Original articleUse of clonidine in children with autism spectrum disorders
Introduction
Children with autism spectrum disorders (ASD) suffer from medical and psychiatric conditions including sleep disturbances, gastrointestinal dysfunction, mood disorders, aggressive behaviors, and attention-deficit hyperactivity [1], [2], [3], [4], [5]. With respect to the sleep disturbances, it has been reported that between 40% and 80% of children with ASD have problematic sleep patterns that are often severe in nature [6], [7], [8], [9]. The sleep problems include difficulty in settling to sleep, lengthy episodes of night waking with or without confusion, early morning awakening, shortened night sleep, parasomnia (including bruxism), and irregularities of the sleep/wake rhythm [1], [10], [11], [12], [13], [14], [15], [16], [17]. The impact of these sleep disorders in children with ASD is of particular concern in light of the increased burden and stress experienced in parenting a child with ASD. Sleep problems have been correlated with family or parental distress in normally developing children and in children with an intellectual disability[18], [19]. The children with ASD who had sleep disorders were frequently reported to have more problems in social relatedness, and other daytime behavior difficulties [20]. Parents reported improvement of daytime performance following treatment of the sleep disorders [21], [22], [23].
In addition to the sleep disturbances, other behavioral disorders occur with higher frequency in children with ASD and present still additional problems for their caregivers. These include mood disorders, aggressiveness and self-injurious behaviors, obsessive- and compulsive-like behaviors, anxiety, and ritualistic behaviors [3], [5], [24]. Unfortunately, treatment of these medical and behavioral symptoms associated with ASD has been challenging. Pakyurek et al. [21] reported behavioral and sleep improvement in two children after tonsillar and adenoidectomy. However, for most children with ASD whose causes of sleep disorder or behavioral disorders remain unidentified, treatment is largely symptom-based. Melatonin has been shown to be efficacious in some ASD children for treatment of sleep onset insomnia. Unfortunately, the beneficial effects of melatonin diminish over time despite administration of increasing doses [25]. Traditional hypnotics and sedatives exhibit various degrees of beneficial effects but present the risk of side effects such as sedation during daytime. The other behavioral disorders associated with ASD could be quite refractory to medication. Atypical neuroleptics, SSRIs, anti-depressants, anti-convulsants, and other agents have all been tried in targeting various behavioral symptoms with variable degree of success, even when used in conjunction with behavioral therapy [26]. Thus, there is a need to identify a safe and efficacious treatment for the broad spectrum of medical and behavioral symptoms associated with ASD.
Clonidine is a centrally acting α2-adrenergic agonist that has been administered to children with ASD for the treatment of hyperactivity and impulsivity, sleep disorder as well as for sedation, prior to EEG recording [27], [28], [29], [30]. A placebo-controlled, double-blind trial of transdermal clonidine showed it to be effective in reducing hyperarousal in children with ASD and that this calming action resulted in improved social relationships, improved affectual responses, and an overall improvement in Clinical Global Impression scales in some subjects [27]. However, Hazell [29] believed clonidine along with dexamphetamine, clomipramine, mirtazapine, and fluoxetine are of unlikely benefit in treating attention deficits and hyperactivity disorder (ADHD) in children with autism. Our own anecdotal observations indicated that clonidine administration may be beneficial for the treatment of sleep disorders in children with or without ASD.
This study is an open-labeled, semi-quantitative pilot study using parental report to examine the efficacy of clonidine in the treatment of sleep and behavioral disorders in children with ASD.
Section snippets
Methods
Seventeen children with sleep and behavioral disorders, and two children with behavioral disorders only were treated with clonidine between 1999 and 2002 were recruited for this study (Table 1). A total of 25 ASD children had been prescribed clonidine during this time period; six were excluded from this study due to (1) loss of follow-up, (2) clonidine was discontinued after only brief period of time as result of side effects, or paradoxical irritability, or (3) parental refusal of study
Results
Seventeen of the 19 subjects were prescribed clonidine for sleep disorder. All 16 children who had prolonged sleep initiation exhibited a reduction in sleep initiation, and 16 of the 17 children with sleep maintenance difficulty had reduction in the frequency of awakening during the nights. The range of average sleep initiation prior to clonidine treatment was 2–5 h with the exception of one child whose sleep initiation was within 30 min. The range of average sleep initiation during clonidine
Discussion
Clonidine is an α-adrenergic agonist that acts on presynaptic neurons predominantly of brainstem to inhibit norepinephrine activity. As a result, sympathetic outflow is inhibited, leading to decrease in peripheral resistance, heart rate, and blood pressure. Such a mechanism could explain the therapeutic benefit of clonidine in the treatment of sympathetic hyper-arousal states associated with ADHD, aggressiveness, tic disorder etc. The sedative effects of clonidine are well recognized and are
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