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Abstract
Methylnaltrexone, a peripheral opioid μ-receptor antagonist is licensed for subcutaneous administration for the treatment of severe opioid-induced constipation in adults. We describe the use of intravenous methylnaltrexone in a 3-year-old boy receiving a subcutaneous diamorphine infusion for palliation from widely metastatic alveolar rhabdomyosarcoma. The patient, who had not opened his bowels for 3 weeks despite use of regular conventional laxatives, was given a 150 mcg/kg dose via indwelling central venous catheter. Constipation was relieved within minutes of the injection. There were no side effects noted during or following injection, and no clinically apparent reduction in analgesia. Intravenous methylnaltrexone may provide a valuable additional treatment option in paediatric palliative care, especially for those with an oncological diagnosis, the majority of whom will have indwelling central venous access devices.
- Cancer
- Paediatrics
- Drug administration
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Case
The patient, a 3-year-old boy, was diagnosed with widely metastatic alveolar rhabdomyosarcoma in 2010. Having achieved local complete remission and metastatic very good partial remission with IVADo chemotherapy (ifosfamide, vincristine, actinomycin D and doxorubicin), radiotherapy was given to the primary site and thorax. Sites for radiotherapy were chosen pragmatically in view of the impracticality of treating all initially involved sites. Following completion of the above therapy, maintenance treatment was commenced with daily oral cyclophosphamide and weekly intravenous vinorelbine.
Six weeks after commencing maintenance chemotherapy, the patient developed signs of right hemiparesis, and MRI confirmed the clinical suspicion of metastatic intracranial relapse. Intracranial relapse was rapidly followed by widespread bony and soft tissue relapse, centred on areas of previous disease. Pain was the major symptom, along with raised intracranial pressure, anorexia and reduced mobility.
To achieve adequate analgesia, the patient required a range of medication, which included strong opioids (up to 120 mg intravenous diamorphine/24 h via continuous infusion).
The patient had pre-existing constipation successfully managed throughout treatment with a combination of sodium docusate and sodium picosulphate. However, following initiation of continuous opioid infusion constipation became refractory to the patient's regular medication. The patient refused alternative oral preparations due to unpleasant taste or unacceptable volume. His parents were reluctant to use a nasogastric tube for medication as they felt it would be too distressing. The rectal route was unavailable for the same reason.
Despite taking docusate sodium 37.5 mg orally three times per day and sodium picosulphate 10 mg orally twice per day the patient did not open his bowels for 3 weeks, developing significant abdominal distension and discomfort. Following discussion at the Palliative Care multidisciplinary team, Methylnaltrexone was suggested as a possible therapeutic option.
Due to the presence of an indwelling central venous access device, the family's reluctance to consider subcutaneous administration and the lack of alternative conventional options the literature regarding methylnaltrexone was reviewed and it was decided to proceed with a 150 mcg/kg intravenous dose. This was given without any adverse effects, and the patient passed a very large volume of stool within 10 min of injection. There was no reduction in analgesia, and no signs of opiate withdrawal.
Oral laxatives were continued following administration of methylnaltrexone, although there were no further bowel movements. Sadly, the patient's overall condition continued to deteriorate, and death followed soon afterwards. Although a second dose of methylnaltrexone had been considered, the patient did not develop further abdominal distension or pain, and this was not administered.
Discussion
Pain is an important symptom for many patients with advanced malignant and non-malignant disease, frequently requiring regular administration of strong opioids. Morphine is the most commonly used opioid,1 either orally (immediate or modified release) or parenterally. Diamorphine is often preferred for subcutaneous infusion due to its greater solubility, allowing high doses to be delivered in small volumes via small, portable syringe drivers.
Although effective analgesics, opioids are recognised to cause a number of side effects, including itch, somnolence, constipation and respiratory depression. Although respiratory depression is the most feared side effect of opioid therapy, its incidence is low, providing doses are titrated carefully in line with the patient's requirements. Constipation is a much more common problem, affecting up to 90% of cancer patients,2 and can in itself become extremely distressing for patients. Unlike most other side effects, tolerance to opioid-induced constipation does not occur.1
Opioid-induced constipation occurs via bowel wall opioid μ-receptors. It is recognised that some opioids are more likely to cause constipation than others, and where practical, the use of transdermal fentanyl may reduce the prevalence and severity. Transdermal fentanyl is not, however, suitable for all patients, including opioid-naive children whose opiate requirements have not yet been established, or for those who require regular escalation of analgesic doses due to ongoing disease progression.
Routine management of opioid-induced constipation starts with prophylactic prescription of laxatives. Laxatives should be titrated according to severity of constipation (within normal dose recommendations), and are effective for many. Some patients remain severely constipated despite appropriate laxative use, and opiates may need to be reduced or discontinued as a result.1 In paediatric practice, there are additional issues relating to compliance and tolerance—the liquid form of many laxatives may be unpalatable or require relatively large volumes which may be unsuitable for terminally ill children.
Naloxone is a μ-receptor antagonist, which acts both peripherally and centrally. It is known to reduce opiate-induced constipation, but only at the cost of a reduction in analgesia2 which is not usually an acceptable compromise in palliative care.
Methylnaltrexone is a quaternary derivative of naloxone. Compared with naloxone, it has high polarity and low lipid solubility, which prevents passage across the blood-brain barrier.1 ,2 As a result, methylnaltrexone is selectively active against peripheral μ-receptors in the gut, causing laxation without significant reversal of analgesia or opioid withdrawal. It is available in parenteral (subcutaneous or intravenous) or oral formulations.1 The subcutaneous form has been shown to be effective in adult palliative care patients suffering from opioid-induced constipation not relieved by conventional laxatives.3 Common side effects include abdominal pain and flatulence.1 ,4 A number of cases of intestinal perforation have been reported in association with methylnaltrexone use, and the drug is contraindicated in patients at risk of mechanical obstruction.1
Methylnaltrexone exhibits dose-dependency with a minimum effective dose of approximately 150 mcg/kg, and a ceiling effect at around 300 mcg/kg/dose. Doses should be halved in renal impairment (creatinine clearance <30/ml/min). Repeated administration does not result in accumulation, and the therapeutic index is high.1–2 ,4
Pharmacokinetic studies in adults have shown that methylnaltrexone is minimally metabolised, with the majority of drug being excreted unchanged in urine (50%) and faeces (40%).1 The intravenous route has been shown to be safe in adults,1 ,4 and there are isolated reports of intravenous methylnaltrexone use in neonates with opioid-induced ileus or urinary retention.5 ,6 Enteral and subcutaneous use has been described in paediatric patients with severe opioid-induced constipation.7 ,8 To our knowledge, this is the first report of intravenous use for the treatment of opioid-induced constipation in paediatric palliative care.
Conclusion
Methylnaltrexone is safe and efficacious in the management of severe opioid induced constipation in adults. The drug has a good safety profile with minimal side effects. With rapid excretion and minimal hepatic metabolism, there is a low likelihood of toxic accumulation, and it is active after intravenous injection. In the case described, successful laxation was achieved rapidly after a single intravenous dose of methylnaltrexone, with no adverse effects. Therefore, in paediatric oncology patients with an indwelling central venous access device, intravenous methylnaltrexone 150 μg/kg provides an option for the treatment of refractory opioid-induced constipation that is worthy of further exploration.
Acknowledgments
The authors would like acknowledge the exceptional level of palliative care provided in the family home by the Paediatric Oncology Outreach Nursing Team (Rachel Ducker, Lindsay Charlish, Paul Coyles, Caroline Stancer) and the patient's parents. We are also grateful to the parents for granting us permission to publish this case report for the benefit of others.
Footnotes
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Contributors DY was the clinician in overall charge of the patients care. AM is the lead for Palliative Care and was involved in initial discussions regarding methylnaltrexone use. OC reviewed the literature regarding the intravenous use of methylnaltrexone. DY wrote the initial draft of the paper, which was reviewed by and contributed to by AM and OC equally; DY acts as guarantor for the finished paper.
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Competing interests None.
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Patient consent Obtained.
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Provenance and peer review Not commissioned; externally peer reviewed.