Can misoprostol be used for refractory chronic constipation?
Question: Can misoprostol be used for refractory chronic constipation?
Answer: Opioid-induced constipation is a well-known side effect affecting patients on chronic opioid therapy for pain management. This occurs when opioid receptors in the gastrointestinal tract are activated with medication use, leading to disruption of motility and secretion. A patient may experience abdominal bloating; formation of hard, dry stools; straining; and incomplete evacuation.1,2 Unfortunately, tolerance to these side effects is not attained and constipation will continue for the duration of opioid treatment.2 These symptoms are collectively referred to as opioid bowel dysfunction (OBD) or refractory opioid-induced bowel disease (OIBD), if symptoms such as nausea, vomiting, and gastroesophageal reflux disease (GERD) are also seen.3
If non-pharmacological methods and over-the-counter laxatives (first-line treatments) are unsuccessful, alternative prescription agents such as naloxone, alvimopan (Entereg), and methylnaltrexone (Relistor) may be considered.2,4 However, naloxone reverses the analgesic effects of opioids, and alvimopan is only FDA-approved for postoperative ileus. The increased risk of myocardial infarction in patients with OBD with alvimopan is also concern. Methylnaltrexone is FDA-approved for opioid-induced constipation, but is administered as a subcutaneous injection.4,5
As the reader noted, misoprostol (Cytotec, generic) maybe another option. First approved in 1988 as a treatment to prevent NSAID-induced gastric ulcers, misoprostol is an oral synthetic prostaglandin analog that inhibits gastric acid and pepsin secretion while stimulating an increase in fluid and bicarbonate secretion in the small intestine. Although misoprostol has not been directly studied in patients on chronic opioid therapy, it’s diarrhea-inducing side effects have been exploited to reduce the severity of refractory chronic constipation (RCC).6-8
Soffer et al compared misoprostol (400 mcg TID) taken before meals with placebo (TID before meals) in a group of 9 women with RCC. During weeks 1 and 3 of the study, patients were randomly given either misoprostol or placebo while week 2 was a wash-out period during which no drug was used. Alternative treatments for constipation were not allowed during weeks 1 and 2, but were allowed during the washout period. At the end of the study, misoprostol was found to significantly decrease colonic transit time in 7 of 9 patients (77.8%). A statistically significant increase in total number of bowel movements (misoprostol 6.5 ± 1.3 vs placebo 2.5 ± 0.5, P = 0.01) and stool weight were seen, with 4 of the 9 patients reporting loose stools. There was no effect on reducing abdominal pain.7
Encouraged by these positive results, a subsequent trial by Roarty et al studied misoprostol (600-2400 mcg/day) in an open label-study of 18 patients with RCC. Misoprostol was started at 200 mcg 3 times daily before meals for 2 weeks, after which time the dose was adjusted dependent on tolerability. At the end of 4 weeks, 6 patients (33%) had discontinued treatment due to abdominal discomfort and cramping, and were considered treatment failures. Ten of the remaining patients (55.5%) had a statistically significant decrease in the interval between bowel movements, and the remaining 2 patients (11%) had no change in constipation symptoms even at the maximum dose.
The authors then looked at long-term effects of misoprostol. They found that of the 10 responders to therapy, 1 patient discontinued treatment after the 4 weeks of the study due to abdominal cramping, 2 patients continued treatment but lost efficacy within 9 months, 4 patients continued treatment with good results until final follow-up at 24 months, and the remaining 3 patients were lost to follow-up or discontinued therapy due to an unrelated medical reason.8
Roarty et al further compared colonic motility using radio-opaque tracers in a subset of 4 study patients with RCC and 5 patients with normal gastrointestinal function. After a single dose of misoprostol 400 mcg administered one hour before a meal, misoprostol was found to exhibit significantly greater effects in the left-side (sigmoid) colon versus the right colon when the paired difference of misoprostol versus placebo was compared.8 This suggests that while misoprostol monotherapy may be ineffective for some RCC patients, its use with cisapride (Propulsid), a drug that affects the right-side of the colon, may yield better results.9 However, more studies are needed to support this theory, which is not supported by strong literature. Also, because cisapride is currently restricted in the US, this is not likely a viable option.
Although misoprostol seems to be effective in RCC, the primary drawback of these 2 studies was the patient population studied. The majority of patients were young females, whose etiology of constipation was not mentioned, making it difficult to extrapolate results to an elderly or OBD population. In addition, the small size and relatively short duration of these preliminary studies limits the external validity of the results. Finally, as misoprostol is a pregnancy category X drug, its use in females of child-bearing age is limited by its potential for teratogenic effects and fetal abortion.
The response to therapy in Soffer et al was generally beneficial, but the response in Roarty et al was variable; some patients responded well, others were unable to tolerate minimum doses of misoprostol, while still others saw no effect at maximum doses. Long-term follow-up found that patients could lose efficacy with continued use or developed therapy-limiting adverse effects.
Due to the limited data available, the potential benefits of therapy should only be considered in patients who have been unsuccessful with all other options and who are able to tolerate the doses necessary for therapeutic effect.
Alby Jacob, PharmD
McKenzie C. Ferguson, PharmD, BCPS
Assistant Professor, Pharmacy Practice
Drug Information & Wellness Center
Southern Illinois University Edwardsville