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

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          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 and function. 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 in CFS. clinicaltrials.gov Identifier: NCT01040429.

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          JAMA Pediatrics
          JAMA Pediatr
          American Medical Association (AMA)
          April 01 2014
          April 01 2014
          : 168
          : 4
          : 351
          [1 ]Department of Paediatrics, Oslo University Hospital, Oslo, Norway2Department of Paediatrics, Lillehammer County Hospital, Lillehammer, Norway
          [2 ]Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway4Department of Anesthesiology and Critical Care, Oslo University Hospital, Oslo, Norway
          [3 ]Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway5Institute of Nursing Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway
          [4 ]Department of Pharmacology, Oslo University Hospital, Oslo, Norway
          [5 ]Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital Rikshospitalet, Oslo, Norway
          [6 ]Department of Microbiology, Oslo University Hospital, Oslo, Norway
          [7 ]Department of Pediatrics, the Johns Hopkins University School of Medicine, Baltimore, Maryland
          [8 ]Department of Pediatrics, Medical University of South Carolina, Charleston
          [9 ]School of Pharmacy, University of Oslo, Oslo, Norway12Norwegian Institute of Public Health, Oslo, Norway
          [10 ]Department of Psychology, University of Oslo, Oslo, Norway14Innlandet Hospital Trust, Lillehammer, Norway
          [11 ]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
          © 2014


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