A toxic placebo

One very frequently used agent in the NICU is metoclopramide, prescribed almost exclusively for gastro-esophgeal reflux, (occasionally in an attempt to improve feeding tolerance).

Let us assume for a moment that a baby does have clinical signs which are due to reflux, that is, gastro-esophageal reflux disease (GERD). Now, this is not a simple clinical diagnosis to make, the literature overwhelmingly shows that apneas are not due to reflux; there is no reliable way to make a clinical diagnosis of reflux disease in premature infants.

But let’s say we got lucky, we thought a baby may have reflux, and we have done a multiple impedance study which clearly shows excessive reflux.  Is metoclopramide actually effective?

Anna Maria Hibbs published a systematic review a couple of years ago, and as far as I can see there are no new relevant studies since her review (Hibbs AM, Lorch SA. Metoclopramide for the Treatment of Gastroesophageal Reflux Disease in Infants: A Systematic Review. Pediatrics. 2006;118(2):746-52 http://pediatrics.aappublications.org/content/118/2/746.abstract) She showed that there is no reliable evidence that metoclopramide reduces reflux. Is this surprising?, well, not really. Metoclopramide is a prokinetic agent, it blocks D2 receptors in the gut and brain, which reduces vomiting; this is because D2 receptors are involved in the chemoreceptor trigger zone, and they trigger vomiting when the CTZ detects something noxious in your food. The CTZ is important on an evolutionary scale as it protected our forefathers and their grand-fore-fathers from the effects of poisonous berries and the like. But, just because the CTZ functions in this way, doesn’t mean that every time we puke it is a good idea to block it. Sometimes, for example, we vomit because we have been given toxins by our oncology doc.,  she might be trying to help us, but the CTZ senses that she is giving us a toxin, so it triggers vomiting, one of the distressing side effects of chemotherapy. Metoclopramide has a modest effect as an agent which reduces vomiting in this situation, which is presumably why it was first used for vomiting which occurs as a result of other mechanisms, such as GE reflux.

But is there any reason to think that a D2 blocker might decrease reflux? In general is there any reason to think that a prokinetic agent will decrease reflux? (D2 blockade has effects on gut motility as well). As reflux is largely a mechanical phenomenon, how could a drug fix it? I guess if a drug specifically increased lower esophageal sphincter tone, and decreased the number of relaxations of the sphincter, then it might have an effect on reflux (metoclopramide has 5HT and muscarinic actions as well, so might just possibly improve LES tone). If a drug just increases the strength of gastric contractions, without any specificity in its effects, then it is unlikely that GERD will be improved, indeed, an increase in gastric contractility without any change in LES function could easily INCREASE reflux. In fact a critical eye on the literature would say that the controlled studies of metoclopramide for reflux are generally very poor studies,with negative results. The only significant effect of metoclopramide on reflux that has been found in an individual study in infants is an increase. That’s right an INCREASE. Machida et al showed more reflux episodes during treatment with metoclopramide compared to control periods in a cross-over study. (Machida HM, Forbes DA, Gall DG, Scott RB. Metoclopramide in gastroesophageal reflux of infancy. J Pediatr. 1988;112(3):483-7. Epub 1988/03/01).

This might be why Eva Wheatley and Kathleen Kennedy showed that bradycardic episodes increased during metoclopramide (Wheatley E, Kennedy KA. Cross-Over Trial of Treatment for Bradycardia Attributed to Gastroesophageal Reflux in Preterm Infants. The Journal of Pediatrics. 2009;155(4):516-21  http://www.sciencedirect.com/science/article/pii/S0022347609003229 ). In a randomized cross-over study they showed that during the periods of metoclopramide treatment the babies had more bradycardias than during the control periods.  I think there  are 2 potential explanations for this. Either reflux causes bradycardias and there are MORE reflux episodes during metoclopramide treatment than during control: or the bradycardic episodes are not due to reflux, but metoclopramide acts directly to increase these episodes (or it was just a random effect in a small study).

Whatever the mechanisms there is certainly no evidence of a benefit. So to summarize: metoclopramide might improve gastric motility, but there is no reason to believe that this would improve reflux; metoclopramide increases bradycardic episodes, and may increase reflux episodes; there has never been ANY evidence of benefit of metoclopramide for reflux in preterm infants. So metoclopramide for reflux may have a placebo effect (latin meaning ‘I please’) which doctors exploit to please parents and nurses and themselves. Unfortunately, unlike other placebos such as homeopathy and acupuncture, metoclopramide is toxic. In Anna Maria Hibbs’ systematic review there were several patients in the minority of studies that reported adverse effects, who had increased irritability, or other potentially extra-pyramidal side effects. Probably the leading world expert on GE reflux in children, Yves Vandenplas said the following “Metoclopramide should be considered contra-indicated as GOR medication in infants because of the high incidence of side-effects”. (Vandenplas Y, Salvatore S, Hauser B. The diagnosis and management of gastro-oesophageal reflux in infants. Early Human Development. 2005;81(12):1011-24 http://www.sciencedirect.com/science/article/pii/S0378378205002021) He also notes that “extrapolation from adult data makes it very unlikely that efficacy data in infants and young children will be convincing”.

If you are going to give a placebo for gastro-esophageal reflux, I think you should at least give something non-toxic! (maybe find a local homeopath).

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , . Bookmark the permalink.

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