Effects of training and albuterol on pain and fatigue in facioscapulohumeral muscular dystrophy

E.L. van der Kooi J.S. Kalkman E. Lindeman J.C.M. Hendriks B.G.M. van Engelen G. Bleijenberg G.W. Padberg 0 1 2 3 0 E. Lindeman, MD , PhD Rehabilitation Center De Hoogstraat and Rudolf Magnus Institute of Neuroscience, Rehabilitation Section University Medical Center Utrecht , The Netherlands 1 J.S. Kalkman, MSc G. Bleijenberg, PhD Expert Center Chronic Fatigue Radboud University Nijmegen Medical Center Nijmegen , The Netherlands 2 E.L. van der Kooi, MD (&) B.G.M. van Engelen, MD , PhD G.W. Padberg, MD , PhD Neuromuscular Center Nijmegen Radboud University Nijmegen Medical Center PO Box 9101 6500 HB Nijmegen The Netherlands Tel.: 3 J.C.M. Hendriks, PhD Department of Epidemiology & Biostatis- tics Radboud University Nijmegen Medical Center Nijmegen , The Netherlands - j Abstract Background We recently reported a randomised controlled trial on the efficacy of strength training and the b2adrenergic agonist albuterol in patients with facioscapulohumeral muscular dystrophy (FSHD). Strength training and albuterol appeared safe interventions with limited positive effect on muscle strength and volume. We concurrently explored the prevalence and the characteristics of pain and fatigue in the participating FSHD patients, because these are probably underreported but clinically relevant symptoms in this disorder. Next, we studied the effects of albuterol and strength training on pain, experienced fatigue, healthrelated functional status and psychological distress. Methods Sixtyfive patients were randomised to strength training of elbow flexors and ankle dorsiflexors or nontraining. After 26 weeks, albuterol (sustained-release, 8 mg bid) was added in a randomised, doubleblind, placebo-controlled design. Outcomes comprised self-reported pain, experienced fatigue, functional status and psychological distress obtained with validated questionnaires at 52 weeks. Results Eighty percent of patients reported chronic persistent or periodic, multifocal pains. Thirtyfour percent of the participants were severely fatigued. Strength training and albuterol failed to have a significant effect on all outcomes. Conclusions Pain and fatigue are important features in FSHD. Strength training and albuterol do not have a positive or negative effect on pain, experienced fatigue, functional status and psychological distress. j Key words exercise therapy albuterol pain fatigue facioscapulohumeral muscular dystrophy In descriptions of facioscapulohumeral muscular dystrophy (FSHD) pain and fatigue are rarely mentioned as important clinical features of the condition. However, a questionnaire-based survey in 270 French and one in 84 Dutch members of patient support groups indicated that pain is present in 5075% of patients [6, 22]. Bushby et al. reported four adult patients with FSHD in whom pain was a presenting complaint and remained their most disabling symptom [10]. In a recent questionnaire-based survey, 61% of 139 Dutch FSHD patients were severely fatigued [19]. Their experienced fatigue severity was associated with the severity of functional impairments in daily life. Actually, pain and fatigue seem to be important symptoms in FSHD; and they are not only underreported, but probably also undertreated. In patients with slowly progressive neuromuscular diseases, such as FSHD, combinations of muscle weakness, pain, fatigue, problems with locomotion and body weight can lead to reduced physical activity and a sedentary lifestyle [26]. Physical inactivity has a negative influence on quality of life and health outcomes [26]. In FSHD the decline in muscle strength and mass is progressive over years and follows in general a recognizable sequence of muscle involvement. However, there is a large, unexplained, interindividual variability in rate of progression, even within families sharing the same mutation [30, 36, 41]. The variable course within families and the typical asymmetric weakness has led to the hypothesis that daily exertion might be responsible for disease progression [9, 18]. Uncontrolled studies on the effects of strength training in neuromuscular disorders, although including only 13 FSHD patients, suggested a positive effect of strength training and did not point towards extra susceptibility for muscle overstrain [1, 25, 28, 39]. The results of a pilot study and a subsequent randomised, controlled trial in FSHD patients with the b2-adrenergic agonist albuterol were indicative for an anabolic effect that wears off with prolonged use [20, 21]. In animals and healthy persons the strength-increasing effect of b2-adrenergic agonists can be augmented when it is administered in combination with resistance exercise [11, 14, 16, 42]. We previously reported a randomised controlled trial in which we evaluated the efficacy of a moderate-intensity strength training program and albuterol in FSHD [35]. Strength training and albuterol were well tolerated and appeared safe interventions with limited positive effects on muscle strength and volume. Contrary to our expectation no synergistic effects between training and albuterol were detected; also no antagonistic effect was observed. A strength training program could potentially induce muscle soreness caused by exercise-induced muscle damage or pain as a result of increased strain on the tendoskeletal apparatus. The imposed extra physical activity could lead to an increase in experienced fatigue caused by a physical overload, as well as a decrease caused by a better physical condition. There is no information available on the effects of b2-adrenergic agonists, such as albuterol, on muscle endurance or on experienced fatigue. Theoretically, albuterol could result in reduced fatigability via increased muscle strength and mass, but also in a decrease in muscle endurance by slow-to-fast muscle fibre type transformation [43]. Ideally, both interventionsstrength training and albuterolshould result in less disability and a better quality of life. The objectives of this study were: (1) to explore the prevalence, magnitude and other characteristics of pain and experienced fatigue in the group of FSHD patients participating in the previously reported, randomised controlled trial [35], and (2) to study the effects of albuterol and strength training on self-reported pain, experienced fatigue, functional status and psychological distress in these patients. Sixty-five genetically confirmed, adult FSHD patients were randomised to strength training of elbow flexors and ankle dorsiflexors or non-training. After 26 weeks, albuterol (sustained-release, 8 mg bid) was added in a double-blind, placebo-controlled design. Treatment was continued for another 26 weeks. For the effect of training the primary outcome measure was the maximum voluntary isometric strength (MVIC) of the elbow flexors and ankle dorsiflexors. Main secondary outcomes were muscle endurance and dynamic muscle strength of elbow flexors and ankle dorsiflexors. To evaluate the effect of albuterol the MV (...truncated)