That’s the danger when new medications are compared against placebo rather than against over-the-counter products with a history of effectiveness.
When was the last time you talked with friends or acquaintances about constipation? I’m guessing it has not been recently! Constipation is just not something people discuss very often, except when it comes to their toddlers or, in my case, grand-toddlers.
But constipation is real and, well, it’s uncomfortable. Remember that the small and large bowels (which, combined, I will call bowel) make up a long tube that constricts in a synchronized fashion to push food and water through it. What goes in at the mouth transits, not by gravity but through peristalsis, the involuntary, wavelike contractions of various parts of the digestive tract. The body removes nutrients as food and drink get pushed on through. What’s left over, including trillions of bacteria, passes through the tube at the other end of the tract.
There are plenty of cases of constipation when the cause is known. Medications, such as opioids, can interfere with peristalsis. Tumors and strictures can create blockages. Neurologic diseases can damage the nerves of the digestive tract. But sometimes the cause of chronic constipation is unknown. Those cases are called chronic idiopathic constipation (CIC).
The American College of Gastroenterology has dedicated a whole monograph to this and its partner condition, irritable bowel syndrome, which in some people also has a component of constipation. Published in 2014, “The American College of Gastroenterology Monograph on the Management of Irritable Bowel Syndrome and Chronic Idiopathic Constipation” documented a 14% prevalence of CIC in the United States and noted that constipation was more common among women, older people, and those with a lower socioeconomic status.
The monograph listed numerous approaches to treating CIC. Nonmedical ones included biofeedback, which came with a weak recommendation, and bran, which came with a strong recommendation. For both of these, the quality of evidence was rated as low. I am guessing there are few grants available to academics to study constipation as it relates to biofeedback and bran!
There are basically two medicinal ways to improve bowel transit time and therefore help ease someone’s constipation: Stimulate the bowel to move faster or increase the amount of fluid within it. The over-the-counter stimulant laxatives include senna, bisacodyl, and old-fashioned castor oil. Stimulant laxatives are fine for occasional use but shouldn’t be taken on a regular basis.
There are two ways to increase the amount of fluid in the bowel: either draw it in (called osmosis) or cause fluid to be secreted by the luminal cells into the lumen of the bowel. The osmotic laxatives include polyethelene glycol and lactulose; both come with a strong thumbs-up.
Linaclotide, sold as Linzess, and lubiprostone, sold as Amitiza, increase fluid in the bowel by promoting secretion by luminal cells. Plecanatide, sold as Trulance, is a newcomer to this group of laxatives. All three of them were discovered by studying the basic biochemical physiology of the bowel. It’s not a glamorous body part, but these laxatives show that the bowel is not just a simple tube but uses some amazingly complex processes to maintain homeostasis and complete the vital work of the digestive system.
Lubiprostone is a bicyclic fatty acid derived from prostaglandin E1 that activates CIC-2 chloride channels and produces a chloride-rich fluid secretion. Linaclotide and plecanatide are polypeptides that mimic the actions of endogenous guanylin and uroguanylin. They have a different mechanism of action but the end result is similar to lubiprostone.
Not your usual endpoints
Studying constipation in a medication clinical trial involves measuring some unusual endpoints, including the frequency of spontaneous bowel movements (SBM), the consistency of the stool, the feeling of completeness of evacuation after the SBM (CSBM), and other sensations such as straining and feeling of incomplete evacuation.
The initial criteria for enrollment in the plecanatide studies required less than three defecations per week, rarely having a loose stool without the use of laxatives, not requiring manual maneuvers to facilitate defecation, and not meeting standardized criteria for the diagnosis of irritable bowel disease with constipation. In addition, patients were required to report at least two of the following during at least 25% of defecations: straining, lumpy or hard stool, sensation of incomplete evacuation, and/or a sensation of anorectal obstruction/blockage. If the patients met these criteria, they then needed to demonstrate other symptoms such as limited CSBMs, either hard or nearly liquid stools and/or feelings of incomplete evacuations.
Efficacy was assessed using a responder analysis and change-from-baseline in the SBM and CSBM endpoints. A responder was defined as a patient who had at least three CSBMs in a given week, as well as an increase of at least one CSBM from baseline in the same week for at least nine weeks of the 12-week treatment period and at least three of the last four weeks of the study.
The two main studies of plecanatide involved nearly 1,800 subjects randomized to receive either a 3 mg dose of drug per day or placebo. In both, the responder rate was 21% in those taking plecanatide and 11.4% in those assigned to take the placebo, for a net efficacy of about 10% of people taking it for 12 weeks.
The drug has a black box warning stating that it is contraindicated in children younger than 6 years old due to deaths due to dehydration with a single dose of plecanatide in juvenile mice. It was not studied in children for this reason. The boxed warning also includes instructions to avoid the use of plecanatide in older children and teens.
Results of the two studies of plecanatide showed that 5% of patients developed diarrhea, compared with 1% of those assigned to placebo. To be fair, most of the diarrhea occurred within four weeks of when people started taking the drug, and severe cases occurred within the first three days. Adverse events led to treatment discontinuation in 4% of people taking the drug, compared with 2% in the placebo arm. The clinical trials did not include sufficient numbers of patients 65 and older to determine whether they respond differently than younger patients.
The price for plecanatide has not been announced, but linaclotide and lubiprostone, its competitors, both have a price of about $370 per month on GoodRx website. It is a good guess that plecanatide will be priced close to its competitors. Given a net (after subtracting the placebo effect) of only about 10% of patients having a positive result, and that efficacy threshold was set at one additional SBM per week, the cost, going by what happened in the clinical trials, is about $850 per SBM.
Let’s do the math: $370 per 30-day supply equals $12.16 per day, and $12.16 per day, seven days a week equals $85.12 per week per user. But only 1 in 10 people have a response, so each costs about $850 per SBM when taking into account the entire group. Am I missing something here? And the study compared plecanatide to placebo, not the over-the-counter products that cost pennies per dose.
Personally, I have a hard time justifying $850 per spontaneous bowel movement when the American health care system is buckling due to the overall cost of care.
I know that constipation can be a serious and painful problem, and we shouldn’t dismiss other people’s suffering. But how many reasonable adults would consider a price of $850 per SBM as a reasonable cost for our country when, in my medical experience, a multitude of over-the-counter laxatives will produce the same result in at least the same number of people? And before I receive too many emails, I recognize that people not responding will probably stop taking the plecanatide so, over the long haul, the cost may be actually $85 per SBM. That is still a lot more than the cost of the over-the-counter products.
Thomas Morrow, MD, is the chief medical officer of Next IT. He has been the founding medical director of five HMOs and a disease management company, a medical director at Genentech, and president of the National Association of Managed Care Physicians.
Paul Lendner ist ein praktizierender Experte im Bereich Gesundheit, Medizin und Fitness. Er schreibt bereits seit über 5 Jahren für das Managed Care Mag. Mit seinen Artikeln, die einen einzigartigen Expertenstatus nachweisen, liefert er unseren Lesern nicht nur Mehrwert, sondern auch Hilfestellung bei ihren Problemen.