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Are Opioid Antagonists Effective in Attenuating the Core Symptoms of Autism Spectrum Conditions in Children: a Systematic Review

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Are Opioid Antagonists Effective in Attenuating the Core Symptoms of Autism Spectrum Conditions in Children: a Systematic Review bs_bs_banner Journal of Intellectual Disability Research doi: 10.1111/jir.12122 293 volume 59 part 4 pp 293–306 april 2015 Are opioid antagonists effective in attenuating the core symptoms of autism spectrum conditions in children: a systematic review A. Roy,1 M. Roy,2 S. Deb,3† G. Unwin3 &A.Roy4 1 Manchester Medical School, Manchester, UK 2 Birmingham Community Healthcare Trust, Birmingham, UK 3 Birmingham University, Birmingham, UK 4 Coventry and Warwickshire Partnership Trust, Birmingham, UK Abstract the available evidence and a systematic review was undertaken. Background ASC (autism spectrum conditions) Methods Four electronic databases were searched may result from a failure of striatal beta endorphins for relevant journal articles. In addition, cross- to diminish with maturation. Many symptoms of referencing of pertinent reviews and a hand search ASC resemble behaviours induced in animals or for articles in major international intellectual dis- humans by opiate administration, including ability (ID) journals between the years 2010 and decreased socialisation, diminished crying, repetitive 2012 was carried out to ensure that all relevant arti- stereotypies, insensitivity to pain and motor hyper- cles were identified. We also searched databases for activity. Naltrexone, an opioid antagonist, has been unpublished clinical trials to overcome publication used in the management of children with ASC and bias. Each database was searched up to present can produce a clinically significant reduction in the (February 2013) with no restrictions on the date of serious and life-threatening behaviour of self-injury publication. The search terms consisted of broad for individuals who have not been responsive to any expressions used to describe ID and autistic spec- other type of treatment and is important for this trum disorder as well as terms relating to opioid reason. It was therefore appropriate to reconsider antagonists and specific drugs. All studies identified by the electronic database search and hand search Correspondence: Dr Ashok Roy, Brian Oliver Centre, Brooklands were examined on the basis of title alone for 37 7 Hospital, Coleshill Road, Marston Green, Birmingham B HL, relevance and duplication. The abstracts of the UK (e-mail: [email protected]). remaining papers were then scrutinised against the †Present address: Division of Brain Science, Department of Medi- cine, The Computational, Cognitive and Clinical Neuroimaging inclusion criteria. Where abstracts failed to provide Laboratory, The Hammesrmith Hospital, London, UK. adequate information, the full texts for these papers © 2014 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd Journal of Intellectual Disability Research volume 59 part 4 april 2015 294 A. Roy et al.•Opioid antagonists autism, intellectual disability, children were obtained. All the full texts were then evaluated striatal beta endorphins to diminish with matura- against the inclusion proforma. Two reviewers tion. Many symptoms of ASC resemble behaviours carried out all the stages of the process indepen- induced in animals or humans by opiate administra- dently. The reviewers met to discuss their selections tion, including decreased socialisation, diminished and where disagreements arose, these were settled crying, repetitive stereotypies, insensitivity to pain by discussion with a member of the study group. and motor hyperactivity (Feldman et al. 1999). In Data from each study meeting the inclusion criteria at least a subgroup of individuals with ASC, there were extracted on a pre-piloted data extraction may be a dysfunction in the pineal–hypothalamic– form. The quality of each study was further pituitary–adrenal axis which modulates assessed using the Jadad scale, a tool developed to propiomelanocortin peptides and serotonin leading assess the quality of randomised controlled trials. to over secretion of opioid peptides and brain sero- Results 155 children participated in 10 studies; tonin (Sandman 1988; Chamberlain & Herman 27 received placebo. Of the 128 that received 1990). Naltrexone, an opioid antagonist, has been naltrexone 98 (77%) showed statistically significant used in the management of children with ASC. improvement in symptoms of irritability and hyper- Elchaar et al.(2006) reviewed the safety and effi- activity. Side effects were mild and the drug was cacy of naltrexone in paediatric patients with ASC generally well tolerated. by examining 25 studies (3 case reports, 8 case Conclusions Naltrexone may improve hyperactivity series and 14 clinical studies) from 1966 to 2006. and restlessness in children with autism but there Their conclusion was that naltrexone was effective was not sufficient evidence that it had an impact on in attenuating hyperactivity, agitation, irritability, core features of autism in majority of the partici- temper tantrums, social withdrawal and stereotyped pants. It is likely that a subgroup of children with behaviour. Participants may also have experienced autism and abnormal endorphin levels may respond improved attention and eye contact after treatment. to naltrexone and identifying the characteristics of This suggests that a subgroup of children with ASC these children must become a priority. may have abnormalities in endogenous opioid system. Keywords autism, children, hyperactivity, intellec- Children with ASC may display problem behav- tual disability, naltrexone, opioid antagonists iours (PB) for which there may be many reasons. Repetitive stereotyped patterns of behaviours may include self-injurious behaviours (SIB). Twenty-five Introduction experts invited by the National Institute of Child The reported prevalence of autism spectrum condi- Health and Human Development (NICHD) to tions (ASC) in children varies from 110 per 10 000 discuss the relations among the genetic, (Kogan et al. 2009) in parent reported studies to neurobiological and behavioural causes and treat- 157 per 10 000 in school population-based studies ments for SIB proposed two distinct patterns. One (Baron-Cohen et al. 2009) in the UK and 11.3 per pattern consists of bouts that are most likely main- 1000 (Autism and Developmental Disabilities tained by environmental contingencies (Schroeder Monitoring Network Surveillance 2012) based on et al. 2002). The second pattern involves protracted information from children’s evaluations records in periods of SIB that are most likely under the the USA. ASC may represent the final expression of primary influence of biological factors. Environmen- various aetiological factors including genetic events tal theories include the balance between arousal and (e.g. tuberous sclerosis), metabolic diseases (e.g. homeostasis (Baumeister & Forehand 1973) where phenylketonuria), infectious diseases (e.g. rubella) SIB may block out excessive stimulation or increase or structural abnormalities (e.g. mild hydrocepha- arousal during periods of under stimulation. SIB lus). Other aetiological factors include subtle may also have learning, social and communicative neuroanatomical and or biochemical abnormalities functions (Schroeder et al. 2002). in the brain that somehow result in ASC Biological factors may include underlying anxiety (Chamberlain & Herman 1990). Panksepp (1979) or a mood disorder, seizure activity or a psychotic proposed that ASC may result from a failure of illness. Anxiolytics, antidepressant, mood stabiliser © 2014 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd Journal of Intellectual Disability Research volume 59 part 4 april 2015 295 A. Roy et al.•Opioid antagonists autism, intellectual disability, children and anticonvulsant medications can all be used biological system may be disregulated in a subgroup appropriately if the cause of self-injury is established of patients. (Unwin & Deb 2011). Opioid antagonists have also Disregulated opioid system may cause both fea- been used in the treatment of SIB. Sandman & tures of ASC and self-injury in some individuals Kemp (2011) have summarised the rationale behind with ASC. While Symons et al.(2004) did not find this by pointing out that some individuals who self a significant treatment outcome with naltrexone injure repeatedly appear to be immune to pain; they between autism status and SIB, Elchaar et al. overcome interventions designed to reduce self- (2006) found that SIB reduced with naltrexone in injury in a manner consistent with seeking positive children with autism. In the recent years, naltrexone reward. Many medications which reduce pain or does not appear to be used in the treatment of SIB. induce pleasure are addicting. According to the Sandman & Kemp (2011) make a strong case for addiction hypothesis (Sandman & Hetrick 1995), reconsidering naltrexone. It is therefore appropriate opioid mechanisms are involved in the maintenance to reconsider the available evidence and a system- of high frequencies of SIB. In Pain Hypothesis, self- atic review was undertaken. injury does not cause pain because excessive basal activity has induced an opioid analgesic state and Methods with the experience of pain reduced, individuals inflict self harm as a form of stimulation. On the Search strategy other hand addiction hypothesis suggests that self- Four electronic databases, namely Psychinfo, injury or more generally stereotypic behaviour MEDLINE, Cochrane and Embase, were searched stimulates production and release of endogenous for relevant
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