The use of opioids to treat the pain of cancer and other advanced diseases is broadly accepted.1 Their use to treat moderate to severe chronic noncancer pain may be considered in patients whose pain is not relieved by nonopioid multimodal drugs (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, antineuropathics), physical therapy, or other interventional techniques.2 When opioid therapy is introduced, it is essential to establish treatment goals with regard to pain relief and, especially when used for the pain of non–life-threatening diseases, functional improvement, with minimal or no side effects associated with the chosen therapy.2 Initiation of opioid therapy should be entered with a clear exit strategy in the event that treatment is unsuccessful.3 Further, the lowest possible dose should be used to achieve the desired effects and tapered or terminated if clear benefit cannot be documented.2,3
The most common side effects associated with the administration of opioid therapy are gastrointestinal (GI) and include nausea, vomiting, and constipation.4–7 Opioid-induced constipation (OIC) is one of the most common and bothersome side effects associated with chronic opioid use,6,8–10 occurring in 262 of 322 patients (81%) taking daily oral opioids and laxatives in a patient survey conducted in the United States and Europe.10 In an analysis of The Oxford Pain Relief Database (1950 to 1994) and Medline, EMBASE, and the Cochrane Library (until September 2003), 15 randomized placebo-controlled trials of the World Health Organization step 3 opioids used for efficacy and safety in chronic noncancer pain were identified.11 In 8 of the randomized trials, constipation was reported as a specific adverse event in 41% of opioid-treated patients compared with 11% of placebo-treated patients, averaged over the 8 studies.11 In another survey of almost 500 patients from the United States with chronic noncancer pain, the most commonly reported OIC symptoms were a sense of incomplete bowel movements, either moderate to severe straining or abdominal discomfort/pain, and changes in stool consistency.12 Further, side effects associated with the chronic administration of opioids have the potential to limit the dose of opioid medication and result in patient discontinuation or deviation from the prescribed opioid regimen, which may lead to inadequate pain relief.7,9,10,12
Among patients with chronic noncancer pain, OIC has been found to substantially impair work productivity and health-related quality of life.9,12 Health care providers often underestimate the daily impact of OIC on quality of life and the ability of patients to manage their underlying pain condition.13 Successful treatment of OIC may both improve patient quality of life and provide a benefit in terms of reduced pain-related surgery and hospitalizations compared with a “do-nothing” strategy, in which patients reduce their analgesia to prevent OIC.14
The enteric neurons that lie within the alimentary canal provide neural regulatory input to the entire digestive tract through the production of a variety of neuroactive molecules, including acetylcholine, 5-hydroxytryptamine (5-HT), and opioid peptides (eg, met-enkephalin, β-endorphin), as all neuronal action requires some synaptic release.15 These molecules control the contraction and relaxation of the longitudinal and circular muscle layer within the GI tract.16 In addition, these molecules regulate the secretion and retention of water within the GI tract through interactions with µ-, δ-, and κ-opioid receptors, particularly the µ-opioid receptors.15 Exogenously administered opioids disrupt a number of activities within the GI tract, which leads to impairment of motility and water resorption (Fig. 1).15,16 Opioids block the release of excitatory neurotransmitters (eg, acetylcholine) resulting in the inhibition of distention-induced peristalsis while also blocking the inhibitory neurons resulting in the increased activity of GI motor neurons, elevated muscle tone, and nonpropulsive motility.15,17 Once activated by µ-opioid receptor agonists, the interstitial cell-muscle network works to inhibit gastric emptying, increases pyloric muscle tone, and delays transit through the small and large intestine.15,17 The inhibition of acetylcholine release from secretomotor neurons prevents the movement of chloride (Cl−) and water from epithelial cells into the GI tract.16 The inhibition of propulsive motility and the reduction of water moving into the colon account for the constipation caused by opioids.16
Guidelines from the American Society of Interventional Pain Physicians on the responsible use of opioids for chronic noncancer pain recommend monitoring for side effects, such as OIC, and initiating a regimen to manage these side effects (eg, use of laxatives) if necessary.2 A consensus statement from the American Academy of Pain Medicine (AAPM), which has been endorsed by the American Gastroenterological Association, has recommended that first-line treatment strategies for OIC include increased fiber and fluid intake, exercise, consideration of opioid switching, over-the-counter stool softeners, natural dietary supplements, and laxatives.18 As opioids can impact multiple regulatory systems within the GI tract, therapies that improve only some aspects of constipation (eg, osmotic laxatives that decrease water absorption from stool) may not be sufficient to alleviate OIC.8,13,18 The AAPM consensus statement recommends that the failure of first-line options to provide adequate constipation relief must be quickly determined to minimize patient distress and discomfort and expedite the consideration of prescription medications for the treatment of OIC in these patients and in those patients who score at least 30 points on the Bowel Function Index, a clinically validated tool for assessing OIC.18,19
Prescription medication for use in patients with OIC are summarized in Table 1.20–25 The first once daily oral peripherally acting µ-opioid receptor antagonist (PAMORA) approved by the Food and Drug Administration (FDA) in September 2014 for the treatment of OIC in adult patients with noncancer pain was naloxegol.26 Of the therapies listed in Table 1, methylnaltrexone is the only prescription medication available in 2 delivery formulations and for 2 indications: OIC resulting from the treatment of chronic noncancer pain (a subcutaneous injection and an oral tablet [the tablet was approved by the FDA in July 2016]) and for OIC in patients receiving opioids for active cancer (subcutaneous injection) and other advanced illnesses.20,27 Naldemedine, which is available as an oral tablet, is the most recently approved therapy (March 2017 approval).28 Originally a schedule II-controlled substance because it can be derived from opium alkaloids, the Drug Enforcement Administration descheduled naldemedine in September 2017, citing limited availability of effective therapies for OIC, its good safety profile, and nonapplicability of criteria for scheduling, due to its distinction from opioid analgesics.29 This article provides a narrative overview of current OIC therapies and therapies in development and discusses a variety of clinical concerns and challenges associated with OIC management.
PRESCRIPTION MEDICATIONS FOR THE TREATMENT OF OIC
Several phase 3 studies have evaluated the efficacy of methylnaltrexone, naloxegol, and naldemedine (PAMORAs) and lubiprostone (a chloride channel activator [ClC-2]) for the treatment of OIC in patients with chronic noncancer pain (Table 2).30–37 In addition, methylnaltrexone has been evaluated in patients with advanced medical illnesses.38–40 These therapies have either limited or no effect on central analgesia, as evidenced by patients in clinical trials reporting similar pain levels at baseline and throughout treatment.30,33–37,41,42 Further, few patients using these therapies reported the need for rescue analgesic medication or an associated increase in opioid dose.34,36,37,41,42
Because no head-to-head comparative trials between prescription medications for OIC have been conducted and outcome measures of published trials vary considerably, direct comparisons among these therapies remain difficult. A meta-analysis was conducted of placebo-controlled trials from 1947 to 2012 that evaluated the efficacy of μ-opioid receptor antagonists in adults with OIC.43 Overall, the meta-analysis demonstrated that μ-opioid receptor antagonists were more effective than placebo for the treatment of OIC with the relative risk (RR) of the failure to respond to therapy similar for patients treated with naloxone (RR, 0.64; 95% confidence interval, 0.56-0.72) and methylnaltrexone (RR, 0.67, 95% confidence interval, 0.54-0.84).43 The calculation of RR for methylnaltrexone was based on combined data from 5 randomized, controlled trials of methylnaltrexone30,39,44–46 for subcutaneous injection and 1 randomized, controlled trial of oral methylnaltrexone.32 Data for lubiprostone were limited, and naloxegol and naldemedine were not included in that meta-analysis.43 A review of randomized, placebo-controlled trials published in 2016 evaluated the use of methylnaltrexone subcutaneous injection, naloxegol, lubiprostone, prucalopride, or linaclotide in adults with OIC, chronic idiopathic constipation, and constipation-predominant irritable bowel syndrome (IBS) by conducting a medical literature search using MEDLINE and the Cochrane central register.47 The analysis of 6 trials of prescription medications for OIC in patients with advanced illness or chronic noncancer pain treated with methylnaltrexone subcutaneous injection or patients with chronic noncancer pain treated with naloxegol demonstrated that rates of persistent constipation (ie, nonresponse) did not differ significantly between patients using methylnaltrexone and naloxegol (P=0.6).47 In addition, the analysis reported that most patients remained constipated with active treatment in the 2 naloxegol trials and in 2 of the 3 methylnaltrexone subcutaneous injection trials (although only 42% of patients remained constipated with active treatment in one of the methylnaltrexone trials), and 31% remained constipated with active treatment in a trial of a benzofuran derivative, prucalopride (not currently indicated for OIC). However, in studies of these 3 prescription medications, rates of persistent constipation differed among placebo groups, which suggests that participants in some studies may have been less likely to remain constipated and underscores the danger of comparing outcomes across studies with different patient populations.47
The number needed to treat for prescription medications varies and is typically calculated based on the primary efficacy end point (Table 3).30,32–34,36,45,48,49 Time to the first spontaneous bowel movement (SBM) is another common efficacy end point that is evaluated in some studies that appears to have varying results depending on the therapy (Table 3).30,33,34,36,39,45 Results from long-term (ie, 36 to 52 wk) safety studies of OIC treatments for improvement of bowel function in patients with chronic noncancer pain are shown in Table 4.21,24,35,50
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.
1. Kurita GP, Kaasa S, Sjogren PBruera E, Higginson I, Von Gunten C. Opioid analgesics. Textbook of Palliative Medicine and Supportive Care, 2nd ed. Boca Raton, FL: CRC Press Taylor and Francis Group; 2015:395–408.
2. Manchikanti L, Abdi S, Atluri S, et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2–guidance. Pain Physician. 2012;15:S67–S116.
3. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain
—United States, 2016. JAMA. 2016;315:1624–1645.
4. Noble M, Tregear SJ, Treadwell JR, et al. Long-term opioid therapy for chronic noncancer pain: a systematic review and meta-analysis of efficacy and safety. J Pain Symptom Manage. 2008;35:214–228.
5. Manchikanti L, Fellows B, Ailinani H, et al. Therapeutic use, abuse, and nonmedical use of opioids: a ten-year perspective. Pain Physician. 2010;13:401–435.
6. Cook SF, Lanza L, Zhou X, et al. Gastrointestinal side effects in chronic opioid users: results from a population-based survey. Aliment Pharmacol Ther. 2008;27:1224–1232.
7. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11:S105–S120.
8. Pappagallo M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg. 2001;182(suppl 5A): 11S–18S.
9. Coyne KS, LoCasale RJ, Datto CJ, et al. Opioid-induced constipation
in patients with chronic noncancer pain in the USA, Canada, Germany, and the UK: descriptive analysis of baseline patient-reported outcomes and retrospective chart review. Clinicoecon Outcomes Res. 2014;6:269–281.
10. Bell TJ, Panchal SJ, Miaskowski C, et al. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med. 2009;10:35–42.
11. Kalso E, Edwards JE, Moore RA, et al. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112:372–380.
12. Rauck RL, Hong KJ, North J. Opioid-induced constipation
survey in patients with chronic noncancer pain. Pain Pract. 2017;17:329–335.
13. LoCasale RJ, Datto C, Wilson H, et al. The burden of opioid-induced constipation
: discordance between patient and health care provider reports. J Manag Care Spec Pharm. 2016;22:236–245.
14. Gupta S, Patel H, Scopel J, et al. Impact of constipation
on opioid therapy management among long-term opioid users, based on a patient survey. J Opioid Manag. 2015;11:325–338.
15. Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 2009;155:11–17.
16. Galligan JJ, Akbarali HI. Molecular physiology of enteric opioid receptors. Am J Gastroenterol Suppl. 2014;2:17–21.
17. Khademi H, Kamangar F, Brennan P, et al. Opioid therapy and its side effects: a review. Arch Iran Med. 2016;19:870–876.
18. Argoff CE, Brennan MJ, Camilleri M, et al. Consensus recommendations on initiating prescription therapies for opioid-induced constipation
. Pain Med. 2015;16:2324–2337.
19. Abramowitz L, Beziaud N, Causse C, et al. Further validation of the psychometric properties of the Bowel Function Index for evaluating opioid-induced constipation
(OIC). J Med Econ. 2013;16:1434–1441.
20. Relistor [package insert]. Bridgewater, NJ: Salix Pharmaceuticals; 2017.
21. Webster LR, Michna E, Khan A, et al. Long-term safety and efficacy of subcutaneous methylnaltrexone in patients with opioid-induced constipation
and chronic noncancer pain: a phase 3, open-label trial. Pain Med. 2017;18:1496–1504.
22. Amitiza [package insert]. Deerfield, IL: Takeda Pharmaceuticals America; 2016.
23. Movantik [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals; 2017.
24. Webster L, Chey WD, Tack J, et al. Randomised clinical trial: the long-term safety and tolerability of naloxegol in patients with pain and opioid-induced constipation
. Aliment Pharmacol Ther. 2014;40:771–779.
25. Symproic [package insert]. Florham Park, NJ: Shionogi Inc.; 2017.
26. Nektar Therapeutics. FDA approves Movantik (naloxegol) tablets for the treatment of opioid-induced constipation
in adult patients with chronic non-cancer pain [press release]. 2014. Available at: http://ir.nektar.com/news-releases/news-release-details/fda-approves-movantiktm-naloxegol-tablets-c-ii-treatment-opioid
. Accessed June 5, 2018.
27. Food and Drug Administration. NDA approval: Relistor (methylnaltrexone bromide) 150 mg tablets, NDA 208271. 2016. Available at: www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/208271Orig1s000ltr.pdf
. Accessed July 31, 2017.
28. Food and Drug Administration. NDA approval: Symproic (naldemedine), 0.2 mg tablets, NDA 208854. 2016. Available at: www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/208854Orig1s000ltr.pdf
. Accessed January 15, 2018.
29. Drug Enforcement Administration. Schedules of controlled substances: removal of naldemedine from control. Final rule. Fed Regist. 2017;82:45436–45438.
30. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid-induced constipation
in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain. 2011;12:554–562.
31. Viscusi ER, Barrett AC, Paterson C, et al. Efficacy and safety of methylnaltrexone for opioid-induced constipation
in patients with chronic noncancer pain: a placebo crossover analysis. Reg Anesth Pain Med. 2016;41:93–98.
32. Rauck R, Slatkin NE, Stambler N, et al. Randomized, double-blind trial of oral methylnaltrexone for the treatment of opioid-induced constipation
in patients with chronic noncancer pain. Pain Pract. 2016;17:820–828.
33. Cryer B, Katz S, Vallejo R, et al. A randomized study of lubiprostone for opioid-induced constipation
in patients with chronic noncancer pain. Pain Med. 2014;15:1825–1834.
34. Jamal MM, Adams AB, Jansen JP, et al. A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation
in chronic noncancer pain. Am J Gastroenterol. 2015;110:725–732.
35. Spierings EL, Rauck R, Brewer R, et al. Long-term safety and efficacy of lubiprostone in opioid-induced constipation
in patients with chronic noncancer pain. Pain Pract. 2016;16:985–993.
36. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid-induced constipation
in patients with noncancer pain. N Engl J Med. 2014;370:2387–2396.
37. Hale M, Wild J, Reddy J, et al. Naldemedine versus placebo for opioid-induced constipation
(COMPOSE-1 and COMPOSE-2): two multicentre, phase 3, double-blind, randomised, parallel-group trials. Lancet Gastroenterol Hepatol. 2017;2:555–564.
38. Bull J, Wellman CV, Israel RJ, et al. Fixed-dose subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation
: results of a randomized, placebo-controlled study and open-label extension. J Palliat Med. 2015;18:593–600.
39. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation
in advanced illness. N Engl J Med. 2008;328:2332–2343.
40. Portenoy RK, Thomas J, Moehl Boatwright ML, et al. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation
in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom Manage. 2008;35:458–468.
41. Spierings EL, Brewer RP, Rauck RL, et al. Lubiprostone for opioid-induced constipation
does not interfere with opioid analgesia in patients with chronic noncancer pain. Pain Pract. 2017;17:312–319.
42. Webster LR, Brenner DM, Barrett AC, et al. Analysis of opioid-mediated analgesia in phase III studies of methylnaltrexone for opioid-induced constipation
in patients with chronic noncancer pain. J Pain Res. 2015;8:771–780.
43. Ford AC, Brenner DM, Schoenfeld PS. Efficacy of pharmacological therapies for the treatment of opioid-induced constipation
: systematic review and meta-analysis. Am J Gastroenterol. 2013;108:1566–1574.
44. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal of constipation
due to chronic methadone use: a randomized controlled trial. JAMA. 2000;283:367–372.
45. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation
in advanced illness patients. J Support Oncol. 2009;7:39–46.
46. Anissian L, Schwartz HW, Vincent K, et al. Subcutaneous methylnaltrexone for treatment of acute opioid-induced constipation
: phase 2 study in rehabilitation after orthopedic surgery. J Hosp Med. 2012;7:67–72.
47. Sonu I, Triadafilopoulos G, Gardner JD. Persistent constipation
and abdominal adverse events with newer treatments for constipation
. BMJ Open Gastroenterol. 2016;3:e000094.
48. Nelson AD, Camilleri M. Chronic opioid induced constipation
in patients with nonmalignant pain: challenges and opportunities. Therap Adv Gastroenterol. 2015;8:206–220.
49. Holzer P. Naloxegol increases frequency of bowel movements and combats inadequate response to laxatives. Evid Based Med. 2015;20:5.
50. Webster LR, Nalamachu S, Morlion B, et al. Long-term use of naldemedine in the treatment of opioid-induced constipation
in patients with chronic non-cancer pain: a randomized, double-blind, placebo-controlled phase 3 study. Pain. 2018;159:987–994.
51. Tack J, Lappalainen J, Diva U, et al. Efficacy and safety of naloxegol in patients with opioid-induced constipation
and laxative-inadequate response. United Eur Gastroenterol J. 2015;3:471–480.
52. Nalamachu SR, Pergolizzi J, Taylor R Jr, et al. Efficacy and tolerability of subcutaneous methylnaltrexone in patients with advanced illness and opioid-induced constipation
: a responder analysis of 2 randomized, placebo-controlled trials. Pain Pract. 2015;15:564–571.
53. Mareya S, Cryer B, Losch-Beridon T, et al. Baseline characteristics associated with response to lubiprostone treatment in patients with opioid-induced constipation
[abstract 1789]. Am J Gastroenterol. 2015;110(suppl 1):S760.
54. Jamal M, Cryer BL, Losch-Beridon T, et al. Lubiprostone for treatment of opioid-induced constipation
: analysis of response by opioid class [abstract Sa2020]. Gastroenterology. 2014;146:S–356.
55. Al-Huniti N, Chapel S, Xu H, et al. Population pharmacokinetics of naloxegol in a population of 1247 healthy subjects and patients. Br J Clin Pharmacol. 2016;81:89–100.
56. Cuppoletti J, Chakrabarti J, Tewari K, et al. Methadone but not morphine inhibits lubiprostone-stimulated Cl- currents in T84 intestinal cells and recombinant human ClC-2, but not CFTR Cl- currents. Cell Biochem Biophys. 2013;66:53–63.
57. Wan Y, Corman S, Gao X, et al. Economic burden of opioid-induced constipation
among long-term opioid users with noncancer pain. Am Health Drug Benefits. 2015;8:93–102.
58. Ishihara M, Ikesue H, Matsunaga H, et al. A multi-institutional study analyzing effect of prophylactic medication for prevention of opioid-induced gastrointestinal dysfunction. Clin J Pain. 2012;28:373–381.
59. Xing JH, Soffer EE. Adverse effects of laxatives. Dis Colon Rectum. 2001;44:1201–1209.
60. US Food and Drug Administration and Center for Drug Evaluation and Research. Relistor (methylnaltrexone bromide) subcutaneous injection drug approval package: medical review. 2008. Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2008/021964s000_MedR_P1.pdf
. Accessed June 20, 2017.
61. US Food and Drug Administration and Center for Drug Evaluation and Research. Approval Package for: Amitiza. 2013. Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2013/021908Orig1s011.pdf
. Accessed June 20, 2017.
62. US Food and Drug Administration and Center for Drug Evaluation and Research. Naloxegol Medical Review. 2013. Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2014/204760Orig1s000MedR.pdf
. Accessed June 20, 2017.
63. US Food and Drug Administration and Center for Drug Evaluation and Research. Division Director Summary Review for Regulatory Action: Symproic/naldemedine. 2016. Available at: www.accessdata.fda.gov/drugsatfda_docs/nda/2017/208854Orig1s000SumR.pdf
. Accessed January 25, 2018.
64. Mackey A, Green L, Greene P, et al. Methylnaltrexone and gastrointestinal perforation. J Pain Symptom Manage. 2010;40:e1–e3.
65. Holzer P. Non-analgesic effects of opioids: management of opioid-induced constipation
by peripheral opioid receptor antagonists
: prevention or withdrawal? Curr Pharm Des. 2012;18:6010–6020.
66. Entereg [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2015.
67. Brenner DM, Chey WD. An evidence-based review of novel and emerging therapies for constipation
in patients taking opioid analgesics. Am J Gastroenterol Suppl. 2014;2:38–46.
68. Gottfridsson C, Carlson G, Lappalainen J, et al. Evaluation of the effect of Naloxegol on cardiac repolarization: a randomized, placebo- and positive-controlled crossover thorough QT/QTc study in healthy volunteers. Clin Ther. 2013;35:1876–1883.
69. Clarke T. UPDATE 2-FDA panel advises against large opioid constipation
drug safety trials. 2014. Available at: www.reuters.com/article/fda-opioid-constipation-idUSL2N0OT14X20140612
. Accessed August 29, 2017.
70. Holder RM, Rhee D. Novel oral therapies for opioid-induced bowel dysfunction in patients with chronic noncancer pain. Pharmacotherapy. 2016;36:287–299.
71. Vickery RG, Li YP, Schwertschlag U, et al. Td-1211 phase 2B study demonstrates increased bowel movement frequency and constipation
-related symptom improvement in patients with opioid induced constipation
(OIC) [abstract 899]. Gastroenterology. 2013;144:S–159.
72. Vickery R, Webster L, Li Y, et al. No evidence of analgesic interference or CNS opioid withdrawal for TD-1211 in a phase 2b study in opioid-induced constipation
(OIC) [abstract 421]. J Pain. 2013;14:S81.
73. Emmanuel AV, Kamm MA, Roy AJ, et al. Effect of a novel prokinetic drug, R093877, on gastrointestinal transit in healthy volunteers. Gut. 1998;42:511–516.
74. Prins NH, Van Haselen JF, Lefebvre RA, et al. Pharmacological characterization of 5-HT4
receptors mediating relaxation of canine isolated rectum circular smooth muscle. Br J Pharmacol. 1999;127:1431–1437.
75. Sloots CE, Rykx A, Cools M, et al. Efficacy and safety of prucalopride in patients with chronic noncancer pain suffering from opioid-induced constipation
. Dig Dis Sci. 2010;55:2912–2921.
76. Prucalopride effects on subjects with chronic non-cancer pain suffering from opioid induced constipation
(OIC) NCT01117051. 2014. Available at: https://clinicaltrials.gov/ct2/show/study/NCT01117051?view=results
. Accessed June 20, 2017.
77. Peixoto Junior AA, Teles BC, Castro EF, et al. Vincristine delays gastric emptying and gastrointestinal transit of liquid in awake rats. Braz J Med Biol Res. 2009;42:567–573.
78. Becker G, Galandi D, Blum HE. Peripherally acting opioid antagonists in the treatment of opiate-related constipation
: a systematic review. J Pain Symptom Manage. 2007;34:547–565.
79. Lin CW, McAuley JH, Macedo L, et al. Relationship between physical activity and disability in low back pain: a systematic review and meta-analysis. Pain. 2011;152:607–613.
80. Stewart AL, Greenfield S, Hays RD, et al. Functional status and well-being of patients with chronic conditions. Results from the Medical Outcomes Study. JAMA. 1989;262:907–913.
81. Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology. 2016;150:1393–1407.
82. Rosti G, Gatti A, Costantini A, et al. Opioid-related bowel dysfunction: prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment. Eur Rev Med Pharmacol Sci. 2010;14:1045–1050.
83. Freye E, Baranowski J, Latasch L. Dose-related effects of controlled release dihydrocodeine on oro-cecal transit and pupillary light reflex. A study in human volunteers. Arzneimittelforschung. 2001;51:60–66.