - 10.1001/jamapediatrics.2013.4647
DO - 10.1001/jamapediatrics.2013.4647
M3 - Article
C2 - 24493300
AN - SCOPUS:84898472854
SN - 2168-6203
VL - 168
SP - 351
EP - 360
JO - JAMA pediatrics
JF - JAMA pediatrics
IS - 4
ER -