Putting the Genie Back in the Bottle: Addressing Constipation in the Opioid Era

Approximately 50 million adults in the United States reported experiencing chronic pain in 2016 while 19.6 million U.S. adults reported experiencing high-impact chronic pain that resulted in a hindrance to at least one major life event, according to statistics from the CDC. These extreme numbers lead some experts to call this timeframe an era of chronic pain.

Prescription opioids are typically used to treat patients with moderate-to-severe pain and are often prescribed to patients following surgery, injury or a cancer diagnosis.

Since 2006, there has been a steady increase in the overall national opioid prescribing rate that peaked in 2012 at a prescribing rate of 81.3 prescriptions per 100 persons, according to data from the CDC. Although the prescribing rate has fallen to 58.7 prescriptions per 100 persons in 2017, the lowest in more than a decade, the relatively high number of prescription opioids have led to significant increases in various side effects associated with opioid use.

One of the most common side effects, constipation, occurs in approximately 40% of patients who are prescribed opioids for chronic non-cancer pain, according to a review published in American Journal of Gastroenterology.

“Approximately one of every three individuals who takes an opioid is going to develop constipation,” Darren M. Brenner, MD, associate professor of medicine and surgery, and director of the neurogastromotility and functional bowel programs and Motts Tonelli GI Physiology Laboratory at Northwestern University Feinberg School of Medicine, told Healio Gastroenterology and Liver Disease. “The real issue is that people don’t develop tolerance, so once constipation emerges, it’s there to stay.”

The significant increase in opioid use in patients with chronic pain, and the subsequent high prevalence of opioid-induced constipation has led to an increased burden of cost and health care use among patients.

Opioid users with constipation (n = 17,384; mean age, 56 years) were twice as likely as those without constipation (n = 17,384) to have one or more inpatient hospitalizations (OR = 2.28; 95% CI, 2.17-2.39) during a 12-month study period, according to results of a retrospective cohort study published in American Health & Drug Benefits. The total mean adjusted overall costs per patient during the study period were $12,413 higher for patients with constipation vs. those without (95% CI, $11,726-$13,116).

With an increased prevalence of constipation associated with opioids and an increased health care use associated with the side effect in mind, Healio Gastroenterology and Liver Disease took a closer look at the phenomenon’s prevalence in the opioid era.

More Constipation, GI Disorders

“As gastroenterologists, we are seeing more and more [patients with] constipation,” William D. Chey, MD, professor of medicine, and director of the GI Physiology Laboratory at the University of Michigan Health System, said in an interview. “There is very good reason for that. We are at the start of the baby boomers entering their golden years. This is important given that one durable risk factor for constipation is advancing age.”

Chey said that there are several database-related studies that have demonstrated a linear relationship between age and the prevalence of constipation, which is a result of a variety of reasons.

As people age, Chey noted, they become less physically active, their diets change and they take more medications, both over-the-counter and prescription medications.

“People oftentimes overlook that commonly utilized over-the-counter medications like non-steroidal anti-inflammatory medications, iron supplements and calcium supplements can cause constipation in some individuals,” he said. “But some individuals develop constipation when they take those supplements and a lot of times the patients don’t make that connection. ... It’s safe to say that often, doctors don’t make that connection. And then there are a whole host of prescription medications that cause constipation; number one on the list are opioid analgesics.”

Brooks D. Cash, MD, director of Gastroenterology with McGovern Medical School at UTHealth and UT Physicians in Houston, agrees that the increased use of opioids is impacting gastroenterologists and other providers from various medical specialties.

“Opioids are important medications that are helpful to many patients, but as we know, they can cause physiological dependence, are prone to misuse and diversion, and have significant adverse effects,” he told Healio Gastroenterology and Liver Disease. “The GI system is particularly susceptible to the adverse effects of opioids. The most common symptoms related to opioids that we encounter in gastroenterology are constipation-related symptoms, but we are also seeing increasing numbers of opioid using patients presenting with chronic nausea, dyspepsia, dysphagia, symptoms of gastroparesis, and even narcotic bowel syndrome. Because of their effects on GI motility and the refusal or inability of patients to discontinue opioid therapy, the evaluation of these clinical syndromes, especially with physiologic evaluations such as motility and manometric testing, is limited and challenging.”

Physicians, according to Chey, are seeing a large number of patients being treated with opioids for myriad reasons including acute and chronic pain-related issues, but luckily a downward trend in opioid prescriptions is developing.

However, Chey did acknowledge that even with a decrease in the prescription of opioids, gastroenterologists and primary care physicians are going to be frequently dealing with patients experiencing constipation.

“It’s very important for them to think about whether opioids may be playing a role because we have specific therapies that target the underlying pathophysiology of constipation in opioid users,” he said.

Understanding OIC

One of the most important things for physicians to recognize, according to Chey, is that it is imperative for them to not fall into the trap that an individual’s opioid use is automatically causing their constipation.

“I say that because now we have a number of different drugs that specifically target [opioid-induced constipation (OIC)],” Chey said. “Peripherally acting mu-opioid receptor antagonists [PAMORAs], including naloxegol (Movantik, AstraZeneca), methylnaltrexone (Relistor, Salix), and naldemedine (Symproic, Shionogi), specifically block the effects of opioids in the GI tract without significantly reducing their [central nervous system] analgesic properties. All three drugs are FDA approved for OIC in the U.S. There’s also another drug that is FDA approved for OIC in the U.S. and that’s lubiprostone (Amitiza, Takeda).”

The problem, as Chey alluded to, is that PAMORAs are relatively ineffective for the treatment of constipation that is not a direct result of the use of an opioid.

“Making that distinction is important for choosing the right treatment for a patient with constipation and avoiding a treatment that is unlikely to provide benefit,” he said. “The introduction of PAMORAs has been a game changer for patients with OIC. For years and years, we have been treating patients who are taking opioids like anybody else who has constipation, and that has met with inconsistent results.”

As a result, there is some confusion regarding how to best treat patients with OIC.

For Brenner, it’s worth noting that working definitions for OIC were recently published with updates to Rome IV criteria in Gastroenterology to hopefully alleviate any confusion physicians might have.

“Most previously completed clinical trials defined OIC based on a self-description of symptoms, but with this now [being] standardized we may see more homogeneity in future clinical trials,” he said.

Rome IV defines OIC as new or worsening symptoms of constipation when initiating, changing, or increasing opioid therapy that must include two or more of the following:

The Rome IV also established a consensus definition of OIC as a change when initiating opioid therapy from baseline bowel habits that is characterized by either reduced bowel movement frequency, development or worsening of straining to pass bowel movements, a sense of incomplete rectal evacuation, or harder stool frequency.

Guidelines

The American Gastroenterological Association published new guidelines on OIC in the January 2019 issue of Gastroenterology which defines OIC in accord with the Rome IV criteria.

“These are all symptoms of ‘constipation’ and the key factor that marks these symptoms as consistent with OIC is the linkage to opioid initiation,” Cash said. “Because constipation is a common symptom of other medical disorders or medicines, the AGA guidelines recommend excluding other causes of constipation and then initiating non-pharmacologic therapies such as minimizing or discontinuing opioids, ensuring adequate fluid and fiber intake and exercise.”

If non-pharmacologic approaches fail to relieve OIC symptoms, the guidelines recommend a scheduled dosing of at least two laxatives from a variety of classes including stimulants, stool softeners, lubricants and osmotics.

The guidelines then recommend the initiation of PAMORAs if symptoms persist despite the use of laxatives.

Naldemedine and naloxegol both received strong recommendations in the AGA guidelines based on a review of their clinical trial data. Methylnaltrexone received a conditional recommendation, and lubiprostone and prucalopride (Motegrity, Shire) received no recommendation for use to treat OIC in the guidelines.

Additionally, the authors of the guideline recommended using the Bowel Function Index – a three-question tool – to determine which patients have inadequately responded to first-line laxative therapy and would potentially benefit from escalation therapy.

A score of 30 or more, as the authors noted, is consistent with a clinically significant diagnosis of constipation.

“Most guidelines and expert opinions recommend the use of over-the-counter therapies as primary interventions for OIC,” Brenner said. “These are simple to use, safe, and inexpensive and appear to be effective in up to 50% of cases. A more difficult decision is when to initiate prescription therapies. Some would argue that these should be started after multiple over-the-counters have failed, but a collaborative effort between GI, pain and palliative care experts resulted in a recommendation to use the Bowel Function Index as a validated scale to determine when prescription medications should be started.”

Once a decision has been made to use a prescription instead of laxative therapy, the choice becomes more difficult, according to Brenner.

“From my perspective this should be based on whether a practitioner is treating opioid-induced constipation or opioid-exacerbated constipation (OEC),” he said. “We recently published treatment algorithms for both in Current Gastroenterology Reports and agree that over the counter agents should be used as initial treatments for both conditions. Subsequently, using medications from the PAMORA class may be more beneficial for individuals with OIC as these directly target the underlying constipating effects of opioids, whereas use of a medication like lubiprostone or linaclotide may be more beneficial for individuals with OEC because these have also proven effective for treating concurrent normal and slow transit constipation.”

Ask Questions

One of the common missed nuances of OIC and OEC, Brenner said, is that the disorder is not dose-dependent. For instance, some individuals may take what is considered a low potency opiate and develop severe constipation whereas others may take a high potency opiate and never develop constipation.

For Brenner, this occurrence often goes unnoticed and can lead to problems in treating the disorder.

“Practitioners take a ‘don’t-ask’ approach to the problem,” he said. “Secondly, practitioners and patients alike lack a good grasp on the different signs and symptoms that define constipation.”

Cash said he agrees that physicians are not asking patients enough and said another issue is that many patients are afraid to bring the complaint up to their physicians.

“There have been a number of surveys conducted in opioid users with self-described OIC that have found that patients hesitate to mention their symptoms to their providers,” he said. “Reasons for this reticence include embarrassment about the symptoms, fear that providers will discontinue or change their pain medications, lack of time with the provider, and/or unwillingness to take more medications. Perhaps most telling, at least one of these surveys found that a sizable percentage of patients with OIC actually had mentioned their symptoms to providers, however, the patient did not feel that their OIC symptoms were adequately addressed or treated.”

Houman Danesh, MD, assistant professor of Anesthesiology, Perioperative & Pain Medicine, and Rehabilitation & Human Performance at the Icahn School of Medicine at Mount Sinai, and director of the Division of Integrative Pain Management at The Mount Sinai Hospital, offered a pain management perspective to this issue.

He said that health care has to develop into a partnership, therefore if a physician does not ask a patient if they are experiencing OIC, then a patient should.

“Patients are often fearful, that if they bring this issue up, then their opiate prescription will be reduced,” Danesh told Healio Gastroenterology and Liver Disease. “That is not the case. It must be managed appropriately so that issues of constipation do not worsen. Severe cases of constipation can lead to hemorrhoids and even herniated discs from the straining which can add to the pain burden. They can even lead to a more serious issue of bowel obstruction which can require surgery. This is an avoidable surgery if patients just discuss this with their physician. Patients are informed when given opiates of their side effects, however when patients are in pain, it is often difficult to digest all that information. At each follow-up, a physician should be asking patients about their bowel habits and if there were any changes. If they do not, a patient should feel comfortable in sharing this information with the physician as this is a known side effect of opiates which can easily be treated.”

Brenner said there is a taboo from a patient’s perspective regarding discussing constipation and agreed that some patients are afraid that if the disorder is a complaint and associated with the opioid, then the medication might be reduced or stopped.

“There needs to be better communication from both sides so we can more accurately define and treat these conditions,” he said.

Future Outlook

“Overall, our long-term goal should be the minimization of opioid use,” Brenner said. “There is an epidemic in this country for sure and pain physicians, primary care physicians and anesthesiologists alike are looking at other ways to treat individuals. From a gastroenterologist’s perspective in the short term, we need to quickly identify opioid bowel disorders and effectively treat them. Improved treatment will come directly from education – practitioners must be able to effectively differentiate OIC from OEC and patients must be better educated on the symptoms consistent with a diagnosis of constipation. A patient with OEC is less likely to respond to individual treatments and requires a multi-modal approach but this can only occur if practitioners ask the right questions and/or patients are familiar with the fact that they are constipated.”

For Chey, the obvious focal point moving forward is paying closer attention to those individuals who need prescription opioids and ensuring that therapy is not extended when it is not deemed necessary.

“We can all play a role in that part of the patient’s management but developing specific guidelines that help providers understand what OIC treatment to use when, will be very helpful,” Chey said. “The AGA guideline will help to start that discussion. Not surprisingly, they say that it’s most practical and cost effective to try standard laxative therapy first and then if they don’t work, and in particular in individual’s where there’s a clear temporal relationship between starting the opioid and the development of constipation that PAMORAs are a very logical and effective treatment choice.”

However, Cash put forth a more mixed forecast: There is greater awareness of inappropriate opioid use and its adverse effects in the population, but he does not see significant signs of decreasing use, despite the well-recognized opioid-related complications highlighted in medical literature.

“The availability of increasingly effective therapies for the symptoms of constipation and the syndrome of OIC is a great start, but obviously these medications have associated costs which can be considerable and, while they can improve OIC symptoms in many patients, they are band-aids that fail to address the root problem of opioid overuse,” he said. “Ultimately, OIC is a problem that has come to the fore as a result of increasing opioid use. If the genie can be put back into the bottle with regards to opioid use, it is a reasonable expectation that the burden of OIC/[opioid-induced bowel dysfunction] will also decrease. Hopefully advances in pain management with non-opioid alternatives or novel opioids will be forthcoming and more available in the future.” – by Ryan McDonald

References:

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Crockett SD, et al. Gastroenterol. 2018;doi:10.1053/j.gastro.2018.07.016.

Dahlhamer J, et al. MMWR Morb Mortal Wkly Rep. 2018;doi:10.15585/mmwr.mm6736a2.

Fernandes AW, et al. Am Health Drug Benefits. 2016;9(3):160-170.

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For more information:

Darren M. Brenner, MD, can be reached at darren.brenner@nm.org.

Brooks D. Cash, MD, can be reached at brooks.d.cash@uth.tmc.edu.

William D. Chey, MD, can be reached at wchey@med.umich.edu.

Houman Danesh, MD, can be reached at newsmedia@mssm.edu.

Disclosures: Brenner reports serving as an advisor, speaker and/or consultant to Allergan, Daiichi Sanyko, Salix and Shionogi. Chey reports financial ties to Allergan, Conti, IM Health, Ironwood, MyGiHealth, Nestle, QOL Medical, Ritter, Salix, Shire, True Self Foods, Volcant and Zespori. Cash reports no relevant financial disclosures. Danesh reports no relevant financial disclosures.