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PRIORITY PRESS - Digestive Diseases Week 2013

Orlando, Florida / May 18-21, 2013

Orlando - Pharmacologic control of constipation has improved as a result of progress in unraveling the brain-gut connection, according to data and expert opinion presented at the 2013 DDW meeting. Newer and emerging therapies are based on a better understanding of both the molecular pathways controlling fecal transit as well as on central pathways of pain perception. The advances are relevant to both chronic idiopathic constipation (CIC) and the constipation phenotype of irritable bowel syndrome (IBS-C). In a series of presentations at DDW evaluating how to apply an expanding array of approved therapies, the consensus placed an emphasis on a symptom-based approach to initial treatment, reserving objective diagnostic studies of bowel function to those who fail effective and well tolerated first-line therapies.

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

Constipation and Abdominal Pain May be Independent

IBS-C and CIC are functional GI disorders differentiated by different sets of predominant symptoms, but progress in both has been generated by a more detailed isolation of the factors that contribute to these symptom complexes. Both can be driven by a heterogeneous set of mechanisms that are not limited to dysfunction in the intestinal tract (Gastroenterol 2012;142:463-72; J Gastroenterol 2012;47:1177-85). Rather, activation of neural pathways that engage centrally-mediated processing of sensory signals is not only capable of contributing to clinical symptoms but should be considered among targets of therapy.

“What the imaging studies have shown us is the importance of the brain-gut axis,” explained Dr. Lin Chang, Division of Digestive Diseases, University of California, Los Angeles. Patients with central dysregulation are “not able to suppress the sensitization that occurs when bowel function is disrupted so that dysregulation persists even when function improves. So it may start in the gut but then centrally-mediated factors begin to play a role.”

The relevance of the brain-gut axis in constipation was raised when the mechanisms of lubiprostone and linaclotide were discussed by Dr. Chang. Lubiprostone and linaclotide  are the two most recently approved therapies for constipation. Both agents facilitate fecal transit by increasing fluid secretion from intestinal endothelial cells but by different mechanisms. Lubiprostone activates chloride channels while linaclotide activates cyclic guanosine monophosphate (cGMP). For each agent, there is a correlation between improved defecation and diminished abdominal pain, but upregulated cGMP also inhibits neural transmission with a delayed but progressive nociceptive benefit observed in clinical trials.

“One of the interesting outcomes when pain control [from a phase III linaclotide trial] is graphed was the difference in maximal response. Unlike the stool frequency response, which occurred in 1 to 2 weeks of starting the drug, the maximal pain response was reached in about 8 to 12 weeks,” reported Dr. William D. Chey, Director, GI Physiology Laboratory, University of Michigan, Ann Arbor. Demonstrated in an IBS-C population, the temporal disparity seen with this agent provides compelling evidence that centrally-mediated pain recovers at a different pace and may be an independent target of symptom control.

Due to heterogeneity of symptoms and presentation, it cannot be presumed that all patients with IBS-C or CIC have a centrally-mediated pain component. However, both Drs. Chang and Chey stressed the importance of addressing the constellation of symptoms in each of these disorders that includes but is not limited to constipation. In the symptom-based approach to treatment advocated by each, first differentiating IBS-C from CIC was considered to be sometimes helpful but not a priority.

“I think where you start in terms of treatment depends on the severity of the constipation and the accompanying complaints. Whether or not the presumed diagnosis is IBS or chronic constipation, an empirical therapy for the predominant symptoms is a reasonable start in the absence of alarm symptoms,” Dr. Chey reported. In patients <50 years of age without such alarm symptoms as unexplained weight loss, a positive stool guaiac test or anemia, he recommended at least 4 weeks on an initial therapy to gauge improvement before considering alternatives.

Symptom-based Approach to Initial Treatment

An empirical trial of therapy in IBS-C and CIC was also recommended by Dr. Chang despite the availability of a lengthening list of sophisticated diagnostic studies to measure intestinal motility, evaluate anorectal function, and rule out underlying diseases. She explained that a symptom-based approach to initial treatment is the preferred strategy in most patients because of the infrequency with which tests of physiologic function yield information that changes management.

In patients with mild symptoms, it is still appropriate to initiate treatment with lifestyle modifications, including exercise, a diet high in soluble fiber and behavioural therapies, but a substantial proportion of patients with constipation do not consult a physician until symptoms are of at least moderate severity. Many have already tried and failed over-the-counter laxatives and lifestyle modifications. In these patients, it is reasonable to consider trials with polyethylene glycol 3350 (PEG 3350), lubiprostone or linaclotide. According to Drs. Chey and Chang, these are added to diet and lifestyle interventions. Predominant symptoms may guide drug choice.

“In fact, there are multiple randomized controlled trials that have shown benefits for PEG in patients with chronic constipation. Where the benefit is less clear for PEG is in the control of abdominal pain, particularly in IBS-C,” Dr. Chey observed.

The same differentiation may be valid for lubiprostone and linaclotide. While these have not been directly compared in randomized and blinded studies, their tolerability profiles, like their mechanisms of action, are distinct, and these agents are not considered interchangeable. While abdominal pain frequently improves with defecation in IBS-C, lubiprostone is not associated with any activity on sensory pathways of pain relief. While the efficacy of lubiprostone is supported by both the initial registration trials as well as extension studies out to one year, the benefit may be greater in CIC than in IBS-C.

“The good news is that both the safety profile and the efficacy profile remains very stable over the course of one year,” Dr. Chey reported. Of adverse events on lubiprostone, the most significant may be dose-related nausea, which reaches an incidence of about 30% in those taking 24 μg twice daily.

Phase III Data

In a recently published phase III trial with linaclotide in IBS-C (Am J Gastroenterol 2012;107:1702-12), control of both constipation and abdominal pain was sustained over a 6-month evaluation. The advantage relative to placebo for abdominal pain reached significance in the first week (P=0.0007), but a downward trend in pain scores in the linaclotide group persisted over the course of the study reaching a 50% reduction relative to baseline and a 30% reduction relative to placebo by 26 weeks (P<0.0001). A new study that was presented at DDW and collated data from two phase III linaclotide trials underscored the clinical significance (Abstract Mo2054).

“We evaluated change in abdominal and bowel symptoms in terms of thresholds for clinically meaningful improvements,” explained Dr. Michael Camilleri, Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota. “When we matched adequate relief thresholds with FDA-defined responder criteria, there was at least a 70% agreement.”

In IBS-C, where visceral hypersensitivity is often or usually a part of the clinical picture, the difference in the speed at which linaclotide relieves pain relative to relief of constipation suggests these phenomena are not fully interdependent.

In another analysis of phase III trial data conducted by Dr. Chey and presented at DDW, benefit from linaclotide continued to accrue after 4 weeks, with nearly one third of patients not improved by 4 weeks achieving clinical improvement by 12 weeks (Abstract Su2033). It is presumed that the favourable effect of linaclotide on pain-sensing nerve activity drives benefit after bowel function is improved.

The interrelationship of altered motility, altered sensation and disturbed central pain perception is now behind an intensive and broad research initiative to develop other pharmacologic agents alone or in combination that will turn off pain signalling while improving bowel function. Although Drs. Chey and Chang advocated a combination of lifestyle and drug therapies to restore normal bowel function, each agreed that altering perceptions is likely to play a critical role in most patients with IBS-C and perhaps some proportion of those with CIC.

Conclusion

There is a substantial body of evidence that restoring normal bowel function is an important but not necessarily a sufficient goal for adequate control of IBS-C and CIC. Centrally mediated pain perception appears to participate in symptom expression and may be an important independent target of therapy. While the causes of IBS-C and CIC appear to be complex and best controlled with a combination of non-pharmacologic and pharmacologic therapies, progress in understanding and addressing physiologic and neurologic disturbances is improving opportunities for effective intervention.   

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