Opioid-Induced Constipation: Considerations for Formulary Decision Makers

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The American Journal of Pharmacy Benefits, May/June 2015, Volume 7, Issue 3

This activity reviews the incidence and impact of opioid-induced constipation (OIC), discusses available treatment options, and what factors should be considered during formulary decisions for OIC.

Overview

While opioids are useful in managing and treating moderate and severe pain, this article will focus on chronic pain, which is a frequently occurring symptom in many medical conditions and is considered the most common cause of long-term disability.1,2 According to a report from the Institute of Medicine of the National Academies, chronic pain affects an estimated 100 million adults in the United States.3 Opioids are among the most commonly prescribed analgesics for pain related to cancer, and for moderate to severe acute and chronic non-cancer pain.4,5 Over the past 2 decades, the use of opioids has escalated due to a number of factors, including the recognition by healthcare providers that opioids often serve as an alternative for patients who have failed to respond to other pharmacological therapies for chronic pain. Additionally, there is a deficit of readily available, comparable, and efficacious alternative treatment options.6 Currently, an estimated 3% of adults in the United States are receiving long-term opioid therapy for chronic non-cancer pain, and nearly 250 million opioid prescriptions are dispensed annually.1,7 The percentage of patients receiving opioid prescriptions for pain-related conditions increased from 23% in 1993 to 37% in 2005, and a Journal of Pain study indicates that the total estimated costs associated with pain range from $560 billion to $635 billion annually.7,8

While opioids are often prescribed for treating chronic pain when other analgesics fail to provide sufficient pain control, common adverse effects such as sedation, gastrointestinal (GI) effects (ie, nausea, vomiting and constipation), and respiratory depression may sometimes affect opioids’ therapeutic pain-relief value; the adverse GI effects potentially undermine their clinical use.9 Opioid-induced constipation (OIC) is one of the most frequent and cumbersome adverse events associated with opioid therapy.10-12 OIC has been associated with increased use of healthcare resources and increased healthcare costs, as well as decreased quality of life for patients.13 Not only can OIC negatively impact an individual’s overall quality of life, but it can result in formation

of hemorrhoids, rectal pain and burning, bowel obstruction, bowel rupture, and death.9

The prevalence of constipation is probably the most studied adverse effect in opioid-treated patients.14 Results from a meta-analysis in 2004 found that in randomized controlled trials of non-cancer patients receiving opioids for moderate to severe pain, 41% experienced constipation; in individual studies, the figure ranged from 14% to 90%.14 Explanations for the large discrepancy in percentages may be attributed to the various definitions of constipation, such as the number of bowel movements per week or the degree of constipation-related discomfort.15,16 Additionally, it can be difficult to estimate the prevalence of constipation caused by opioid therapy, because patients may be responding to other potential causes, such as the use of other pharmacological agents, other medical conditions, and lifestyle and dietary habits.15

In a recent study of ambulatory patients with moderate to severe chronic non-cancer pain on opioid therapy for a median of 1 year, 47% reported constipation, 27% reported nausea, and 9% reported vomiting.16 The incidence of OIC is often underestimated, underassessed, and under-treated by many healthcare professionals. Consequently, some patients attempt to manage OIC on their own, not even mentioning it to their primary healthcare provider.17 Unfortunately, self-treatment is typically ineffective, because patients usually do not understand the mechanism causing the constipation.17 Moreover, tolerance of OIC does not develop over time, thus leaving patients to deal with its continued presence for the duration of their opioid pharmacotherapy.17

If OIC is not effectively treated, patients may be at risk for bowel dysfunction and further complications such as fecal impaction, pseudo-obstruction of the bowel, inadequate absorption of drugs, and incontinence.18,19 Since patients treated with opioids for non-cancer pain frequently suffer from OIC symptoms, it is not uncommon for OIC to limit their work productivity, affect their performance of other day-to-day activities, and significantly impact their overall health-related quality of life.20, 21 One study of work productivity in patients on chronic opioid therapy found that because of OIC, 9% of patients reported missed work time, another 32% reported impairment while on the job (equivalent to an estimated 14 hours of lost productivity per week), and 38% reported activity impairment.22 Participants in this study also reported that OIC interfered with their opioid medication’s ability to control their pain; 49% reported moderate or complete interference, and 8% reported that they changed how they took their opioid to attempt to resolve the constipation.22

In another study, Bell et al reported that approximately one-third of patients changed their dosing regimen in response to the adverse effects of opioid medication.20 Twenty-eight percent used lower opioid doses, and 33% skipped, decreased, or eliminated doses to ease constipation. These alterations in the opioid regimen resulted in increased pain in 92% of patients.20

A recent study suggested that some physicians are not aware of the negative effect of OIC on their patients, nor of the self-treatment measures that many patients attempt to find relief from this often devastating and debilitating adverse effect.23 The study also revealed a possible discon-nect between how prescribers and patients perceive the impact of OIC and the effectiveness of laxative therapy.23

Unfortunately, the significant burden of OIC on chronic pain patients leads some to halt their opioid therapy.24 While current management of OIC can include laxatives considered by some clinicians to be partially effective and a therapy to which some patients respond well—laxatives do not treat the underlying cause of OIC.24 Fortunately, newer therapies are emerging that target the underlying cause of OIC by acting specifically and locally within the GI tract and targeting mechanisms impacted by opioids.24 Clinicians should have a thorough understanding of OIC and employ aggressive prevention and early treatments for OIC to optimize pain control when opioids are used. Moreover, increased understanding of OIC will result in enhanced patient care by providing early diagnosis; improving the patient’s quality of life; and increasing the likelihood of adherence to opioid therapy with fewer complications.24

Pharmacists are an essential resource for patients suffering from OIC. They are integral to the healthcare team and are in a pivotal position to identify the signs and symptoms of OIC and recognize when uncontrolled pain may be due to lack of patient compliance. They can make clinical recommendations regarding pharmacological agents that can effectively prevent, manage, and treat OIC.

Pathophysiology of OIC

It is vital for clinicians to know the pathophysiology of OIC so they can understand and recognize OIC’s symptoms and select appropriate preventive and/or management measures. Multiple mechanisms influence the development of OIC in fact, the very mechanisms that enable opioids to provide analgesia are also involved in causing OIC.9

Opioid receptors are located in the mucosa and mysenteric plexus of the ileum and colon.25 Activation of these opioid receptors in the bowel has numerous effects that lead to constipation, including slowing of the intrinsic propulsive movement in the colon; augmenting nonpropulsive motility, segmentation, and tone; increased tone in the pylorus and ileocecal sphincter; decreased fluid secretion in the small bowel; and increased water absorption by the colon.25,26

Opioids also contribute to reduced bowel motility by decreasing the release of acetylcholine, resulting in a reduction in parasympathetic activity.25 All these opioid effects result in decreased fluid content in the stool and bowel movement, leading to decreased stool volume, causing symptoms of straining on defecation, prolonged duration of bowel movements, and abdominal pain.25,26

Assessment and Diagnosis of OIC

While there is no standard definition of OIC, the American College of Gastroenterology defines constipation as unsatisfactory defecation characterized by infrequent stools, difficult stool passage, or both.27,28 Moreover, difficult stool passage, according to this definition, includes straining, a sense of difficulty passing stool, incomplete evacuation, hard/lumpy stools, prolonged time to stool, and/or the need for manual maneuvers to pass stool.27,28 Moreover, the Rome III criteria for functional constipation requires 2 or more of the following in at least 25% of bowel movements: straining; lumpy or hard stools; sensation of incomplete evacuation; sensation of anorectal obstruc-tion; manual maneuvers to facilitate defecation; and/or <3 bowel movements/week.28,29 In addition, loose stools should rarely present without laxatives, and the criteria must be fulfilled for the last 12 weeks, although the 12-week requirement may be inappropriate in patients who are taking short-term opioids.28,29 Although these criteria are not specific to OIC, they are commonly applied to these patients.28,29 In a 2015 publication in the Journal of Clinical Gastroenterology, Gaertner et al proposed a definition of OIC as a change, when initiating opioid therapy, from baseline bowel habits, defecation patterns, and what patients would perceive as abnormal that is characterized by any of the following criteria: decrease of spontaneous (in contrast to induced) bowel movements, beginning or worsening of straining, having a sense of incomplete rectal evacuation, and reporting harder stool consistency.12

If patients taking opioids present with complaints of constipation, the probable cause is opioid-induced. However, when assessing patients, it is imperative for clinicians to exclude other potential causes before selecting a potential therapy to manage and treat the constipation. Clinicians should: obtain a complete medical history to ascertain when the constipation started relative to the initiation of the opioid therapy; complete a review of medical and medication history; evaluate diet and lifestyle habits; ascertain bowel patterns, including straining, occurrence, and consistency of stool; and determine the presence of abdominal symptoms, such as bloating, discomfort, and pain.28

Clinicians can assess the severity of symptoms in patients with OIC by using various tools such as the Patient Assessment of Constipation Symptoms (PAC-SYM), the Bowel Function Index, and the Bristol Stool Chart, as well as conducting a physical examination when warranted and ordering diagnostic imaging tests to rule out bowel has been reported to correlate with treatment response in prospective studies for evaluating the use of prucalopride in OIC, such as the study conducted by Sloots et al who used the PAC-SYM to assess patients.31 This assessment was based on interviews of patients with chronic constipation, not opioid-induced, and it also required a prolonged 14-day recall period, which may be susceptible to recall bias.28 Clinicians may also assess patients using the Bowel Function Index (BFI), a simple, 3-item, clinician-administered questionnaire designed to evaluate OIC in cancer and non-cancer chronic pain patients.28 Each of the 3 items include ease of defecation, feeling of incomplete bowel evacuation, and personal judgment of constipation, each evaluated on a 0-to-100 numerical rating scale, where 0 indicates no problem and 100 indicates the most severe problem.28 Correlations between each item of the BFI and total scores to stool frequency are statistically significant.28 A BFI score change of at least 12 points is reported to represent a clinically consequential change in constipation.28 This clinician-administered tool allows easy assessment of OIC from the patient’s perspective.28 Clinicians may also utilize the Bristol Stool Chart, which enables patients to identify their stool form using 7 different images plus a written description of stool types.32

Management of OIC: Overview of Nonpharmacologic and Pharmacologic Therapy

The increase in chronic opioid use and the assessment, management, and treatment of patients with OIC is becoming a significant clinical challenge for many healthcare providers. Clinicians should emphasize the importance of aggressive prevention and early treatment of OIC to optimize pain control when opioids are used. It is especially imperative for pharmacists to be informed about the most effective treat-ment approach for managing OIC to increase the likelihood of optimal patient outcomes. Unfortunately, while numerous potential treatment options are available for constipation, only a few have been demonstrated to be more effective than placebo in managing and treating OIC.33

Many traditional treatments employed to manage and treat “typical” (or functional) constipation are often ini-tially utilized to treat OIC,9,21 including stool softeners, hydrating agents/lubricants, and laxatives such as stimu-lants.21 Bulk-forming laxatives such as psyllium are not recommended for OIC because opioids prevent peristalsis and the increased fiber may increase the chances of bowel obstruction and potential impaction.9 Results from surveys of patients with OIC suggest extensive dissatisfaction with over-the-counter remedies.9,21 Stimulant laxatives are often used as first-line therapy due to their low cost and efficacy, although they do not correct the underlying mechanism associated with OIC.9,21

In general, the management and treatment of OIC requires both nonpharmacological and pharmacological measures.9 Results from various clinical studies demonstrate that the implementation of nonpharmacological measures alone, such as increasing dietary fiber intake, fluid intake, and physical activity, seldom effectively treat OIC symptoms.9,33 The current consensus is that treatment with traditional laxatives should be initiated with the opioid therapy and continue throughout treatment. Some patients are effectively managed that way.9,21 Others are not, however, because use of traditional laxatives may prove difficult for some patients, as these agents do not target the principal cause of OIC: opioid binding to the receptors in the enteric system.34 In addition, opioid treatment stimulates enteric opioid receptors, thus affecting neuronal activity across the entire GI tract.34-36 Most commonly used laxatives aid defecation mainly via localized effects in the colon. Moreover, large-scale studies report that many patients taking opioids still suffer from OIC despite using laxatives, and more than 50% of patients treated with laxatives do not achieve their desired result.36 Hence, although laxatives are routinely prescribed to address OIC, Brenner et al state that the use of stool softeners, osmotic laxatives, and stimulant laxatives are considered ineffective in more than 50% of patients.35 Additionally, no available clinical evidence exists to recommend one laxative agent over another, and no consensus exists on which laxative, if any, is most appropriate for managing OIC.37-40 Ruston et al investigated whether docusate sodium, sennosides, and lactulose have equal efficacy and adverse effect profiles compared with polyethylene glycol (PEG) in the manage-ment of OIC in adults, and their study concluded that there was insufficient evidence to compare docusate sodium, sennasides, lactulose, and PEG in patients with OIC.41

Pharmacological Agents

The failure of lifestyle modification and aggressive laxative therapy to treat OIC symptoms has fortunately led to the development of several FDA-approved novel therapies to effectively manage and treat OIC.21 Therapies used for OIC include opioid antagonists: oral naloxone, classified as a competitive opioid receptor antagonist; lubiprostone, a chloride channel activator; and peripherally acting mu (μ)-opioid receptor antagonists (PAMORAs), marketed as methylnaltrexone bromide and naloxegol.21

Oral Naloxone

Studies have shown that single large doses of oral naloxone can be efficacious in reversing OIC; however, due to the very narrow therapeutic index of oral naloxone, it often causes the unwanted adverse effect of analgesia reversal.27,42 Because of the significant risk of decreasing the analgesic efficacy of the opioids, many experts recommend using an agent that does not cross the blood-brain barrier.27,42

Lubiprostone

In April 2013, the FDA approved lubiprostone (Amitiza) as the first oral treatment for OIC in adults with chronic non-cancer pain. Lubiprostone was first approved by the FDA in 2006 for the treatment of chronic idiopathic constipation.43,44 In 2008, lubiprostone received FDA approval for another indication, the treatment of irritable bowel syndrome (IBS) with constipation in women 18 years or older, making it the first drug available in the United States for IBS with constipation.43,45 This agent is classified as a selective type 2 chloride channel activator that enhances a chloride-rich intestinal fluid secretion without altering sodium and potassium concentrations in the serum.43,45 Lubiprostone specifically activates CIC-2, a normal constituent of the apical membrane of the human intestine, in a protein kinase A-independent fashion.46 By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, thereby facilitating the passage of stool and alleviating symptoms associated with OIC.46 Through its activation of apical CIC-2 channels in intestinal epithelial cells, lubi-prostone bypasses the antisecretory action of opiates that results from suppression of secretomotor neuron excitability.46 The activation of CIC-2 by lubiprostone has also been shown, in ex vivo studies of ischemic porcine intestine, to stimulate recovery of mucosal barrier function and to reduce intestinal permeability via the restoration of tight junction protein complexes.46 The recommended dosing is 24 mcg twice daily and capsules should be taken with food and water, swallowed whole, and not be broken apart or chewed. The dosage should be reduced in patients with moderate or severe hepatic impairment.46

The most common adverse reactions associated with the use of this agent include nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence, as well as dyspnea within an hour of the first dose. Use is contraindicated in patients with known or suspected mechanical GI obstruction.46 The drug’s efficacy in patients taking diphenylheptane opioids, such as methadone, has not been established.46

Marciniak et al investigated the efficacy of lubiprostone compared with senna on bowel symptoms and constipation in postoperative orthopedic patients treated with opioids.47 The study concluded that both lubiprostone and senna improved constipation-related symptoms and quality of life in patients with OIC, with no significant differences between groups.47

Cryer et al evaluated the efficacy and safety of oral lubiprostone for relieving symptoms of OIC in patients with chronic non-cancer pain in a randomized, double-blind, placebo-controlled trial, concluding that lubiprostone effectively relieved OIC and associated signs and symptoms and was well tolerated in those patients.48

A recent meta-analysis concluded that the limited data existing for lubiprostone means that more trials are required before a definitive recommendation can be made on its use in OIC.49

Methylnaltrexone

In 2008, methylnaltrexone subcutaneous injection was approved by the FDA for the treatment of OIC in patients with advanced illness receiving palliative care, when the response to laxative therapy has not been sufficient.50 Most recently, in September 2014, the FDA approved methylnaltrexone bromide subcutaneous injection (Relistor), 12 mg/0.6 mL, for the treatment of OIC in patients taking opioids for chronic non-cancer pain, making subcutaneous methylnaltrexone bromide the first clinically available peripherally acting opioid antagonist.21,51,52 Methylnaltrexone bromide is classified as a selective antagonist at the mu receptor that poorly crosses the blood-brain barrier. It acts as an antagonist in the gastrointestinal tract, decreasing opioids’ constipating effects without undermining centrally mediated analgesia.9,33

In a study, Baker reported that methylnaltrexone appears effective in the therapy of OIC and will be useful for patients failing to respond to traditional laxative regi-mens.53 Nalamachu et al evaluated the efficacy of subcutaneous methylnaltrexone in treating OIC and reported that it is effective and well tolerated.54

The usual dose schedule is once every other day as needed, but no more than once in a 24-hour period; dosage is based upon patient weight.52 Methylnaltrexone bromide is contraindicated in the presence of known or suspected mechanical GI obstruction.52 Furthermore, patients with localized or diffuse reduction in the structural integrity of the GI tract wall such as that associated with cancer or peptic ulcer have developed severe adverse effects, including GI perforation, while taking methylnal-trexone bromide.52 The most common adverse reactions reported with methylnaltrexone compared with placebo in clinical trials were abdominal pain, flatulence, nausea, dizziness, diarrhea, and hyperhidrosis. No known drug interactions are associated with this agent at this time.52

Naloxegol

On September 16, 2014, the FDA approved the opioid antagonist naloxegol (Movantik), a polyethylene glycol (PEG)ylated form of naloxone. Classified as a PAMORA, it inhibits opioid binding in μ-opioid receptors in the gastrointestinal tract.55 It is indicated as the first orally ad-ministered, once-daily PAMORA for OIC in patients with chronic non-cancer pain.21,55 When administered at recommended dose levels, naloxegol functions as a peripherally acting μ-opioid receptor antagonist in tissues such as the GI tract, thereby decreasing the constipating effects of opioids.56 Naloxegol binds to μ-opiate receptors in the gastrointestinal tract, preventing opioids from attaching to them, which prevents the GI slowing and constipation that typically occur with opioid use.56

In patients receiving naloxegol, clinicians should monitor for symptoms consistent with opioid withdrawal, which can include hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.56 The recommend-ed dosage is 25 mg once daily, in the morning. If patients are unable to tolerate that dose of naloxegol, it should be reduced to 12.5 mg once daily. Patients with a creatinine clearance of <60 mL/min should start at a dosage of 12.5 mg once daily, and if they tolerate that amount, increase to 25 mg once daily.57 Naloxegol should be taken on an emp-ty stomach at least 1 hour prior to the first meal of the day or 2 hours after the meal. Grapefruit and grapefruit juice should not be consumed during naloxegol therapy.56,58

Clinical studies report that naloxegol has been shown to be efficacious in patients who have taken opioids for at least 4 weeks.58 Patients should discontinue all maintenance laxative therapies prior to initiating the medication; laxatives may be continued if a suboptimal response is observed after 3 days.58 No alteration in analgesia is required prior to initiating naloxegol. The most common adverse effects are abdominal pain, diarrhea, nausea, flatulence, vomiting, and headache.58

The use of naloxegol is contraindicated in patients with known or suspected GI obstruction and in patients at increased risk of recurrent obstruction, due to the potential for GI perforation.58 In addition, its use is also contraindicated in patients concomitantly using strong CYP3A4 inhibitors, because these agents significantly increase exposure to naloxegol, which may precipitate opioid withdrawal symptoms; and in those patients who have had a known serious or severe hypersensitivity reaction to naloxegol.58

Garnock-Jones reports that naloxegol demonstrated clinical efficacy and was well tolerated in placebo-con-trolled trials in patients with non-cancer pain and OIC, including those with an inadequate response to laxatives, and was well tolerated in a long-term safety study.59 As a (PEG)ylated naloxone derivative, naloxegol is associated with improvements in spontaneous bowel movements, while maintaining levels of opioid-related analgesia due to its reduced ability to cross the blood-brain barrier.59

Chey et al investigated the efficacy and safety of naloxegol for the management and treatment of OIC, finding that response rates were considerably better with 25 mg of naloxegol than with placebo.60 The study concluded that treatment with naloxegol, compared with placebo, re-sulted in an improved rate of treatment response without decreasing opioidmediated analgesia.60

Leonard et al reported in their study that naloxegol was shown to be effective for increasing the average weekly number of spontaneous bowel movements (SBMs) in a single phase 2 trial that enrolled 208 patients.61 Patients taking naloxegol 25 mg had a mean of at least 3 bowel movements per week, an improvement over the placebo group.61

In another study, Webster et al evaluated the long-term safety and tolerability of naloxegol in patients with non-cancer pain and OIC.62 It was a 52-week, multi-center, open-label, randomized, parallel-group phase 3 study conducted with outpatients taking 30 to 1000 morphine-equivalent units per day for ≥4 weeks.62 Patients were randomized 2:1 to receive naloxegol 25 mg/day or investigator-chosen laxative regimen treatment for OIC. The researchers concluded that in patients with non-cancer pain and OIC, naloxegol 25 mg/day for up to 52 weeks was safe and well tolerated.62

Currently, several other PAMORA medications are in clinical trials, with anticipated results for these agents expected in 2015 and 2016, and several emerging PAMORAs are in development (

Table

).21,63-65

The Role of the Pharmacist in Evaluating Formulary Considerations

Clinicians should take a proactive approach to preventing and treating OIC. Pharmacists are in a key position to identify those patients at risk for OIC, to recommend proactive measures to prevent or reduce OIC, and to aid physicians and patients by making clinical interventions, when warranted, to meet the challenges associated with OIC, especially by providing clinical recommendations regarding available treatment options when laxatives do not work. Ideally, prevention is a key part of OIC treatment, with a regular bowel movement at least every 3 days being a common therapy goal.66 According to the American Society of Health-System Pharmacists Guidelines on Pharmacy and Therapeutics Committee and the Formulary System, pharmacists’ expertise should give them a key role in drug reviews. Collaborative work with physicians, coupled with patient education, means pharmacists can reduce or prevent the incidence of OIC.67 Formulary management enables healthcare professionals (eg, pharmacists, physicians, nurses) to work together to provide OIC patients with safe, effective, and affordable medications offering the best chance of optimal therapeutic outcomes.

As more and more new drugs are introduced to the market, Pharmacy and Therapeutic (P&T) Committees are faced with the challenge of selecting cost-effective drugs that meet patient needs safely and successfully. P&T Committees generally consider numerous factors in determining whether a drug should be added to the formulary, including safety, efficacy, drug interactions, potential for errors, adverse drug reactions, contraindications, warnings, precautions, use in specific patient populations, monitoring parameters, and drug cost.68 In a study by Segal et al, the 2 most important factors in hospital formulary decision making were the effects of the potential formulary addition on the quality of drug treatments available in the hospital, followed by its impact on hospital costs.69 Information about the therapeutic advantages of the potential drug addition, the relative adverse effect profile, and cost information were also perceived as especially significant.69

Since each medication used for OIC has advantages and disadvantages, formulary decision makers should consider the cost, efficacy, safety, dosage form, need for dosage adjustments, potential for medication errors, contraindications, and drug interactions. Unfortunately, many drugs used to manage OIC are expensive, and their addition to a formulary may depend on restrictions for use.70 Proposed criteria for use may include prior unsuccessful treatment with laxatives, restricted duration of treatment, and no bowel movements >48 hours.70 As essential members of P&T Committees, pharmacists are in a critical posi-tion to recommend drugs for formulary selection that will effectively treat OIC. Pharmacists must keep abreast of the most effective value-based agents that will provide optimal therapeutic effects for patients. When selecting thera-py for OIC, pharmacists can emphasize the importance of considering the ease of use of delivery for the drug, dosing intervals, and route of administration, as well as distinctive properties of the drug. While a few opioid antagonists are available, approval of oral formulations may be preferred over other dosage forms. Clinical studies show that fac-tors that may affect patient compliance include frequency of dosing, lack of understanding about the benefits of the medication, and cost.

Conclusions

OIC is a frequent and bothersome consequence of chronic opioid pharmacotherapy that negatively impacts a patient’s overall quality of life. Since patients are often unaware of the potential for their opioid medications to cause OIC, pharmacists must increase awareness about this cumbersome adverse effect and create an open dialogue with patients to discuss various means of prevention, and, should it occur, the available treatment options to reduce its severity. While nonpharmacological strategies and laxatives are commonly used to manage and treat OIC, these treatment strategies often prove to be ineffec-tive, unfortunately. For patients suffering with OIC, clinical studies demonstrate that the drug class of agents known as PAMORAs can be an effective OIC therapy that targets the underlying cause of OIC. The continuing development of new agents to combat OIC gives healthcare providers an opportunity to offer patients effective pain relief while reducing or preventing the incidence of OIC. Aggressive prevention and early treatment of OIC are important to optimize pain control when opioids are used.21 When healthcare professionals have an in-depth understanding of OIC, and it is shared with patients, those patients may benefit by obtaining effective therapy, improving their overall quality of life without compromising pain relief, experiencing fewer complications, and maintaining increased adherence to opioid therapy. Since medications approved for OIC may be expensive, a proper cost-benefit analysis should always be conducted for both formulary guidelines and individual drug selection.