Annals of Long-Term Care: Clinical Care and Aging. 2013;21(5):53-56.
Methylnaltrexone Demonstrates Potential to Treat Opioid-Induced Constipation in Critical Care Setting
Critical care patients, many of whom are taking opioids to treat pain, experience gastrointestinal side effects, including constipation. Managing these side effects not only improves patients’ quality of life, but studies also show that normal gastrointestinal function is essential for protecting against bacterial translocation leading to sepsis and shortening intensive care stay. Methylnaltrexone (MNTX) is a peripheral opioid antagonist that is FDA-approved to treat opioid-induced constipation in patients with advanced illness receiving palliative care when treatment with a laxative is inadequate. Given the success of MNTX in the palliative care setting, a new study sought to evaluate the efficacy of subcutaneous MNTX in the critical care setting.
Sergio Sawh, MA, Department of Emergency Medicine, Charing Cross Hospital, London, and associates followed 88 nonsurgical critical care patients receiving fentanyl infusions, 15 of whom had constipation despite treatment with senna and sodium docusate. Of these patients, seven received subcutaneous MNTX injection 0.15 mg/kg, and eight received conventional rescue therapy with combination sodium picosulfate 5 mg and two glycerin suppositories. Within 24 hours, six of the seven patients treated with MNTX experienced laxation, compared to none of the patients receiving conventional rescue therapy (P<.001). All seven patients progressed to full target enteral feeding, compared to half of the patients receiving standard therapy, but this finding did not reach statistical significance. However, the researchers noted that the intensive care mortality rate was two of seven MNTX patients compared to four of eight standard treatment patients. These results indicate that MNTX can play an important role in restoring normal bowel function in patients with advanced and critical illness; however, larger, controlled studies in the intensive care environment are needed. “In this retrospective study, MNTX was well tolerated and did not demonstrate any signs of reversing the central effects of fentanyl,” the authors concluded. “In addition to its benefit in reversing gut dysmotility, MNTX may be of further benefit in improving enteral feeding.”
Comparing the Evidence of Injectable Bulking Agents for Treatment of Fecal Incontinence: What Does the Literature Say?
Injection of perianal bulking agents have been introduced as a minimally invasive surgical option and used successfully to treat fecal incontinence; however, data comparing the benefits of available bulking agents and standardizing techniques are lacking. Yasuko Maeda, MRCS, MPhil, Sir Alan Park’s Physiology Unit, St. Mark’s Hospital, United Kingdom, and colleagues conducted a systematic literature review that identified key areas of methodological weakness in the randomized and quasi-randomized controlled trials of the most commonly used injectable bulking agents. In the study, the results of which were published in February in the Cochrane Database of Systematic Reviews (www.ncbi.nlm.nih.gov/pubmed/20464759), Maeda and colleagues observed that due to numerous study limitations, a definitive conclusion cannot be drawn regarding the efficacy of one anal injectable agent over another to treat fecal incontinence. Annals of Long-Term Care® (ALTC) had the opportunity to interview Maeda about the quality and limitations of the current evidence supporting these agents in the treatment of fecal incontinence.
ALTC: Your conclusions are based on the findings of five randomized controlled trials (RCTs) that met your inclusion criteria. These trials involved a total of 382 patients and compared the therapeutic benefits of injectable bulking agents to any alternative treatment or placebo. What are some of the difficulties in assessing the quality of evidence generated by these RCTs?
Maeda: The main issue of these trials is small sample size. It is difficult to ascertain the efficacy when the treatment is tried on so few patients. Also in some studies the selection criteria was not clear, thus the findings are difficult to be applied universally. Randomization method and blinding of patients and/or assessor—which are keys to avoiding bias—were unclear in some of the studies. Additionally, the agents need to be implanted around the internal anal sphincter, but there have been many techniques deployed (eg, via skin, via anal canal, with/without aid of endoanal ultrasound). The technique has not been compared very rigorously in these studies and may need different approaches according to the consistency of agent. It is also important to note that few RCTs enroll elderly subjects and particularly frail elders, who represent a large portion of patients with fecal incontinence, so data to guide treatment specifically in this large population is severely lacking.
Injectable silicone biomaterial is one of the most widely used bulking agents. What did your review reveal with regard to the safety and efficacy of this agent?
There were two conflicting outcomes from the two studies we reviewed, but the study that compared silicone biomaterial to placebo injection showed no difference in outcome; thus, despite a number of publications showing efficacy of this agent, the evidence supporting this agent is not robust.
Anal injection with carbon-coated microbeads suspended in water-based carrier gel is FDA-approved to treat adult women with stress urinary incontinence due to intrinsic sphincteric deficiency, but it has also been tested to treat symptoms of fecal incontinence as well. What does the literature show with regard to the safety and efficacy of this agent to treat fecal incontinence?
There was little evidence to support this agent and a number of documented adverse events, such as pain, type 3 hypersensitivity, and erosion of mucosa. I do not think there are many surgeons who are currently actively using this agent.
Dextranomer in hyaluronic acid is the most recent bulking agent to be approved by the FDA. How does this new agent compare to other currently available agents?
The study of dextranomer in hyaluronic acid (Solesta) was by far the largest and most well-designed study, which showed efficacy compared to sham injection. It showed improvements in 52% of patients, defined as more than 50% of improvements in incontinence episodes, at 6 months after injection. The study did not compare dextranomer in hyaluronic acid to other agents, so it is not feasible to say this agent is superior to other agents.
Since there are numerous limitations in the available literature about these bulking agents, how do clinicians decide which agent to administer to older adult patients?
Bearing in mind the limitations of the available literature, there was no sound evidence to support one agent over another. However, from the design of the study and the number of participants, dextranomer in hyaluronic acid is perhaps the most feasible agent to be used when considering this treatment. There was no specific mention of the elderly population regarding this treatment, so as things stand, we should consider this treatment for the elderly population in the same way as we do for other age groups. Due to lack of evidence, my colleagues and I are currently under process to write up a systematic review of treatment of fecal incontinence for the elderly population in collaboration with Cochrane Review Group.
What are the key areas that future studies on treatment of fecal incontinence should aim to address?
Any treatment for fecal incontinence is aimed at improving patients’ quality of life. From this perspective, it is important to focus on what matters to patients most. All the outcome scores used to date are generated by physicians and concentrate on physical leakage of stool/gas, but we will need to assess the outcome more focused on patients’ perspectives, such as loss of confidence due to the symptoms, embarrassment, and restriction to their lives.
Conservative management modalities have more miles to be explored, particularly for frail patients who are not surgical candidates. Anal plugs that are more comfortable, pads that are more absorbent and limit odor, and portable irrigation systems to ensure bowel emptying need to be looked at, as these interventions may be further improved from current prototypes.
Finally, minimally invasive neuromodulation, such as sacral nerve stimulation and tibial nerve stimulation, have received attention in recent years. These modalities will need further investigation in terms of elucidating efficacy so that patients suitable for these treatments can be identified more easily.
Ask the Expert: Conservative Management of Constipation in Older Adults
Constipation is estimated to affect as many as 40% of older adults. Although constipation has multiple etiologies, the standard advice when patients present with constipation is conservative treatment with lifestyle modification (ie, diet and exercise) and over-the-counter (OTC) agents. However, this standard of care is in need of scrutiny, according to Lawrence Leung, MBBChir, CCFP, FRACGP, FRCGP, Department of Family Medicine, Queen’s University, Canada. In a recent review of the literature (www.jabfm.org/content/24/4/436.full), Leung and colleagues reported that treatment of constipation should be guided by the evidence and individualized according to its etiology. Annals of Long-Term Care® (ALTC) had the opportunity to interview Leung about the body of evidence supporting the use of conservative treatment in the management of constipation in older adults.
ALTC: What challenges do clinicians face when treating and managing constipation in their older adult patients?
Leung: The main challenges in treating and managing chronic constipation in older adults include varying diagnoses of constipation (in terms of frequency of motion, texture of stool or subjective feeling of defecation), degree of underdiagnosis in the older adult population (especially in those with cognitive impairment), and the degree of self-medication with OTC medications. In view of the common occurrence of constipation, clinicians in a busy practice very often prescribe medications without considering the possibility of structural etiology of constipation in older adult patients (ie, pelvic-floor dysfunction), in which case will respond poorly to laxatives.
When patients present with concerns of constipation, it is common practice for physicians to recommend that patients modify their lifestyle first, for example, by increasing dietary fiber, fluids, and exercise—but what does the literature reveal with regard to the effectiveness of these modifications?
In our review, the standard advice of increasing dietary fiber, fluids, and exercise as dietary lifestyle modifications is not universally beneficial to all patients with constipation. For dietary fiber, evidence is inconclusive (level 2C) and benefits are only seen in patients with actual fiber deficiency. Increasing exercise can decrease self-reported symptoms in women but evidence is not strong (level 2C). A large prospective study revealed a link between fluid intake and constipation, but there were no trials looking at effects of increased fluids on constipation (level 2C). In summary, there will only be benefits for increasing fiber, fluids, and exercise if there is an actual lack of any of the three, and physicians should refrain from encouraging such increase as standard advice.
There is a plethora of OTC agents that physicians can recommend to patients with constipation. These include oral osmotics, oral bulk-forming agents, oral stool softeners, oral stimulations, and rectal stimulants. Could you briefly discuss what the literature says about the efficacy and side effects of each of these OTC products?
Bulk-forming agents are mainly fiber supplements that absorb water to increase the bulk of the stool and enhance bowel motions. Examples are bran, psyllium, and methylcellulose. Of the three, psyllium has the best evidence (level A) as supported by randomized controlled trials. Bulk-forming agents are in general safe to use, and for them to work properly, adequate fluid intake with the bulk-forming agents is mandatory; otherwise constipation can worsen and bowel obstruction may even ensue. Stool softeners work by its detergent effects. Docusate sodium is the most common agent with a moderate level of evidence (level B). It is often used when bulk-forming agents fail as the first-line agent. Polyethylene glycol (PEG) and lactulose are the common prescribed osmotic agents and they simply increase and retain the water content of the stool. Both have good evidence of use (level A) and lactulose has fewer side effects than PEG, which can cause nausea and diarrhea in the older adults (hence dose titration is needed sometimes). Finally, sennosides and bisacodyl are probably the most commonly prescribed laxatives, which belong to the bowel stimulant group. They act on the myenteric plexus of the colon and enhance peristaltic contractions, stimulating bowel movements. Both have good evidence (level A) of use supported by results from randomized controlled trials. The association of chronic sennosides use with increased risk of colonic cancer remains controversial and unfounded.
What are the considerations for managing constipated elderly patients with OTC products?
In general, for elderly patients, it is advisable to start with oral bulk-forming agents and add in stool softeners as the first step; if results are not satisfactory, one can move up to osmotic agents and finally to bowel stimulants. For the frail older adult patient, it is important to avoid polypharmacy by not using more than two classes of laxatives at the same time. If appropriate, investigations to exclude pelvic floor dysfunction should be done to refine the diagnosis of chronic constipation.
In the past few years, two new classes of agents have been marketed for treating chronic constipation: chloride channel activators and 5-HT4 agonists. How do these new agents work, and how do they compare to the available OTC products?
Chloride channel activators increase intestinal fluids secretion by activating the type 2 chloride channel in the membrane of the gastrointestinal epithelium. So far evidence is good (level A) but known side effects of nausea, headaches, and diarrhea must be considered before prescribing to older adults. In contrast, 5-HT4 agonists act on the 5-HT4 receptors in the myenteric plexus of the bowel and stimulate peristalsis. Evidence of use for 5-HT4 agonists has been tarnished by the recall of the first marketed product (tegaserod) on grounds of increased risk of cardiovascular events. Yet, the next generation product prucalopride has demonstrated a safer cardiovascular profile with particular efficacy in severe cases of constipation. Both agents are more costly than the traditional agents that can be bought over the counter.
When conservative treatment with lifestyle modification and OTC products has failed to adequately manage an older patient’s constipation, what is typically the next course of action?
Physicians should be cognizant of other possible etiologies for chronic constipation when lifestyle modifications and OTC products have failed to bring improvement. A minority of patients with chronic constipation have pelvic floor dysfunction as the cause of constipation and they should be referred to specialists for corrective surgery if appropriate. Also, in extreme cases of chronic constipation leading to bowel obstruction or perforation due to impaction or fecalith formation, surgical treatment will be mandatory as a life-saving measure. Otherwise, specialist management of chronic constipation is rarely necessary.