Novel and Emerging Strategies
Fecal Microbiota Transplant
The microorganisms that populate the gut, known as the microbiota, are critical to normal, healthy function of the gastrointestinal tract (Dima 2012; Choi 2015; Rossen 2015; Furnari 2012). In fecal microbiota transplant, the colonic microorganisms of a healthy person are transferred to a symptomatic person. A number of different fecal microbiota transplant methods are under investigation, including direct infusion of prepared fecal matter into the gastrointestinal tract and encapsulation of a highly refined preparation for oral administration. Fecal microbiota transplant is an effective treatment for recurrent Clostridium difficile infection, an increasingly common and difficult to treat cause of severe infectious diarrhea (Youngster 2014; Brown 2014). The potential of fecal microbiota transplantation to treat many diseases including inflammatory bowel disease, Parkinson’s disease, multiple sclerosis, and metabolic syndrome is an area of active investigation (Xu 2015; Kelly 2015).
A series of five case reports of patients with chronic constipation-predominant irritable bowel syndrome (IBS-C) treated with fecal microbiota transplant describe immediate remission in all five cases; stool frequency increased to one to two bowel movements per day without the use of laxatives. These patients were followed for 6‒28 months, during which the improvement was stable (Borody 2004).
Because the FDA regards human feces as an unapproved drug, fecal microbiota transplants require FDA approval under their Investigational New Drug program, except in cases of recurrent bowel infection due to the bacterium Clostridium difficile (Moore 2014).
Biofeedback therapy is a behavioral treatment for chronic constipation that has demonstrated superiority to laxatives in several controlled clinical trials. In biofeedback training, patients learn how to coordinate muscular activity in the pelvic floor, abdomen, and diaphragm to achieve normal and complete defecation. There are no known adverse effects of biofeedback therapy for constipation. On average, four to six 1-hour sessions, two weeks apart, are required for successful retraining, and periodic sessions to reinforce training may be of use in the long term (Rao 2011; Lee 2014; Basilisco 2013; Camilleri 2010).
Biofeedback therapy is not widely utilized, perhaps due to the shortage of skilled practitioners, as well as the labor-intensive and time-consuming nature of the therapy. There is also no consensus on biofeedback’s importance: some sources suggest it to be a last resort after other treatments have failed, while some researchers recommend it as first-line treatment (Basilisco 2013; Camilleri 2010). The ability to use home-based biofeedback training protocols, some of which are currently under investigation, may enhance the acceptance and use of this promising therapy (Rao 2011).
Sacral Nerve Stimulation
Sacral nerve stimulation involves the use of an electrical lead that is inserted through the skin and through an opening in the lowest part of the spine (the sacrum). Low voltage/low frequency electrical impulses are delivered directly to the third or fourth sacral nerve (Sharma 2013; Thomas 2013; Norderval 2011). The degree of stimulation is adjusted for each patient so it is close to the threshold at which the electrical impulse can be felt (Duelund-Jakobsen 2013; Koch 2005).
This technique has been used successfully to treat urinary retention and urinary and fecal incontinence, and has more recently been employed to treat chronic constipation. Sacral nerve stimulation appears to increase peristaltic waves in the colon and increase bowel movement frequency in people with slow-transit constipation (Thomas 2013; Sharma 2013; Norderval 2011). A study of sacral nerve stimulation enrolled 45 participants with at least one year of severe slow or normal-transit constipation and who had not responded to other treatments. Subjects were followed for a median of 28 months after implantation of a permanent sacral nerve stimulation device. Constipation scores decreased significantly and 87% of participants were considered to have achieved treatment success (Kamm 2010).
Side effects of sacral nerve stimulation include infection, pain around the stimulator, and pain in the perineum or extending down to the leg. In addition, 16‒54% of people with a sacral nerve stimulator implant have needed a second surgery due to discomfort or a device malfunction, while 8‒20% have had their device removed for these reasons (Norderval 2011).
Interferential therapy, which involves the application of electrical current via electrodes taped onto the skin, has been used to treat musculoskeletal pain. For the treatment of constipation, two of the electrodes are placed on the lower back and the other two are placed opposite these on the lower abdomen, so there is an opposing pair on the front and back of the body (Queralto 2013). The electrodes emit different medium-frequency electrical currents, resulting in therapeutic stimulation where they intersect inside the body (Fuentes 2010).
In a pilot trial, 11 adults with slow-transit constipation who had been unsuccessful with other therapies used home-based devices to apply interferential therapy, one hour per day, for three months. At the end of the trial, seven of the participants had significantly increased bowel movement frequency, reduced constipation symptoms, and improved quality of life, with no adverse events (Queralto 2013). Preliminary research suggests interferential therapy may also be beneficial in individuals with irritable bowel syndrome (Coban 2012).
Prucalopride. Prucalopride (Resolor or Resotran) is a highly selective serotonin receptor activator and appears to be safer than earlier serotonergic agents for constipation. Prucalopride has been found to increase bowel movement frequency, reduce symptoms, and improve quality of life in people with chronic constipation (Tack 2015). The drug’s side effects are usually short-lived and include headache, nausea, and diarrhea (Liu 2011; Shin 2014; Quigley 2012b; Thayalasekeran 2013).
Prucalopride has limited approval in Europe and Canada, where its authorized use is limited to treating women in whom laxatives have failed (Quigley 2012b; HC 2011). Prucalopride is not yet approved for use in the United States (Lee 2014).
Anti-opiates. Opiates are powerful sedative pain relievers. Examples include morphine, codeine, hydrocodone, fentanyl, and oxycodone. Constipation is a very common side effect of this class of medication (Gold Standard 2003; Coles 2007; Allouche 2014; Siemens 2015).
Naloxegol (Movantik) and methylnaltrexone (Relistor) are anti-opiates, drugs that block the effects of opiate drugs in the digestive tract but do not interfere with their pain-reducing properties. These medications can improve bowel movement frequency in people with opioid-induced constipation; their most common side effects are nausea, diarrhea, and abdominal pain. Naloxegol and methylnaltrexone are approved for treatment of opioid-induced constipation. Alvimopan (Entereg), another anti-opiate, is approved for opioid-induced constipation but only during hospitalization. It has been associated with an increased risk of heart attack with long-term use, but more data are needed to determine if alvimopan consistently elevates heart attack risk (Corsetti 2015; FDA 2013; Siemens 2015; Watkins 2011). Naloxone (Narcan) is an anti-opiate that has been studied for the treatment of opiate-induced constipation and IBS-C (Gold Standard 2014).
. Neurotrophin-3 is a growth factor produced by the body that modulates the development and function of the nervous system. Neurotrophin-3 and related compounds may be able to combat age-related neurodegeneration in the gut, which could help relieve constipation (Camilleri 2008; Chalazonitis 2004; Zhou 1996). In a randomized controlled trial, 107 subjects with chronic constipation received injections of neurotrophin-3 or placebo in one of several dosing schedules for four weeks. Compared with placebo, those who received 9 mg of neurotrophin-3 three times per week had higher stool frequency, easier bowel movement passage, and more complete bowel movements at the end of the trial (Parkman 2003). Neurotrophin-3 is not currently available for the treatment of constipation.