Anna Sutherland, palliative medicine doctor, looks at Cochrane evidence on the effectiveness and safety of mu-opioid antagonists for managing opioid-induced constipation in people with cancer and people receiving palliative care for whom laxatives have failed.
Morphine and other strong opioids cause constipation. Mu-opioid antagonists are used to treat opioid-induced constipation that stubbornly refuses to budge despite throwing bucket loads of laxatives at the problem. By blocking the mu-opioid antagonist effect on the gut, it reverses the constipating effect of opioids. However, there have been concerns that mu-opioid antagonists might partially reverse pain relief benefits of the opioid.
Candy et al. recently updated their Cochrane Review “Mu-opioid antagonists for opioid-induced bowel dysfunction in people with cancer and people receiving palliative care” [i]. They define opioid-induced bowel dysfunction (OIBD) as “constipation, incomplete evacuation, bloating, and gastric reflux… resulting in increased morbidity and reduced quality of life.” They report “laxation response” time, which seems to be unrelated to how long your morning newspaper is and means time until participants opened their bowels.
So do mu-opioid antagonists ease the strain?
They found 8 randomised controlled trials assessing:
- Oral Naldemedine
- Oral Naloxone (alone or with oxycodone)
- Subcutaneous Methylnaltrexone
Naldemedine (Naloxegol®) is the new kid on the block. Candy et al found it doubled the likelihood of unblocking bowels within 14 days with a Number Needed to Treat to Benefit of 2.88. The more you have the more you poo, with no impact on pain control. Unfortunately, there is a stumbling block to prescribing; a delay in licensing it in the UK has led to NICE suspending their appraisal of it. [ii]
Additionally, there were five serious adverse events and the adverse events profile including diarrhoea, abdominal pain, nausea, and vomiting looks surprisingly similar to the description of the condition they are licensed to treat! Then there are the altered white blood cell counts which raises issues, particularly those on chemotherapy who would be potentially at risk of neutropenic sepsis even before taking Naldemedine.
Surprisingly oral naloxone (alone or with oxycodone) trials didn’t check how quickly after administration participants pooed! There was only “very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone” didn’t alter pain relief. This is a real pain, not just for participants and patients, but also for prescribers because there is a maximum dose for the oxycodone/naloxone combination therapy (Targinact®). This leaves prescribers no choice but to top up with extra oxycodone once the maximum dose is reached. Inevitably, this in turn risks more constipation, which could lead to more laxatives and so on.
Methylnaltrexone is a subcutaneous injection. Candy et al found that 59.1% of participants on methylnaltrexone passed a bowel motion within 24 hours compared to 19.1% of participants who had a placebo. For those who don’t poo there is always a second injection, which might help prevent people “falling between two stools”! In practice, though, doctors have been concerned that methylnaltrexone might worsen patients’ pain. Whilst Candy et al found that “moderate-quality evidence that the rate of opioid withdrawal was not affected” but there was an increased likelihood of abdominal pain and flatulence.
If we’re puzzled about poo, how about prognosis?
If we’re not sure that these drugs are the side effect free dynamite are there other reasons to prescribe them? Well, time from needle to loo might predict how long you live. No, joking aside, Janku et al did actually find promising results in an unplanned post-hoc analysis which reported that the quicker people pooed the longer their prognosis. [iii]
What’s my bottom line then?
Personally, if all else failed to move things I’d consider giving subcutaneous methylnaltrexone a try, but only after abdominal imaging had excluded bowel obstruction. And as for longer survival, well I guess time will tell!
Anyway, I’m off to put my feet up now. At least a foot stool might help pass a stool without the need for these muddled musings or the gut ache they might cause. [iv]