Constipation is a common problem in patients regularly taking opioids for the treatment of chronic pain [3
]. While laxatives are commonly recommended and prescribed to prevent OIC, no randomized controlled trials of laxatives for OIC have been reported. Laxatives may be effective in many patients with OIC, but they may not be effective or suitable in all patients. A recent survey in the USA among patients with constipation (including opioid-induced constipation) demonstrated that 47% of patients using laxatives were not completely satisfied with their treatment, mainly for reasons of efficacy [30
]. Osmotic laxatives can be unpalatable [31
], while bulk-forming laxatives require large water intakes and are therefore not ideal in elderly or immobile people.
Opiate antagonists are being investigated for the treatment of OIC and postoperative ileus. Currently in the UK and Europe, Relistor®
(methylnaltrexone bromide) has been approved for the treatment of OIC in patients with advanced illness. Methylnaltrexone bromide, which is administered by injection only, improves the 4-h laxation response versus placebo, and is generally well tolerated, although serious AEs have been reported [32
]. Addition of oral naloxone to oxycodone has also been shown to improve bowel function with no reduction in analgesic efficacy [33
], and use of alvimopan, a peripherally acting opioid antagonist, is also promising in early-phase studies in OIC [35
], although this agent currently only has limited approval for short-term hospital use in postoperative ileus.
Prucalopride is the first selective serotonin 5-HT4
receptor agonist that has been shown to be effective in patients with chronic constipation [14
]. In this phase II study of patients with OIC, prucalopride was effective during the first week of treatment with a relatively stable effect thereafter. Over the 4 weeks of treatment, 40% of patients taking 4 mg prucalopride achieved the primary efficacy endpoint of an increase of ≥1 SCBM from baseline, and half of patients taking 4 mg achieved this endpoint at week 1 (P
≤ 0.05 versus placebo). There was a corresponding significantly greater decrease in laxative use in the prucalopride groups than in the placebo group.
In the present study, prucalopride-treated patients had also improvements in a range of additional outcomes, including symptoms and QOL. Constipation is not just related to frequency of BM, but also to symptoms, which together impact patients’ functioning and well-being, and result in dissatisfaction with bowel function and ineffective treatments. More than 70% of constipated patients refer to the discomfort of hard stools, straining, bloating, abdominal discomfort, and feelings of incomplete evacuation as being severe [30
]. It has been suggested therefore that treatment of constipation should have an impact on “at least several” of the attributes that are rated as most important by patients, including relief of constipation symptoms such as straining, hard or lumpy stools, infrequent stools, and improved quality of bowel movements [30
]. There is little consistent evidence from double-blind, randomized controlled trials that traditional laxatives treat symptoms other than frequency of bowel movements in the long term [30
]. In the present study, patients taking prucalopride reported a larger improvement than did patients taking placebo in the severity of their constipation and the efficacy of treatment, as measured by the patient-reported PAC-SYM and PAC-QOL questionnaires.
The effect size on bowel movements observed was comparable to those in larger trials of prucalopride in chronic constipation (non-opioid-induced). Of patients in the 2 and 4 mg prucalopride groups, 36% and 40% (versus 23.4% of patients in the placebo group) had an improvement of ≥1 SCBM per week, over the 4 weeks of treatment. This compares well with the prucalopride phase III studies, where 38–47% of patients improved by ≥1 SCBM from baseline with 2 mg prucalopride versus 21–28% with placebo [22
]. Results with 4 mg prucalopride in these phase III studies were similar to those with the 2 mg dose. Although, in the current study, statistical significance was not reached for the primary and key secondary endpoints over the whole treatment period, this is most likely due to the smaller sample size in this study based on a power calculation estimating a 30% difference. However, a consistent trend was observed in prucalopride’s effect on bowel movements, symptoms, and quality of life.
Consistent with the three phase III trials of prucalopride in chronic constipation, there was little difference in the frequency of AEs between placebo and prucalopride groups. The most frequent AEs reported in chronic constipation patients on prucalopride treatment were abdominal pain, nausea, diarrhea (related to the pharmacodynamic effect of the compound), and also headache. The incidence of these AEs in the OIC population of this trial was similar across all groups, except for abdominal pain, which was more commonly reported in the 4 mg prucalopride group than the 2 mg prucalopride and placebo groups, possibly related to the pharmacodynamic effect of prucalopride.
There was no difference between treatment groups in severity of AEs, except for a slightly higher incidence of severe abdominal pain in the 4 mg prucalopride group versus placebo. There were no deaths during this trial, and serious AEs were considered to be doubtfully or not related to prucalopride treatment.
There were no clinically relevant differences in laboratory abnormalities between the groups, and there were no significant changes in vital signs from baseline in the prucalopride groups. There were also no cases of serious cardiac events with prucalopride. As prucalopride is not metabolized via CYP 3A4, no interactions with other medications are expected.
In general, the 2 mg dose of prucalopride is effective in this population, but as there was little increase in AEs with the 4 mg dose, it may be appropriate to increase to the 4 mg dose in patients with more severe complaints or in whom the 2 mg dose is well tolerated but not effective.
In this population with OIC, more patients in the 2 and 4 mg prucalopride groups had an increase of ≥1 SCBM per week from baseline compared with placebo over weeks 1–4, reaching significance at week 1. Over the 4 weeks of treatment, improvements were seen in other efficacy parameters with 2 and 4 mg prucalopride versus placebo, although not always reaching statistical significance.
The results in this smaller group were in line with those seen in larger pivotal studies of prucalopride in chronic constipation and suggest improved bowel movement frequency, reduction of symptoms, and improvement of patients’ quality of life and satisfaction.
In addition, prucalopride was safe and well tolerated in this population with OIC.