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Original Investigation |

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

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, PhD1,15,16
[+] Author Affiliations
1Department of Paediatrics, Oslo University Hospital, Oslo, Norway
2Department of Paediatrics, Lillehammer County Hospital, Lillehammer, Norway
3Institute of Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway
4Department of Anesthesiology and Critical Care, Oslo University Hospital, Oslo, Norway
5Institute of Nursing Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway
6Department of Pharmacology, Oslo University Hospital, Oslo, Norway
7Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital Rikshospitalet, Oslo, Norway
8Department of Microbiology, Oslo University Hospital, Oslo, Norway
9Department of Pediatrics, the Johns Hopkins University School of Medicine, Baltimore, Maryland
10Department of Pediatrics, Medical University of South Carolina, Charleston
11School of Pharmacy, University of Oslo, Oslo, Norway
12Norwegian Institute of Public Health, Oslo, Norway
13Department of Psychology, University of Oslo, Oslo, Norway
14Innlandet Hospital Trust, Lillehammer, Norway
15Division of Medicine and Laboratory Sciences, Medical Faculty, University of Oslo, Oslo, Norway
16Department of Paediatrics, Akershus University Hospital, Nordbyhagen, Norway
JAMA Pediatr. 2014;168(4):351-360. doi:10.1001/jamapediatrics.2013.4647.
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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

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Figure 1.
Flowchart of the Randomized Clinical Trial Section of the Study

A total of 176 patients with chronic fatigue syndrome (CFS) were assessed for eligibility, 151 fulfilled criteria for randomization and 120 fulfilled the inclusion criteria and started treatment: 60 were allocated to clonidine, and 60 to placebo. At week 8, a total of 55 patients had completed the clonidine intervention and 51 had completed the placebo intervention. At week 30, a total of 54 vs 49 patients, respectively, had completed the investigational program.

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Figure 2.
Changes of Efficacy Variables During the Intervention Period

A, Number of steps per day: the placebo group had an increment in steps per day during the intervention period (an expected placebo effect), whereas no increment (no placebo effect) was demonstrable in the clonidine group. B, Plasma norepinephrine: the clonidine group had a stronger decrease in plasma norepinephrine compared to the placebo group. C, Serum C-reactive protein (CRP): the clonidine group had a slight decrease in CRP concentration, whereas the concentration increased in the placebo group. To convert CRP to nanomoles per liter, multiply by 9.524; norepinephrine to picomoles per liter, multiply by 5.914.

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