Dag Sulheim1, Even Fagermoen2, Anette Winger3, Anders Mikal Andersen4, Kristin Godang5, Fredrik Müller6, Peter C Rowe7, J Philip Saul8, Eva Skovlund9, Merete Glenne Øie10, Vegard Bruun Wyller11. 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.
Abstract
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 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.
RCT Entities:
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 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.
Authors: Peter C Rowe; Rosemary A Underhill; Kenneth J Friedman; Alan Gurwitt; Marvin S Medow; Malcolm S Schwartz; Nigel Speight; Julian M Stewart; Rosamund Vallings; Katherine S Rowe Journal: Front Pediatr Date: 2017-06-19 Impact factor: 3.418
Authors: Even Fagermoen; Dag Sulheim; Anette Winger; Anders M Andersen; Johannes Gjerstad; Kristin Godang; Peter C Rowe; J Philip Saul; Eva Skovlund; Vegard Bruun Wyller Journal: BMC Pediatr Date: 2015-09-10 Impact factor: 2.125