title: Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial.
abstract: BACKGROUND
  Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A-adrenoceptor agonist clonidine.
  
  
  METHODS
  A total of 176 adolescent CFS patients (12-18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 μg or 50 μg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 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 (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model.
  
  
  RESULTS
  A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period.
  
  
  CONCLUSIONS
  Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance.
  
  
  BACKGROUND
  Clinical Trials ID: NCT01040429, date of registration 12/28/2009.
authors.affiliation: Institute of Clinical Medicine, Medical Faculty, University of Oslo, P.O.Box 1171, Blindern, 0318, Oslo, Norway. feef@online.no.|Department of Anaesthesiology and Critical Care, Oslo University Hospital, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. feef@online.no.
authors.forename: Even
authors.initials: E
authors.lastname: Fagermoen
authors.affiliation: Department of Paediatrics, Oslo University Hospital, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. dag.sulheim@medisin.uio.no.|Department of Paediatrics, Lillehammer County Hospital, P.O.Box 104, 2381, Brumunddal, Norway. dag.sulheim@medisin.uio.no.
authors.forename: Dag
authors.initials: D
authors.lastname: Sulheim
authors.affiliation: Institute of Nursing Sciences, Oslo and Akershus University College of Applied Sciences, P.O. Box 4 St., Olavs plass, 0130, Oslo, Norway. Anette.Winger@hioa.no.
authors.forename: Anette
authors.initials: A
authors.lastname: Winger
authors.affiliation: Department of Pharmacology, Oslo University Hospital, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. Anders.Andersen2@oslo-universitetssykehus.no.
authors.forename: Anders M
authors.initials: AM
authors.lastname: Andersen
authors.affiliation: National Institute of Occupational Health, P.O Box 8149, Dep, 0033, Oslo, Norway. johannes.gjerstad@stami.no.|Department of Biosciences, University of Oslo, P.O.Box 1066, Blindern, 0316, Oslo, Norway. johannes.gjerstad@stami.no.
authors.forename: Johannes
authors.initials: J
authors.lastname: Gjerstad
authors.affiliation: Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital Rikshospitalet, P.O.Box 4950, Nydalen, 0424, Oslo, Norway. kgodang@ous-hf.no.
authors.forename: Kristin
authors.initials: K
authors.lastname: Godang
authors.affiliation: Department of Paediatrics, Johns Hopkins University School of Medicine, 200 N. Wolfe Street, Baltimore, MD, 21287, USA. prowe@jhmi.edu.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Rowe
authors.affiliation: Department of Paediatrics, Medical University of South Carolina, 169 Ashley Avenue, Charleston, SC, 29425, USA. Phil.Saul@nationwidechildrens.org.
authors.forename: J Philip
authors.initials: JP
authors.lastname: Saul
authors.affiliation: Department of Pharmaceutical Science, University of Oslo, P.O.Box 1068, Blindern, 0316, Oslo, Norway. eva.skovlund@farmasi.uio.no.|Norwegian Institute of Public Health, P.O.Box 4404, Nydalen, 0403, Oslo, Norway. eva.skovlund@farmasi.uio.no.
authors.forename: Eva
authors.initials: E
authors.lastname: Skovlund
authors.affiliation: Institute of Clinical Medicine, Medical Faculty, University of Oslo, P.O.Box 1171, Blindern, 0318, Oslo, Norway. brwylle@online.no.|Department of Paediatrics, Akershus University Hospital, P.O.Box 1000, 1478, Lørenskog, Norway. brwylle@online.no.
authors.forename: Vegard Bruun
authors.initials: VB
authors.lastname: Wyller
mesh_terms: D000293:Adolescent; D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage* / Q000097:blood; D003000:Clonidine / Q000008:administration & dosage* / Q000097:blood; D003404:Creatinine / Q000652:urine; D004311:Double-Blind Method; D004837:Epinephrine / Q000097:blood / Q000652:urine; D015673:Fatigue Syndrome, Chronic / Q000188:drug therapy* / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D009638:Norepinephrine / Q000097:blood / Q000652:urine; D054971:Orthostatic Intolerance / Q000188:drug therapy / Q000503:physiopathology; D018667:Tilt-Table Test
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D003404:Creatinine; D003000:Clonidine; D009638:Norepinephrine; D004837:Epinephrine