Opioids have an important place in the three-step 'Analgesia ladder' adopted by the cancer pain relief programme of the World Health Organization (WHO) . The relief of pain with such drugs is associated with well known undesirable side effects such as nausea, vomiting and constipation. We report a case of intestinal pseudo-obstruction associated with the use of oral morphine in a terminally ill cancer patient.
A 52-year-old man was admitted with diffuse abdominal pain and abdominal distension, associated with nausea, vomiting and constipation of 3 days duration. He had suffered a myocardial infarction 3 years previously and had complained of angina on exertion since then. Ten days before this admission, he had been admitted with right upper quadrant abdominal pain. Investigations on that admission revealed abnormal liver function tests (serum alkaline phosphatase 153 U Litre−1; ALT 44 U Litre−1; γGT 106 U Litre−1). Computerized tomography scan and ultrasonography of his abdomen showed multiple secondaries in his liver, of unknown primary origin. He was discharged 6 days later, on Oromorph 20 mg prn together with nifedipine SR 30 mg once a day, aspirin 150 mg once a day, ibuprofen 400 mg 6 hourly, cocodamol two tablets 6 hourly, ranitidine 150 mg orally 12 hourly and dexamethasone 4 mg orally 12 hourly.
On examination at this admission, he was apyrexial, with a regular heart rate of 80 beats min−1 and blood pressure 120/80 torr. His abdomen was distended and diffuse tenderness was present; high pitched bowel sounds were audible on auscultation. Rectal examination revealed an empty rectum. Initial laboratory studies including full blood count, urinalysis, serum electrolytes and creatinine were within normal limits, except for elevated liver enzymes and slightly raised urea concentration (11.2 mmol L−1) indicating dehydration. Plain and upright abdominal X-ray showed dilated small bowel loops and multiple gas and fluid levels consistent with intestinal obstruction. At laparotomy, ascites were present with multiple malignant miliary deposits throughout the peritoneal cavity and a grossly distended transverse colon. An obstructive growth at the spleenic flexure was identified. In view of the advanced state of his disease, only a defunctioning colostomy was fashioned. Post-operatively, patient-controlled analgesia (PCA) with morphine was started (1 mg bolus dose, 5-min lockout interval) for pain relief. The patient's condition improved and he started to take oral fluids on the fourth post-operative day. The PCA was discontinued on the sixth post-operative day and oral morphine sulphate (MST) 30 mg 12 hourly was started. The same day, after two doses of oral MST, he developed distension of the abdomen and vomiting. Abdominal X-ray showed loops of dilated small bowel with normal serum electrolytes. This was managed conservatively with intravenous (i.v.) fluids, nil by mouth and i.v. analgesia (PCA as above). The obstruction resolved over the next 2 days and the patient was started on oral fluids again, on the eighth post-operative day. Oral medication (including oral MST 30 mg 12 hourly) was restarted on the ninth post-operative day. Yet again, he developed signs of pseudo-intestinal obstruction, which was managed conservatively. PCA was started for analgesia and continued until the 17th post-operative day, even though he started to take oral fluids from the 12th post-operative day. PCA was replaced by a continuous subcutaneous diamorphine infusion at a rate of 15 mg day−1 on the 17th post-operative day. The diamorphine requirements were increased gradually to 80 mg day−1 by 24th post-operative day. The patient died of an acute myocardial infarction on the same day.
Following major abdominal surgery, many factors may affect the rate of post-operative recovery of gastrointestinal function. Opioids, by inhibiting motility in the ileum and colon, increase transit time and may prolong post-operative ileus . Their actions are mediated by stimulation of specific opioid receptors in the gastrointestinal tract and central nervous system. Opioid receptors (μ, κ, δ) and their endogenous ligands, enkephalins, endorphins and dynorphins are found in the intestinal wall of mammals . In vivo experiments by Bianchi and colleagues showed that intraperitoneal administration of tritium-labelled morphine 0.15 mg kg−1 in rats, not only resulted in high morphine tissue levels in the intact small intestine and small intestinal longitudinal muscle, but also significantly prolonged gastro-intestinal transit compared with i.v. administration of the drug . The local intestinal effects of morphine have also been demonstrated in another study as a smaller dose failed to alter gastrointestinal transit when injected intracerebroventricularly, although it did so when injected intraperitoneally . In vivo and in vitro binding studies in rats suggest that the site of action of morphine is on the myenteric plexus in the gut.
This patient's gastrointestinal function had returned to normal by the fourth post-operative day, despite the use of parenteral opioids (PCA) for pain relief. Subsequently he developed pseudo-obstruction after starting oral morphine, on two separate occasions. From the results of animal experiments, it is our hypothesis that oral morphine may have been responsible for post-operative pseudo-obstruction in this patient. The direct activation of peripheral opioid receptors in the intestinal wall, may have resulted in the inhibition of intestinal migrating myoelectric activity and smooth muscle contraction. Such an effect may not have occurred with i.v. morphine (PCA), because a lower concentration of the drug reached the small intestinal longitudinal muscle and myenteric plexus.
We wish to thank the librarians Mrs P. Smith and Miss J. McKie at Broadgreen Hospital for their assistance.
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Geneva: WHO, 1986.
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