Scenario

A 12-year-old boy undergoing treatment for acute lymphoblastic leukaemia has been receiving oral morphine for pain. He has constipation that is refractory to high-dose osmotic and stimulant laxatives and weaning of the morphine led to an increase in pain. You are aware of the use of peripheral acting mu-opioid receptor antagonists (PAMORA) in treating adults with opioid-induced constipation and wonder whether they could be used effectively in children.

Clinical question

In children (population), are peripheral acting mu-opioid receptor antagonists (intervention) effective in treating opioid-induced constipation? (outcome)?

Search

All searches were performed in October 2023. PubMed, MEDLINE and Embase were searched using the following search terms: (child* OR paediatric OR pediatric) AND (naloxegol OR naltrexone OR naldemedine OR peripheral opioid receptor antagonist) AND (constipation OR dysmotility). A total of 23 unique articles were identified. Exclusion criteria included adult study population, case reports and reviews. Five articles were identified that were relevant to the clinical question and were not disqualified by the exclusion criteria. These articles have been summarised in table 1.

Similar search terms were used to search the Cochrane Library; this identified one article which was excluded as the study population were adults.

Summary

Commentary

Constipation is a common cause of morbidity among children, with a global prevalence of 0.7–29.6% (median 12%) and a prevalence of 10–20% in the UK and the USA.1 As well as pain and discomfort it can be a significant source of emotional distress for children and their carers, particularly when associated with involuntary soiling, and can lead to behavioural problems, self-esteem issues and school absenteeism. A 2019 systematic review and meta-analysis found that children with functional constipation had lower health-associated quality of life scores compared with their peers (65.6 vs 86.1; p<0.01).2

Opioids are very effective analgesic agents through their action on mu, kappa and delta opioid receptors in the brain and although they are less widely used in children than adults, their use is more common in the critical care setting, in surgical and oncology patients and in palliative care. Opioid receptors are also associated with enteric motor neurons and secretomotor neurons in the gastrointestinal tract that, when activated, cause decreased gastric emptying, reduced gut peristalsis, increased sphincter tone and inhibition of ion and fluid secretion, and can lead to opioid-induced constipation.3 Constipation is therefore a common side effect of opiates and can be difficult to manage.

National Institute for Health and Care Excellence (NICE) guidelines for the management of constipation in children and young people advise a stepwise approach starting with osmotic and stimulant laxatives and then later consideration of enemas.4 This regimen is generally effective but it is not uncommon in patients on opioids to have constipation refractory to first and second-line treatments. In these circumstances we should try to wean the opioids to the minimum dose to achieve effective analgesia or sedation and, if able, to stop them completely, but in practice this is not always possible. PAMORAs have become more widely used over the past 10 years in the treatment of opioid-induced constipation in adults with a NICE technology appraisal guidance supporting the use of the PAMORAs naloxegol and naldemedine in the treatment of adults with opioid-induced constipation following failure of conventional laxative treatment.5 6

There is expert consensus on the use of methylnaltrexone for opioid-induced constipation in the Association of Paediatric Palliative Medicine Master Formulary but there is currently no other national guidance on the use of peripheral opioid receptor antagonists in the treatment of opioid-induced constipation in children.7

The review yielded five case series which all reported an improvement in laxation in children with opioid-induced constipation following treatment with a peripheral acting opioid receptor antagonist. Most patients included in these studies were critically unwell children with opioid-induced constipation. The average age of patients varied between the five studies from 3.5 years to 14 years with an age range of 0–22 years across the five studies. None of the studies reported their criteria for diagnosing opioid-induced constipation and due to the complex nature of critically unwell patients it is possible that the constipation was made worse through their underlying diagnosis, other treatments or comorbidities.

All patients received either daily oral naloxegol or daily subcutaneous or intravenous methylnaltrexone. The dose of methylnaltrexone administered was consistent between studies; the dose of naloxegol administered varied between studies. This makes it more difficult to extrapolate a minimum effective dose of naloxegol to achieve laxation. There was also significant variation between studies and between patients within studies of which laxatives and prokinetic agents had been trialled prior to commencing a PAMORA and which agents were being used once a PAMORA had been added in. Most patients received at least two laxatives or prokinetic agents, but which agents used varied from patient to patient. Only Rodrigues et al examined clinical guidelines to ensure that first and second-line laxatives had been optimised prior to adding in a PAMORA (16% optimised).8

There was some variation in how outcomes were measured between study groups but they all objectively showed an increase in stooling following starting PAMORAs. This was regardless of if examining mean stool frequency (from 0.63±0.12 stools per day to 1.71±0.13 stools per day)9 or the time to the first bowel motion following administration of PAMORA.8 10–12 Most studies did not go into detail about whether the laxative effects were sustained and the patients continued to open their bowels regularly or whether there was any improvement in symptoms of constipation. None of the studies found evidence of significant opioid withdrawal following commencing PAMORA treatment. All studies found no increase in pain following administration of a PAMORA.8–12

There is evidence from these five studies that there is an association between the use of PAMORAs and successful laxation in children of various age groups with opioid-induced constipation. Nevertheless, the studies suffer from small population sizes, variation in adjunctive treatments and lack of data on changes to opioid doses after intervention. Objective withdrawal tools and subjective assessment of symptoms found no significant evidence of opioid withdrawal or increase in pain following use of PAMORA. We can derive from the studies that a dose of 0.15 mg/kg of methylnaltrexone is likely to be an effective dose but the effective dose of naloxegol is difficult to ascertain.

Importantly, we cannot definitively conclude from these studies that PAMORAs are any more effective at treating opioid-induced constipation than optimised conventional laxative therapy, though the study of Rodrigues et al suggests even when optimising, PAMORAs have important advantages.8 This comes at a cost though, as PAMORAs are more expensive per dose than conventional laxatives: macrogol 15.7p per sachet, senna 2.8p per tablet, docusate sodium 7p per capsule, lactulose 2.7p per 5 mL versus naloxegol £1.84 per tablet and methylnaltrexone bromide £21.05 per vial (prices taken from British National Formulary for Children and British National Formulary drug tariff price).13 Currently, there are no PAMORAs available in orodispersible or oral solution formulations, but naloxegol tablets can be crushed and dissolved in water for administration.

Further prospective controlled studies are required to be able to recommend the routine use of PAMORAs in the treatment of opioid-induced constipation. In the meantime, there may be a role for the cautious use of PAMORAs in children with opioid-induced constipation refractory to optimised conventional laxative and in particular, methylnaltrexone which is already used in the paediatric palliative care setting and for which there is an established consensus on dosing.