Comparison With Laxatives
As stated earlier, current guidelines recommend increased fluid and fiber intake and a laxative regimen with the initiation of opioid therapy.3 However, because laxatives do not address the underlying cause of OIC, constipation, and straining to pass a bowel movement may still be observed in patients receiving laxative therapy.10 Most clinical trials of newer prescription OIC treatments compare these agents to placebo, making it difficult to assess the advantage of a prescription OIC medication versus laxatives for laxative-naive patients. However, naloxegol has been shown to improve bowel function in patients with OIC who were unresponsive to ≥1 laxative.36,51 Similarly, studies have indicated that treatment of adult patients with advanced illness receiving opioids and constipated at baseline despite receiving laxatives had a positive laxation response to methynaltrexone subcutaneous injection compared with placebo.38,39
In clinical trials, the use of rescue laxatives was typically lower in patients receiving methylnaltrexone subcutaneous injection or naloxegol, compared with placebo.30,36 In contrast, lubiprostone did not significantly reduce the percentage of patients who used rescue laxatives versus placebo each month during two 3-month studies.33,34
Predictors of Response to OIC Therapy
The ability to predict a patient’s responsiveness to a specific OIC therapy would be beneficial. Although few studies have evaluated baseline or demographic factors that influence therapeutic response, those that have demonstrate no obvious impact of such factors on the overall efficacy profile for the treatment of OIC. For patients receiving opioids for both cancer and noncancer pain, the efficacy of methylnaltrexone subcutaneous injection was not substantially impacted by demographic characteristics (age, <65 vs.≥65 y; sex; primary diagnosis, cancer vs. noncancer), constipation-related distress score (≤3 vs.>3), or morphine equivalent dose (<150 vs.≥150 mg/d).52 Lubiprostone provided constipation relief for patients with chronic noncancer pain with severe and very severe straining, very hard stool consistency, absent-to-normal bowel function, and severe constipation, and for those receiving phenanthrenes (eg, oxycodone, morphine, hydrocodone) but not phenylpiperidines (eg, fentanyl) or diphenylheptanes (eg, methadone) at baseline.53,54 In an analysis of data from 2 studies of naloxegol for OIC in patients with chronic noncancer pain, the only demographic/clinical characteristics at baseline that impacted naloxegol treatment and provided a more therapeutic benefit for patients were fewer SBMs and treatment with more potent opioids.55
Two studies indicate that the type of opioid analgesic causing constipation may predict a patient’s responsiveness to lubiprostone54 or naloxegol55 and should therefore be taken into consideration when selecting an OIC therapy. Methadone, but not morphine, may inhibit the chloride secretion stimulated by lubiprostone and thereby interfere with lubiprostone’s mechanism of action.56 Accordingly, a pooled analysis of data from 3 phase 3 studies demonstrated that response rates (≥1 SBM/wk improvement over baseline SBM frequency) were significantly greater in patients treated with lubiprostone compared with those receiving placebo among those treated with phenanthrenes (eg, oxycodone, morphine, and hydrocodone), but not in patients taking diphenylheptanes (eg, methadone).54 In addition, naloxegol administration in patients taking methadone for pain has been associated with an increased risk of GI adverse events (eg, abdominal pain and diarrhea) versus patients taking other opioid analgesics with naloxegol; this difference may be related to features of opioid withdrawal that vary from drug to drug.23
The onset of action of most OIC therapies (≤1 wk for all)30,33,34,36 ensures that responsiveness should be detectable early after treatment initiation and allow for quickly switching therapies if necessary.
Additional Efficacy Considerations for Individual Prescription OIC Therapies
Beyond nonresponse, the possibility of “over-response” (diarrhea) is another key consideration when treating patients for OIC. In an analysis of 7 randomized, controlled trials of OIC prescription medications (methylnaltrexone subcutaneous injection [n=2], naloxegol [n=3], lubiprostone [n=1], and prucalopride [n=1]), the percentage of patients with diarrhea ranged from 6% to 13% with active treatment and from 2% to 6% with placebo.47 For patients who are overresponders (eg, those who develop diarrhea or intolerable abdominal distress with OIC medications), a dose reduction may prove helpful. Because these agents are likely producing a limited opioid withdrawal response within the GI tract, it follows that doses might be titrated to mitigate the response to peripheral opioid receptor antagonism.
The cost of prescription medications for the treatment of OIC can be substantial (Table 1), but the cost burden of hospitalization resulting from OIC should also be considered when weighing the costs and benefits of prescription OIC therapies. Patients with OIC are more likely to be hospitalized than patients without OIC (33% vs. 20% in the nonelderly; 51% vs. 31% in the elderly; P<0.001 for both), have longer mean (SD) hospital length of stay (3.0 [8.4] vs. 1.0 [3.0] d in the nonelderly; 5.2 [12.2] vs. 2.1 [4.0] d in the elderly; P<0.001 for both), and higher total health care costs ($23,631 [$67,209] vs. $12,652 [$19,717] in the elderly; $16,923 [$38,191] vs. $11,117 [$19,525] in the nonelderly; P<0.05 for both).57
SAFETY OF APPROVED PRESCRIPTION OIC TREATMENTS
Although laxatives are considered safe and commonly prescribed by physicians to patients who are receiving long-term opioid treatment,9,58,59 they do not treat the underlying cause of OIC10 and are associated with side effects such as flatulence, nausea, vomiting, diarrhea, and abdominal pain. In addition, laxatives may disrupt mineral metabolism (patients using these products may develop hypermagnesemia, hyperphosphatemia, hypercalcemia, or hypernatremia) and elicit enteric changes, such as neuron loss and lumen dilation in susceptible patients.59
Overall, integrated safety summaries have most commonly reported GI-related adverse events such as nausea, diarrhea, abdominal pain, or distention for prescription therapies to treat OIC (Table 5).60–63 For naloxegol, a trend for an increased incidence of adverse events was reported in patients treated with higher doses;62 therefore, at the discretion of the prescribing clinician, the lower dose formulation (12.5 mg) might be considered for patients who are unable to tolerate the 25-mg dose.23 Patients treated with lubiprostone reported nausea as the most common GI-related adverse event (14.4%);61 eating may help minimize nausea.22 The majority of the adverse events experienced with all of these OIC therapies were mild to moderate in severity.60–63
Additional clinical data analyzed after drug approval have brought to light adverse events that have prompted label changes to specific OIC therapies. The occurrence of dyspnea in patients treated with lubiprostone after drug approval and during clinical trials for chronic idiopathic constipation and constipation-predominant IBS prompted the addition of dyspnea to the Warnings and Precautions section of the label.22 The incidence of dyspnea in trials of lubiprostone for OIC was 1%, which is lower than that reported for lubiprostone 24 µg twice daily (BID) in trials for chronic idiopathic constipation (3%).22
During safety monitoring for methylnaltrexone following drug approval, perforation of the GI tract was reported in patients with OIC, advanced illness, and conditions impacting the structural integrity of the GI tract lining after they received methylnaltrexone subcutaneous injection.20 Between April 2008 and October 2009, 7 bowel perforation incidents were reported in patients with pathologic or anatomical abnormalities of the GI tract; only 1 of these cases was thought to be related to methylnaltrexone subcutaneous injection.64 Opioid withdrawal symptoms have also been documented in patients treated with methylnaltrexone subcutaneous injection following approval.20 It was suggested that the intermittent (ie, once every other day [QOD]) use of methylnaltrexone, which is the recommended regimen for adults with advanced illness,20 may have precipitated withdrawal symptoms within the GI tract and predisposed the patient to GI perforation.65 However, no such evidence of withdrawal symptoms has been observed in clinical trials of patients with chronic noncancer pain.42 Disruptions to the blood-brain barrier may also increase the risk of opioid withdrawal.20 For patients with altered GI integrity (eg, Crohn’s disease), a careful assessment of the potential risk: benefit profile of methylnaltrexone, naloxegol, and naldemedine is critical, with the label containing warnings with regard to GI perforation and opioid withdrawal and advising clinicians to consider the risk: benefit profile in patients at risk for these events, since both GI perforation and opioid withdrawal are considered class effects.20,23,25
The potential for cardiac adverse events with PAMORAs was raised after an imbalance in the number of myocardial infarctions and severe cardiovascular (CV) events was observed in patients with OIC who received alvimopan BID compared with rates of these events for patients receiving placebo.66,67 Alvimopan is a peripherally selective opioid receptor antagonist that has been approved for the acceleration of the time to upper and lower GI recovery after surgeries that include partial bowel resection and primary anastomosis.66 No apparent CV safety signal was observed with methylnaltrexone injection or oral tablet in clinical or postmarketing data.20 Moreover, the evaluation of preclinical, electrocardiogram, thorough QT, vital sign, and major cardiac adverse events outcomes with naloxegol demonstrated no definitive CV safety signal.62,68 Long-term studies of naloxegol, methynaltrexone, and naldemedine (each ≥48 wk in duration) were conducted in patients with OIC and noncancer pain.21,24,50 All 3 studies revealed no new safety signals. Adverse events were mostly GI related, consistent with the mechanism of action of these PAMORAs.21,24,50 Overall, however, additional long-term safety data from clinical studies and postmarketing surveillance for these drugs are lacking.
In 2014, after review of the cardiac safety data from several PAMORAs, the Anesthetic and Analgesic Drug Products Advisory Committee agreed that the CV safety raised with alvimopan was not class specific and recommended that large-scale clinical trials to evaluate CV concerns of other related drugs were not required and could be assessed during postmarket observational studies.69 Although alvimopan was developed for the treatment of patients with both OIC and postoperative ileus, this opioid antagonist ultimately received FDA approval only for the short-term treatment of ileus in hospitalized patients. Alvimopan studies in patients with OIC had a numerical imbalance in the occurrence of CV adverse events resulting in regulatory authorities to recommend large-scale safety studies for long-term use of this drug class. Alvimopan clinical studies conducted in patients with OIC used lower doses compared with those used in patients with postoperative ileus (eg, 0.5 vs. 12 mg BID for up to 7 d, respectively). Currently, alvimopan is still only available, under a Risk Evaluation and Mitigation Strategy, as short-term therapy for the indicated treatment of ileus in hospitalized patients.66,67
In a 9-month open-label study of the safety and efficacy of lubiprostone conducted in patients with chronic noncancer pain, the most common treatment-related adverse events included nausea and diarrhea and were consistent with the preceding 12-week studies.35 All serious adverse events were unrelated to treatment and therefore did not raise any serious safety concerns.35 Long-term safety information on the label for lubiprostone has remained the same since its approval in 2008, suggesting consistent safety data since product approval.70
Potential drug-drug interactions and restrictions with regard to use in specific patient populations are important considerations in initiating treatment with OIC therapies. Concomitant use of methylnaltrexone, naloxegol, or naldemedine with other opioid antagonists should be avoided because of the possibility of additive effects and increased risk of opioid withdrawal.20,23,25 Concomitant use of moderate and strong CYP3A4 inhibitors may increase plasma concentrations of naloxegol and naldemedine and increase the risk of adverse events, while strong CYP3A4 inducers may decrease concentrations of naloxegol and naldemedine and thereby negatively affect their efficacy.23,25 In vitro, methylnaltrexone does not significantly inhibit or induce the activity of cytochrome P450 isozymes CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A4, nor is it a substrate for these isozymes.20 Methadone and other diphenylheptane opioids may interfere with the efficacy of lubiprostone.22 Patients treated with naldemedine and P-gp inhibitors such as cyclosporine may have elevated plasma naldemedine concentrations and should be monitored for naldemedine-related adverse reactions.25 Treatment with methylnaltrexone is not recommended for use in women who are nursing, lubiprostone should be used with caution in women who are nursing, and methylnaltrexone, naloxegol, and naldemedine may cause opioid withdrawal in a fetus.20,22,23,25 However, naloxegol and naldemedine may be used in nursing mothers depending on a risk: benefit assessment.23,25 Naloxegol and naldemedine should be avoided in patients with severe liver impairment.23,25
THERAPIES IN DEVELOPMENT FOR TREATMENT OF OIC
Axelopran (TD-1211) is a peripherally selective, multivalent µ-opioid receptor antagonist. Presentation of a 5-week, double-blind, phase 2B study conducted in patients with chronic noncancer pain treated with 3 formulations of TD-1211 for OIC demonstrated significant improvements from baseline in weekly average complete SBMs (CSBMs) during weeks 2 through 5, compared with patients receiving placebo (2.5 complete CSBMs/wk with 15 mg TD-1211, P=0.0003; 2.6 CSBMs/wk with 10 mg TD-1211, P=0.001; and 1.5 CSBMs/wk with 5 mg TD-1211, P=0.04, vs. 0.8 CSBM/wk with placebo).71 The most common adverse events associated with TD-1211 treatment included abdominal pain (13%), nausea (9%), and diarrhea (9%).71 There were no indications of opioid withdrawal effects or reductions in opioid analgesia in patients treated with TD-1211.71,72
The benzofuran derivative prucalopride (R093877) is a highly selective serotonin 5-HT4 receptor agonist with strong GI prokinetic activity.73,74 The efficacy and safety of prucalopride for the treatment of OIC in patients with chronic noncancer pain was demonstrated in a phase 2, randomized, double-blind, placebo-controlled study.75 A phase 3 study of prucalopride in patients with chronic noncancer pain and OIC was terminated early when the clinical development program for prucalopride was stopped based on a business priority decision.75,76
CLINICAL CONSIDERATIONS FOR THE TREATMENT OF OIC
Constipation can have a variety of origins, including underlying functional disorders (eg, IBS, evacuation disorders), neurologic, endocrine, metabolic, myopathic disorders, mechanical obstruction, or malignancy.67 In addition, some chemotherapeutic agents (eg, vinca alkaloids) may reduce bowel motility.77 Constipation is often multifactorial in patients receiving opioid therapy (eg, those with malignancy).78 Chronic pain may lead to poor functional status and diminished activity.79,80 Hence, evaluation and treatment of constipation should include a multidimensional approach targeting all suspected causes. Clinical evaluation of a patient with suspected OIC includes a careful clinical history, physical examination, and diagnostic tests only as clinically indicated (eg, complete blood count, complete metabolic profile, thyroid-stimulating hormone, serum calcium).81 An etiology other than OIC should be considered if a patient has a history of constipation and the onset of or exacerbation of the symptoms of constipation are not closely associated with the initiation of opioid therapy.67
Revision of the diagnostic criteria for functional bowel disorders by the gastroenterology community has resulted in the addition of OIC as a new category of GI disorder.81 OIC is defined as a change from baseline bowel habits and defecation patterns that occurs when initiating opioid therapy and is associated with reduced bowel frequency, the development or exacerbation of straining, a sensation of incomplete evacuation, and/or patient distress related to bowel habits. The diagnosis of OIC requires new or worsening symptoms of constipation that occur when initiating, switching, or increasing the dosage of opioid therapy and that include at least 2 of the following signs and symptoms: (1) straining during >25% of defecations, (2) lumpy or hard stools involving >25% of defecations, (3) sensation of incomplete evacuation involving >25% of defecations, (4) sensation of anorectal obstruction or blockage affecting >25% of defecations, (5) the need for manual maneuvers to facilitate >25% of evacuations, or (6) fewer than 3 SBMs/wk.81 Loose stools should rarely occur unless the patient is using laxatives.
Treatments that do not influence opioid-related mechanisms (eg, laxatives, increased fiber in the diet) may provide insufficient relief for patients with OIC. However, such treatments should nonetheless be considered, both as first-line therapy and as adjunctive strategies for those taking prescription medications. Ensuring that patients are adequately hydrated and maintaining a healthy diet is also important for OIC treatment. It should additionally be considered that constipation is often multifactorial, and factors beyond opioid effects may contribute to the clinical picture. Thus, patients with OIC will often require a comprehensive treatment plan rather than a single-drug approach.
The balance of opioid-related side effects (including constipation) may vary with the specific opioid administered (Fig. 2).6,82 Each individual patient may have a different adverse event profile response to the efficacy profile of the opioid administered, which may impact the development of opioid-related side effects, such as OIC. Consensus recommendations from the AAPM advocate for physicians to consider switching opioids before initiating prescription medication for OIC.18 However, in this author’s experience, the majority of patients who develop OIC do so for all opioid medications. When prophylactic laxatives and conservative therapies do not work, reduction or elimination might be the best remaining therapies. In all cases, medical professionals should implement multimodal analgesic strategies to reduce the need for opioids, and patients should be titrated to the lowest effective opioid dose. Published results, however, do not indicate that there is a dose-response relationship between OIC and opioid dose, and many patients experiencing OIC continue to experience it even following dose titration to a lower opioid dose.83
To achieve an optimal effect, patients must show willingness to adhere to their prescribed OIC therapy. Therefore, patient preferences with regard to the mode of administration (subcutaneous vs. oral) and daily dosing required (QD vs. BID) should be considered. Prescription medications for OIC are available as oral formulations, and a subcutaneous formulation of methylnaltrexone is also available (Table 1). Methylnaltrexone injection and oral tablet20 and naloxegol23 are available as QD formulations and lubiprostone22 is available as BID formulations. Further, the patient experience with constipation may vary over time. It is highly recommended that patients receiving opioid therapy are assessed regularly by medical professionals for the occurrence of opioid-related adverse events, including constipation, such that the risk: benefit profile of the medication can be established.
OIC is prevalent in patients receiving long-term administration of opioid analgesics. Laxatives are often insufficient to alleviate OIC because they do not affect the underlying disruption of GI motility and water retention produced by opioid analgesics. Several PAMORAs (eg, methylnaltrexone [injection and oral tablet], naloxegol, and naldemedine) and a ClC-2 activator (eg, lubiprostone) are available in the United States for the management of OIC. Most of these agents may improve constipation within days of treatment initiation. GI-related adverse events are common with these medications but do not usually necessitate discontinuation, especially with proper dose adjustment. Opioid withdrawal symptoms are generally rare. Health care providers should be aware of the probability of OIC in patients receiving opioid analgesics and monitor constipation-related symptoms in these patients to optimize pain management and improve patient quality of life.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
chronic pain; constipation; μ-opioid receptor; opioid receptor antagonists