Opioid use has achieved epidemic proportions in the United States, yet few interventions have been implemented to successfully combat this issue. From a medical perspective, many assume that most opioid use is illicit; however, according to a recent Centers for Disease Control analysis, more than 191 million opioid prescriptions were written in 2017, representing a ratio of 58.7 prescriptions per 100 people, enough for each person in 16% of US counties to receive one (1). Most opioids are prescribed for advanced illnesses and chronic noncancer pain syndromes, and although they may effectively treat certain types of pain, multiple untoward side-effects can result from the use of these medications. The most common is opioid-related constipation (ORC), affecting between 40% and 80% of individuals using opioids for noncancer pain–related illnesses (2,3), and individuals developing ORC do not develop tolerance to this adverse event. In fact, a recent comprehensive meta-analysis indicated that the number needed to harm (i.e., the number of individuals needing to take opioids to develop 1 case of ORC) is estimated to be ∼3.3. ORC can also lead to secondary complications including hemorrhoids, fissures, fecal obstruction, and impaction if not properly recognized and managed (4). The impact of ORC can be so severe that up to one-third of individuals will reduce, skip, or discontinue their opioids to overcome their constipating effects. More than 90% of these individuals endorse worsening pain, but they admit that they would rather experience the pain than deal with the consequences of ORC (3). Obviously, this should inform the medical community that additional attention is needed regarding prescription practices surrounding this class of medications and their unintended consequences. There remain, however, instances when the use of opioids is justified, and in these circumstances, when ORC develops, recommendations for combating this side-effect without requiring reduction of analgesia are needed.
The ability to successfully manage ORC relies on 2 major factors: (i) an understanding of disease pathogenesis and (ii) unified criteria to define this patient population. Regarding pathogenesis, the mechanisms of ORC have been well elucidated. Opioids provide analgesia through activation of μ-opioid receptors in the central nervous system. However, opioids are not targeted molecules and thus do not have selectivity for these receptors restricted to the central nervous system. Identical receptors are also located throughout the submucosal and myenteric nerves and muscles of the gastrointestinal (GI) tract, and opioids bind freely to these receptors, resulting in constipation by delayed transit, decreased intestinal secretion, and increased fluid reabsorption (5). More recent data suggest that opioids may also induce pelvic floor dysfunction (6). Thus, the mechanisms of ORC appear multifactorial.
In defining this disorder, it was not until 2014 when the first working definition of ORC was proposed by Camilleri et al. Individuals met criteria for opioid-induced constipation (OIC) if they experienced changes from baseline bowel habits in any of the following—stool frequency or consistency, straining or sensations of incomplete evacuation—upon initiation of opioid therapy (7). This definition was later updated in 2016 with the current Rome IV criteria defining OIC as new or worsening constipation symptoms (defined as 2 or more of the 6 Rome symptoms used to define functional constipation) that develop with initiation, formulation changes, or dose escalation of opioid therapy (8). The strengths of both definitions are concessions that patients can experience signs and symptoms of constipation before the onset of opioid therapy and that the addition of opioids can worsen, or exacerbate, a prevalent disorder. Thus, ORC may develop directly as result of a new exposure to opioids (for which the term OIC would be appropriate), or worsening of baseline constipation symptoms, more accurately termed opioid-exacerbated constipation (OEC) (9). From a clinical perspective, these nuances are important to appreciate because more than 15% of the population suffers from occasional or chronic constipation unrelated to the use of opioids. Although these definitions and distinctions may seem semantic, treatment protocols can and should differ for OIC and OEC, taking into account the multifactorial pathogenesis of OEC (Figure 1). To that end, a simple diagnostic algorithm for differentiating OIC and OEC has been proposed (Figure 2).
Treatment of ORC can be complicated because it must take into account the underlying pathogenesis of an individual's constipation symptoms and history. Furthermore, there is now evidence to support the use of multiple therapeutic classes, including the US Food and Drug Administration (FDA)-approved peripherally acting μ-opioid receptor antagonists (PAMORAs), chloride C-2 (Cl-C2) channel and guanylate-cyclase-C agonists, and serotonergic agents (10). So how does one choose which therapy is most likely to benefit an individual patient with ORC? The Pain/Palliative Care and GI societies have published guidelines on the treatment of these disorders (11,12); however, these recommendations are specific to individuals with OIC. This is not surprising because all clinical trials with the aforementioned ORC therapies conducted to date have focused on OIC. There is consensus among the societies that initial interventions for OIC should use over-the-counter (OTC) agents including fiber, osmotic, and stimulant laxatives. Although evidence to support these recommendations is sparse, a recently published open-label, randomized, head-to-head study evaluating patient preferences for the OTC osmotic laxative polyethylene glycol 3350 (PEG 3350) or the PAMORA naloxegol for the treatment of OIC in individuals with chronic noncancer pain syndromes revealed an approximate 50/50 split in preference (47.9% favored PEG 3350 vs 50.4% naloxegol) (13). Furthermore, OTC interventions are inexpensive and safe—including stimulant laxatives which are historically yet inappropriately considered harmful when used chronically (14,15).
The questions that remain include what to do when OTC therapies fail, when to switch to a prescription medication, what prescription medication should be used, and should individuals with OEC be treated differently than those with OIC? The answer to the first 2 of these queries was proposed by a multisociety committee that identified the Bowel Function Index as the most accurate and validated survey for identifying clinically significant OIC (16). This simple 3-item survey uses a 0–100 visual analog scale to identify clinically significant OIC, and it has been recommended that an average score >30 be considered the threshold for initiation of prescription therapy. The answer as to which treatment to use in this situation is a bit more complicated because 3 PAMORAs (methylnaltrexone bromide, naloxegol, and naldemedine) and lubiprostone have all been FDA approved for the treatment of OIC, and there are emerging data from phase II and IIb trials supporting the use of prucalopride and linaclotide, respectively, for OIC (Table 1). Recent guideline recommendations from the American Gastroenterological Association Institute (12) may help differentiate these products (Table 2), but it is difficult to discern any differential therapeutic benefits across classes because there have been no head-to-head trials of the various prescription therapies, the populations and outcomes of the existent studies vary widely, and all these medicines appear to be more effective than placebo for the treatment of OIC. Cost and coverage may play a role because one of the challenges associated with the PAMORAs is their limited coverage and high cost. According to the website GoodRx, Medicare coverage of these medications is variable, with naloxegol covered by 75% of Medicare Part D and Advantage enrollees, methylnaltrexone covered by 44%, and naldemidine not covered by Medicare plans. Coverage from private insurers varies. Copays for the PAMORAs in the typical deductible situation range from as low as $19 to nearly $2,000 (17).
Finally, it is important that OEC be recognized and considered its own entity. Given its multifactorial nature, combating just the opioid receptor agonism component of OEC is doomed to be at best partially effective in many patients. One benefit we have as practitioners is that there are now therapeutics in our armamentarium which have been proven in rigorous evidence-based trials to target multiple etiologic mechanisms of constipation. For example, lubiprostone, FDA approved for the treatment of irritable bowel syndrome with constipation in women, chronic idiopathic constipation, and OIC, may improve symptoms in individuals with overlapping components of each of these disorders. The same could be said for linaclotide which is also approved for the former 2 conditions or prucalopride which was recently approved for chronic constipation. Thus, for successful management of ORC, the choice of treatment is predicated on discerning the underlying pathogenesis of the constipation. To this end, and based on updated data, we have revised our previously published algorithms (9,18) for the treatment of OIC and OEC (Figures 3 and 4).
ORC represents a spectrum of disorders differentiated by the onset of constipation symptoms as they relate to opioid initiation and dosing and can be functionally classified as OIC and OEC, representing 2 separate entities. These entities should be differentiated to promote optimal opportunities for adequate symptom control. Practitioners, especially those in the GI field, should be aware of these differences because initial treatment failures (especially in patients with OEC) are likely to be referred to our clinical practices.
CONFLICTS OF INTEREST
Guarantor of the article: Darren M. Brenner, MD.
Specific author contributions: D.M.B. outlined and prepared the initial and final drafts of the manuscript and tables/figures. M.B.-E. assisted with the initial draft of the manuscript. B.D.C. provided critical revision of the manuscript and tables/figures. All authors have seen and approved the final version of this article.
Financial support: D.M.B. serves as consultant, advisor, and/or speaker for Salix, Ironwood, Allergan, Shire/Takeda, Arena Pharmaceuticals, AlphaSigma, Alnylam, and Bayer Pharmaceuticals. M.B.-E. has nothing to disclose. B.D.C. serves as consultant and/or speaker for Salix, Ironwood, Allergan, Shire/Takeda, and Arena Pharmaceuticals. No external financial support was obtained in conjunction with the preparation of this article.
Potential competing interests: None to report.
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