Wednesday 2 March 2011

Naltrexone and autism - what 'dose' it do?

I hope that readers will understand my attempt at a pun with the title of this post and not simply think that I have had one beer to many. I have to admit that I was never particularly good at telling jokes and funny word-play because I always told the punch-line at the wrong time (perhaps a so-called 'lack of theory of comic timing' to borrow a concept idea). Those in the UK who are old enough to remember classic Reeves and Mortimer will understand the tumble-weed scene that Vic was most famous for after his jokes.

Anyway, my reasons for posting about naltrexone follows some recent re-reading I did on the use of naltrexone to manage certain 'challenging behaviours' associated with autism spectrum and other conditions.

Naltrexone has been in the background of many studies that I have been involved with in autism research; mostly as a result of an interest in the opioid-excess theory and the suggestion that exogenous dietary-derived peptides could exert a biological effect on the central nervous system by means of hyperpermeability of the gastrointestinal and/or blood-brain-barrier. Certain elements of the theory have been the source of some speculation but I don't think we can quite consign the whole thing to the 'failed hypotheses of autism' bin just yet, particularly in light of the leaky gut side of things still being an important finding for at least a sub-group.

Anyway, getting back to naltrexone. Naltrexone is a compound in demand given its use in treating alcohol and narcotic misuse. The primary mode of effect from naltrexone is by competitively binding to various opioid receptors and blocking the action of other compounds seeking to bind to those receptors (an antagonist). In the case of opioid dependency it is used for treating morphine and heroin addiction. There are other potential effects of naltrexone under discussion (i.e. as to why it is effective in treating alcohol dependency) but at the moment these are still discussions.

For autism, the administration of naltrexone to ameliorate certain challenging behaviours has a long and chequered history. There have been some studies suggesting positive effects from administration, and some suggesting no primary effects from naltrexone use. Unlike other pharmaceutics that have shown no consistent effects for behaviours associated with autism, naltrexone has at least showed some promise and is still listed in most reviews of pharmacotherapy options for autism.

Naltrexone has, over quite a few years, also developed quite a following for many other conditions outside of its primary remit. One of the major driving forces to this is the potential effect of low-dose naltrexone (LDN) (now you get the title pun) and the proposed mode of action. Typing in 'low dose naltrexone' into PubMed this morning, presented me with a total of 389 article abstracts to view. Granted some of these won't actually be about low dose naltrexone but flicking through them, many of them are. One of the papers which offers a particularly comprehensive review of LDN is this one by Brown and Panksepp. Attendant readers might recognise the name Panksepp as being the same Jaak Panksepp who first proposed a neurochemical theory of autism way back in 1979 (and indeed the suggestion of opiate antagonist therapy for autism).

LDN is being suggested for everything from Crohn's disease to Multiple Sclerosis (MS); with varying degrees of evidence on effectiveness and safety being presented. There is also a dedicated society for LDN which is very active in promoting research into the potential effects to be had.

At about this point a few questions should be entering your mind, questions like: how does LDN work? and is it really such a multi-purpose medication? Those same questions that have been in my mind for several years. I don't have the answers (hence the title of this blog!) but there are a few clues which might be of interest.

Regarding the action of LDN, there are many possibilities outside of the direct antagonistic effect on opioid receptors. Given the immune system involvement in things like Crohns and MS, speculation has turned to naltrexone acting either directly or peripherally (via the opioid receptor effects) interfering with inflammatory processes (cytokines et al) alongside other possibilities. The immune system and autism has been the source of multiple investigations; suggesting that in some cases of autism, there are clear signs of immune dysfunction. Whether this is causative or epiphenomenal is still under debate.

The question of whether naltrexone is the multi-purpose medication that it is claimed to be remains unanswered. I know many people would run away from something that claims to cover so many conditions; indeed specificity of an intervention to more than one or perhaps two applications is listed on many a site covering how to spot a quack therapy. What I will say in naltrexones' defence is that it is not unusual for one medication designed for one purpose to show an effect in one or more other conditions (one only has to look at the example of viagra to know that); the key is really to assess the amount and quality of the evidence being presented.

Given all the factors discussed here on naltrexone, low dose naltrexone and the potential modes of action, there is perhaps some further investigation required in relation to autism spectrum conditions. If there is a sub-group of people with autism where the mechanisms (opioid chemistry, immune system) pertain or where co-morbidities such as those related to the immune system (and the gut?) may be present, this could be another tool to potential improve quality of life both in respect to challenging behaviours and also any discomfort caused by co-morbidity.

I would stress that pharmacotherapy should only be undertaken by a medical physician and only after all other options have been exhausted (challenging behaviours happen for many, many different reasons; sometimes more obvious than you think).

Now, a horse walks into a bar and asks for a drink....

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