Drug choices for the management of secretions in malignant bowel obstruction
Presentations at national conferences and courses can have a lasting influence on symptom management. Following a talk at one of the ‘Oxford’ courses(1), an increasing number of prescribers are now using ranitidine to reduce the secretions which make inoperable bowel obstruction such a challenging condition. Treatment in the past would often involve insertion of a nasogastric tube plus or minus the use of antispasmodics such as hyoscine butylbromide or steroids.
In more recent years, octreotide has been used, off licence. Octreotide is one of the synthetic analogues of somatostatin, an inhibitory hormone which reduces the secretion on many peptides in the GI tract, including insulin. It is perhaps surprising to read that it shows some anti-inflammatory and analgesic activity and directly inhibits the growth of some solid neuroendocrine and GI tumours. All three of these pharmacological actions could be additionally useful in symptom management. Although this group of drugs may act differently depending on the physiological state and region of the GI tract(2), their inhibitory effect on gastrointestinal motility and secretions, and ability to increase the absorption of water and electrolytes from the intestinal lumen in obstruction, makes them a logical choice.
A report in the New England Journal of Medicine(3) in patients with scleroderma affecting the gut showed significant decreases in pain, nausea and bloating with daily 50mcg injections of octreotide. Mercadante and colleagues’ 2007 review(4) on medical treatment for inoperable bowel obstruction was based on a around 200 patients and observed the superiority of octreotide in just over half. A literature review of the pharmacological treatment of malignant bowel obstruction in 2012(5) found no clear evidence base but recommended octreotide as first line treatment, with hyoscine as an alternative. A more recent comparison(6) found no significant difference between effectiveness of octreotide and hyoscine apart from superiority in reducing vomiting by the former. It called for more examination with clearly defined end points and measures.
So the use of octreotide has developed in a similar way to many other pharmacological treatments for symptom management in palliative care, based on expert opinion and published studies of small groups of patients with low heterogeneity. Possibly because of this, there is no specific guidance from NICE on this topic but the Palliative Care Formulary recommends its use if vomiting persists and antiemetics with or without dexamethasone have not resolved symptoms, but ranitidine is suggested within its own monograph as an alternative because the H2 antagonists are more effective than proton pump inhibitors at reducing the volume of gastric secretions. A number of papers from the 1990s onwards compared the effects of proton pump inhibitors and ranitidine in pre-operative gastric fluids and all came to the conclusion that a single dose of ranitidine is effective in a reduction of volume and pH(7). A paper by Clark et al seems to have encouraged more prescribers to use this option(8) but there seem not to have been any direct comparisons between ranitidine and octreotide. A systematic literature review by Longford et al in 2015(9) in the Marie Curie Hospice in Liverpool accepts both ranitidine and octreotide are beneficial alongside antiemetics and the possibility of venting gastrostomies for people with a longer prognosis. Their local guidelines choose octreotide as first line with hyoscine butylbromide and ranitidine as second line choices(10). This guideline was due for review in 2018 and a search for other local guidelines has yielded a number which were written around 2014, with no newer versions online. It feels as if the jury is still out.
Octreotide and ranitidine, like all drugs, have side-effects and potential interactions. The adverse drug reactions reported for octreotide are mostly due to its action on hormones. Hyperglycaemia, gastrointestinal disorders and headaches are listed as ‘very common’ (up to one in ten people) and, perhaps surprisingly, cardiac effects may occur – both bradycardia and tachycardia have been reported. Insulin and other antidiabetic medication may need to be reviewed but other drug interactions involve drugs unlikely to be used towards the end of life. Ranitidine has no adverse reactions that are within either the very common or common categories which means only 1 in 100 to 1 in 1,000 people taking it may experience GI side-effects. The other reports are judged to occur in fewer than 1 in 1,000 to 1 in 10,000 people. It has a few more potential drug interactions but they are all theoretical due to its metabolism by the CYP450 enzyme system, competition for renal tubule secretion and the alteration of gastric pH, which may increase or decrease the absorption of other drugs. By comparison, hyoscine butylbromide has side-effects and interactions almost entirely related to its anticholinergic properties. We know it will increase the likelihood of dry mouth, dizziness, tachycardia and ocular accommodation disorders. This group of medicines is relatively unremarkable from the toxicity point of view and no one stands out as being more hazardous(9).
Perhaps the main difference is in their cost. As we know, this should not be the main concern when selecting a medicine, but we all need to prescribe cost-effectively and where there are a few options and no single drug shows clear superiority over another, we are encouraged to use the least costly. As the doses of octreotide can vary, it is difficult to make precise price comparisons but there is no doubt that octreotide is considerably more expensive than ranitidine and hyoscine butylbromide. Until we have better quality data, it is difficult to recommend changing the first line drug choice for the management of inoperable bowel obstruction.