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12 Articles in Volume 16, Issue #10
2016 Practical Clinical Advances: Ketamine and Metformin
Case Challenge: Amniotic Allograft Reduces Joint and Soft Tissue Pain
Challenges of Treating Young Patients With a Terminal Prognosis
Defining Palliative Care
Discussing Benefits of Palliative Care
Evaluation of Antiemetic Pharmacotherapy in the Setting of Opioid Withdrawal
Fibromyalgia, Chronic Fatigue, and Chronic Fatigue Syndrome
Gabapentin Dosing for Neuropathic Pain
IV Acetaminophen Reduces Need for Opioids in Burn Patients
Opioid-Induced Constipation: New and Emerging Therapies—Update 2016
Osteopathic Treatment Considerations For Head, Neck, and Facial Pain
Tips From the Field: Deconstructing the Art of Headache Medicine

Opioid-Induced Constipation: New and Emerging Therapies—Update 2016

There has been much focus in pain management on preventing the dangerous and bothersome complications of opioid therapy, including opioid-induced constipation (OIC). One positive effect of all this attention may be the reduction in opioid-induced side effects. This review will present the latest literature on the diagnosis and management of OIC.

Opioid-Induced Bowel Dysfunction

Almost all patients requiring opioid therapy develop side effects, the most common of which affect the gastrointestinal (GI) and central nervous systems (CNS).1,2 Although tolerance develops to many of the CNS side effects over time, resolution of opioid-induced bowel dysfunction (OIBD), and more specifically OIC, does not occur with continued use.1

Mu-opioid receptors, and to a lesser extent kappa- and delta-opioid receptors, are located throughout the GI tract. The large abundance of mu receptors in the GI tract contributes to the enteric nervous system, which appears to mediate the GI effects of opioid agonists by reducing bowel smooth muscle tone and contractility, which prolongs transit time.1 There is an increase in nonpropulsive contractions as well as enhanced fluid absorption. Opioid-mediated increased anal sphincter tone and decreased reflex relaxation in response to rectal distension contribute to the difficulty in rectal evacuation characteristic of OIC.3

How prevalent is OIC? The numbers vary widely based on study design and patient populations. Based on an analysis of 16 clinical trials and observational studies, OIC has been reported to occur in 15% to 90% of patients.4 When these studies are qualified according to type of chronic pain, estimates from observational studies in the United States suggested that the prevalence of OIC in patients with noncancer pain ranged between 40% and 50%.5

In addition to being a common side effect, OIC significantly affects a patient’s quality of life.6 A study of work productivity in patients on chronic opioid therapy found that OIC impacted productivity and activity levels. Specifically, the study found that patients reported 9% work time missed, 32% impairment while working (the equivalent of 14 hours of lost productivity per week), and 38% activity impairment.7

Additionally, participants in a recent OIC study commonly reported that their constipation interfered with the ability of their opioid medication to control pain, with 49% reporting moderate or complete interference, and 8% reporting that they changed how they used their opioid in order to have a bowel movement.7

Diagnosis of OIC

Opioids affect the entire gut, from the mouth to the anus, and OIBD refers to the constellation of GI effects.2 This includes gastroparesis, gastroesophageal reflux disease (GERD), and other GI-related disorders.8 Although no delineation for constipation has been universally accepted, various definitions of constipation exist, and guidelines for initiating prescription therapies for OIC have been developed.1,9-11

According to the American College of Gastroenterology definition, constipation is defined as unsatisfactory defecation with infrequent bowel movements, difficult stool passage, or both.12 Functional constipation, as outlined by the Rome IV criteria, requires 2 or more of the following symptoms to occur no less than 25% of the time over the preceding 12 weeks: straining with bowel movements, passing lumpy or hard stools; feeling of incomplete evacuation; feeling of anorectal obstruction; using manual maneuvers for facilitation of defecation; and having less than 3 bowel movements per week.13,14

In late 2015, a consensus guidelines was published that recommended the Bowel Function Index (BFI) as a simple assessment tool with a validated threshold of clinically significant constipation.11 The authors wrote: “With only 3 items, the BFI15 is the shortest assessment tool. Each item is scored using a numerical analog scale from 0 to 100 points. Furthermore, clinicians can quickly assess OIC severity by calculating the total BFI index score using the average score of the 3 items.”11 According to a study by Ueberall, a BFI range from 0 to 28.8 defined non-constipated pain patients; a ≥ 12 point change in BFI scores would correlate with clinically meaningful changes in a pain patient’s bowel habits. For example, a reduction in BFI score from 63.4 to 28.8 (34.6 points) “would represent clear improvement in symptoms,” noted the authors.16

Treatment Options

There are a variety of nonpharmacologic treatments and over-the-counter options for management of constipation, including increasing dietary fiber intake, increasing fluid intake, and increasing physical activity.1 Exercise has been shown to improve functional constipation; however, there is inadequate evidence to support its use in OIC, and pain patients are often limited in their tolerance for physical activity.1

Perhaps overlooked in the discussions with patients is positional strategies (ie, squatting) that can help ameliorate constipation.17 When sitting on the toilet, the position of the puborectalis muscle clutches the rectum, thus preventing free release of waste from the anus. However, by squatting, the puborectalis muscle remains relaxed, thus straightening the pathway to the anus. This allows waste to pass easily. Squatting posture, which can be accomplished by using a stool to raise the knees while sitting on the toilet, straightens the “kink” in the colon and relaxes the puborectalis muscles.

When dietary strategies are ineffective, laxatives, stool softeners, enemas, suppositories, or even manual disimpaction are often employed. Table 1, describes categories of laxative agents.

 

Stimulant laxatives, including senna and bisacodyl, work by increasing muscle contractions. Patients, however, may develop tolerance to and dependence on stimulant laxatives.1 In addition, laxatives have been shown to be frequently ineffective or suboptimal, perhaps due to their inability to directly or indirectly impact the cause of OIC at the peripheral mu receptors.18

Docusate, a surfactant stool softener, is not habit forming but also does not assist with muscle contractility.1 Bulk-forming laxatives, for example psyllium, may lead to increased abdominal pain and bowel obstruction, and are often avoided my most pain practitioners.4 Lactulose and polyethylene glycol are osmotic laxatives that pull water into the GI tract and have evidence for use in OIC, but they do not target the actual OIC cause, and they may provoke electrolyte abnormalities.1,9,10,12 Unfortunately, patients may have inadequate symptom relief from OIC with these laxatives alone or combined. Additionally, clinicians may rotate through different opioids to assess patient response and constipation profile. According to the 2015 consensus statement, “Prescription treatments for OIC should be considered for patients who have a BFI score of ≥ 30 points and an inadequate response to first-line interventions.”11

Pharmaceutical Therapy

It is not often in medicine that a pharmacological antidote exists to a drug treatment or adverse effect. Although newer select agents (ie, ion channel activators) have been approved for OIC, there is only 1 class of drug that targets the specific underlying cause of OIC—binding of opioids to the mu receptors in the enteric nervous system. This new class, known as PAMORAs (Peripheral Acting Mu Opioid Receptor Antagonists), work by selectively inhibiting opioid receptors in the gut, thereby decreasing the constipating effects of opioids without affecting opioid-mediated analgesic effects within the CNS or precipitating withdrawal symptoms (Table 2).2,19

Alvimopan

The first available medication in this class was alvimopan (Entereg), which is indicated to accelerate the time to upper and lower GI recovery following surgeries that include partial bowel resection with primary anastomosis.20 It is not specifically approved for OIC. In a study assessing alvimopan for patients on opioids with chronic non-cancer pain (CNCP), alvimopan was associated with an increased risk of myocardial infarction compared to placebo, leading to the issuance of a boxed warning and Risk Evaluation and Mitigation Strategies (REMS) program.20

Methylnaltrexone 

The next PAMORA introduced to the market was methylnaltrexone bromide (Relistor).21 In 2010, methylnaltrexone subcutaneous injection was Food and Drug Administration (FDA)-approved for the treatment of OIC in patients with advanced illness receiving palliative care. With further study, the agent was approved for the treatment of OIC in adult patients with CNCP.22 In July 2016, the FDA approved an oral formulation of methylnaltrexone bromide (450 mg/day).23 Methylnaltrexone bromide is a quaternary amine with limited penetration through the blood-brain barrier.

The clinical trials leading to approval of methylnaltrexone injection approval found that the agent produced reliable relief of constipation in opioid-treated pain patients—59% of patients receiving methylnaltrexone (12 mg subcutaneous injection daily for 4 weeks) had more than 3 spontaneous bowel movements (SBMs) per week compared to 38% in the placebo treatment group.22 The most common side effects are abdominal pain, nausea, and vomiting. Furthermore, methylnaltrexone did not appear to reverse the opioid’s analgesic effect or cause opioid withdrawal symptoms.21

In addition, significantly more methylnaltrexone-treated patients had a bowel movement within 4 hours than did placebo-treated patients (52% vs 9%; P<0.0001). In approximately 30% of treated patients, laxation was reported within 30 minutes of a dose of methylnaltrexone. Two open-label extension studies suggested the laxation response appeared to be maintained over the course of 3 to 4 months.24

For approval of the oral tablet formulation, the FDA reviewed a randomized placebo-controlled trial of 200 noncancer patients taking methylnaltrexone (450 mg/day) and 201 patients assigned to placebo. The patients had been on opioid therapy for 1 month or longer and had been diagnosed with OIC (< 3 bowel movement per week). The study findings reported significant improvements in rescue-free bowel movement within 4 hours of administration in the treatment arm over 28 days of dosing compared with placebo treatment. In addition, the treatment group also had a higher percentage of responders (those with 3 or more bowel movements per week, with an increase of 1 or more from baseline for at least 3 of the 4 weeks) than the placebo group.21

According to the prescribing information, methylnaltrexone is available in single-use vials, single-use pre-filled syringes, and a tablet oral formulation The dosage for injection is 12 mg, similar to those patients with OIC in advanced illness weighing 62 to 114 kg; patients weighing 38 to 62 kg should receive 8 mg. Outside of this range, dosing is recommended at 0.15 mg/kg. For tablets, the recommended dosage is 450 mg once daily in the morning. Administration for CNCP is daily, with the caveat to discontinue all maintenance laxative therapy prior to methylnaltrexone; laxative(s) can be used as needed if there is a suboptimal response to the agent after 3 days. Dosage reduction is recommended for patients with severe renal impairment.21 The most common adverse reactions with the new oral formulation were abdominal pain, diarrhea, headache, abdominal distention, vomiting, hyperhidrosis, anxiety, muscle spasms, rhinorrhea, and chills. Patient taking methylnaltrexone injection experienced abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.21

Naloxegol

Naloxegol (Movantik) was the first orally administered, once-daily PAMORA approved for OIC in patients with CNCP. Naloxegol is a polyethylene glycol (PEG)ylated form of naloxone.25 The efficacy of naloxegol was studied in over 1,300 patients who had been on oral opioids for an average of 3.6 years. OIC was defined as less than 3 SBMs per week with hard/lumpy stools, straining, or sensation of incomplete evacuation or obstruction in 25% or more bowel movements in the preceding 4 weeks.26

Patients were randomly assigned to 3 treatment arms: naloxegol 25 mg daily, naloxegol 12.5 mg daily, or placebo daily for 12 weeks. During the study, no other bowel regimens were permitted, but bisacodyl was allowed as rescue medication if patients did not have a bowel movement in 3 days.26

Two identical efficacy and safety studies were performed (Study 1 and Study 2). The primary endpoint was defined as ≥ 3 SBMs per week and a change from baseline of ≥ 1 SBM per week for at least 9 out of the 12 study weeks, and 3 out of the past 4 weeks.26 There was a statistically significant difference in response for the 25 mg naloxegol treatment group versus placebo for the primary endpoint in Study 1 and Study 2. Statistical significance for the 12.5 mg treatment group versus placebo was observed in Study 1 but not in Study 2.26

One secondary endpoint in both studies was response in laxative users with OIC symptoms. In this subgroup, 42% and 50%, respectively, reported using laxatives on a daily basis. A statistically significantly higher percentage of patients in both studies responded with naloxegol 25 mg versus placebo. This was also seen with naloxegol 12.5 mg in Study 1, but it was not tested in Study 2.

Time to first bowel movement was 6 to 20 hours in naloxegol-treated patients compared to 36 hours in the placebo group. The most common adverse events were abdominal pain (12% to 21%), diarrhea (6% to 9%), nausea, and flatulence.28 Contraindications for naloxegol include known, suspected, or at increased risk of GI obstruction; concomitant administration of strong cytochrome P (CYP) 450 3A4 inhibitors; and serious or severe hypersensitivity reaction to naloxegol or any of its ingredients.26

Prior to initiation of naloxegol, it is recommended to discontinue all maintenance laxative therapy, which can be resumed after 3 days if there is a suboptimal response to naloxegol. Standard dosing of naloxegol is 25 mg by mouth once daily 1 hour before or 2 hours following the first meal of the day. In patients unable to tolerate this dose, a 12.5 mg dose of naloxegol is recommended. Renal adjustment of the starting dose is suggested in patients with a creatinine clearance < 60 mL/min.25 Serious adverse reactions that may occur include opioid withdrawal. Opioid withdrawal, considered in this trial to be at least 3 symptoms potentially related to opioid withdrawal, occurred in 1% of patients on naloxegol 12.5 mg compared to 3% on naloxegol 25 mg; less than 1% of patients on placebo experienced opioid withdrawal. 

The FDA recently approved a supplemental New Drug Application (sNDA) for naloxegol tablets. The sNDA proposed changes including: information regarding the administration of crushed tablets mixed in water given orally or via nasogastric (NG) tube, the addition of severe abdominal pain and/or severe diarrhea to the Warnings and Precautions and Adverse Reactions sections, and a clarification to the effects of race on pharmacokinetics.25

The updated labeling for Movantik now states that for patients who are unable to swallow the tablet whole, the pill can be crushed to a powder, mixed with 4 oz (120 mL) of water,  and consumed immediately. The glass should be refilled with 4 oz (120 mL) of water, stirred and the contents consumed. Also, naloxegol can be administered via a NG tube with specific instructions listed under Dosage and Administration.25

Lubiprostone

In April 2013, the FDA approved lubiprostone (Amitiza) as the first oral treatment for OIC in adults with CNCP. Lubiprostone had previously been approved for the management of chronic idiopathic constipation and irritable bowel syndrome with constipation (IBS-C).27

Lubiprostone works by activating type 2 chlorine channals (ClC-2) in epithelial cells lining the intestinal tract. Once ClC-2 are activated, the chloride concentration in the intestinal lumen increases. As chloride moves into the intestinal lumen, sodium ions and fluids then passively follow.27,28 By increasing intestinal fluid secretion, lubiprostone increases motility in the intestine, easing the passage of stool.27

The efficacy of Amitiza in the treatment of OIC was assessed in 3 studies. The proportion of lubiprostone-treated patients (24 mcg twice daily) in the studies who qualified as “overall responder” was 27.1%, 24.3%, and 15.3% compared with 18.9%, 15.4%, and 13.0% of the placebo-treated patients.27

A study by Marciniak et al, concluded that both lubiprostone and senna improved constipation-related symptoms and quality of life in patients with OIC, with no significant differences between groups.29

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.30

The most common adverse reactions associated with this agent include nausea, diarrhea, headache, abdominal pain, abdominal distension, and flatulence, as well as dyspnea within an hour of the first dose. This symptom generally resolves within 3 hours, but may recur with repeat dosing. Patients who experience dyspnea should inform their HCP. Some patients have discontinued therapy because of dyspnea.27 The dosage should be reduced in patients with moderate or severe hepatic impairment. The drug’s efficacy in patients taking methadone has not been established.

Combination Therapies

A combination of prolonged-release (PR) oxycodone and naloxone (Targiniq; Purdue Pharmaceuticals) was approved by the FDA in 2014 for the treatment of patients with severe pain.31 One aim of this formulation is to counteract OIC through the local antagonist effect of naloxone in the gut wall, while maintaining analgesia due to the low bioavailability of oral naloxone.

Three large, 12-week, randomized, double-blind, phase 3 trials in patients with moderate to severe, chronic, non-malignant pain, plus a prospectively planned pooled analysis of 2 of these studies, demonstrated that PR oxycodone/naloxone (OXN)improved bowel function, as measured by the BFI, compared with PR oxycodone alone. Additionally, OXN relieved pain more effectively than placebo and no less effectively than PR oxycodone after 12 weeks.32

More recently, a study of 68 laxative-refractory OIC patients with severe chronic pain were treated for 91 days with OXN (median daily dose, 20 mg). Treatment with OXN resulted in a significant and clinically relevant decrease of pain of 2.1 units (P < 0.001; 95% CI, 1.66-2.54) and of BFI by 48.5 units (P < 0.001; 95% CI, 44.4-52.7) compared with PR oxycodone treatment alone; use of laxatives was also significantly reduced (P < 0.001). Approximately 95% of patients were responders, and quality of life (as measured by using the EQ-5D) improved significantly. Adverse events were opioid related, and OXN treatment was well tolerated.33

In addition to lowering the rate of OIC, a small study of 37 patients found that treatment with OXN had an “overall positive effect on patients, consisting mainly of decreasing the severity of the constipation problems, increasing health-related quality of life, and decreasing the use of healthcare resources.”34 In addition, the author reported patients had fewer problems with OIC after the initiation of OXN according to the BFI score.

More Favorable Opioids

There is some evidence that not all opioids are created equal when it comes to causing OIC. For example, tapentadol (Nucynta) is a mu-opioid agonist that also inhibits the reuptake of norepinephrine, which contributes to its analgesic effect. Tapentadol has been shown to have a better GI profile compared with oxycodone, with similar pain control efficacy.35 In a study involving 343 cancer patients, the incidence of gastrointestinal treatment-associated adverse events was lower in the tapentadol group (55.4% [93/168]) than in the oxycodone group (67.4% [116/172]).36

According to the prescribing information, among treatment-emergent adverse events, constipation was the highest at 8% compared with 3% of placebo patients. Adverse reactions that occurred in < 1% of patients were abdominal discomfort and impaired gastric emptying.37

Other newer opioids have reported lower rates of constipation, including extended-release oxycodone (Xtampza). In the Phase 3 efficacy trial, constipation was reported at 13.0% in the open label portion, and only 5.2% during the randomization period.38

A buccal buprenorphine, Belbuca, which has been approved for chronic pain, reported 13% in its open label portion, and only 4 % in the double-blind treatment phase.39

Emerging Therapies

A variety of PAMORA and other medications are currently in development to target OIC.

Axelopran

Axelopran (formerly TD 1211) is an oral, once-daily, peripherally selective, multivalent inhibitor of the mu-opioid receptor.40 It successfully completed a Phase 2b study that demonstrated a sustained increase in bowel movement frequency in patients regardless of duration of OIC.41 Theravance Biopharma presented Phase 1 data of an agent that combines axelopran and oxycodone “as a single, once-daily, abuse-deterrent pill for the combined treatment of pain and OIC.”42

Twenty-eight healthy subjects were enrolled in an open-label, randomized, 4-period crossover study to determine the effect of axelopran on oxycodone exposure. Subjects received either axelopran alone, oxycodone alone, axelopran and oxycodone together as 2 separate tablets, or the fixed-dose combination (FDC) product, consisting of a spray-coat application of axelopran onto oxycodone.

“The relative bioavailability of oxycodone met criteria for bioequivalence between all treatments, demonstrating no interaction of axelopran or the FDC formulation on oxycodone pharmacokinetics. Axelopran relative bioavailability also met area under the concentration-time curve bioequivalence criteria between the FDC and the co-administration of the individual treatments,” noted a press release from the company. “Oxycodone and axelopran bioequivalence was demonstrated for all statistically powered comparisons between treatments.”42

Naldemedine

Probably closest to approval is naldemedine, a naltrexone-based PAMORA. The drug’s developer, Shionogi Inc, reported that naldemedine met its primary and secondary endpoints in 3 phase 3 studies (COMPOSE I, II, and IV; the latter study was conducted in Japan).

At Digestive Disease Week 2016, researchers reported that naldemedine (0.2 mg once daily) statistically significantly improved the frequency of SBM over the 12 week trial compared with placebo. Improved frequency of SBMs was seen in 47.6% and 52.5% of naldemedine-treated patients, compared with 34.6% and 33,6% of placebo-treated patients in COMPOSE I and II, respectively.Treatment-related adverse events were reported in about 48% of patients across both trials. Major adverse cardiovascular events (MACE) of concern occurred in 1 patient in treated with naldemedine and 1 in the placebo group.43

The agent was found to be generally well-tolerated, with the most commonly reported side effects being gastrointestinal disorders. According to a presentation at PAINWeek 2016 of the COMPOSE III longterm trial, GI side effects that were reported in over 5.0% of patients on naldemedine included, abdominal pain (8.2%), diarrhea (11%), and vomiting (6%).44

Prucalopride

Prucalopride (Resolor; Shire Pharmaceuticals) is currently being evaluated for OIC and is approved in several countries (but not in the United States) for the treatment of chronic constipation. Prucalopride is a high-affinity serotonin (5HT) type-4 receptor agonist. Studies of prucalopride for chronic constipation were conducted in patients, largely women with idiopathic constipation, who showed improved spontaneous complete bowel movement at a dose of 2 mg a day.45

Prucalopride has not been found to have a significant interaction with the hERG potassium channel, which was assumed to have been responsible for the development of adverse cardiovascular effects seen with cisapride (Propulsid), which was pulled from the market in 2004. The 3 pivotal clinical trials of prucalopride did not demonstrate any relevant electrocardiographic changes.45

Linaclotide

Linaclotide (Linzess; Ironwood Pharmaceuticals Inc), a locally acting guanylate cyclase-C receptor agonist, is currently approved for the treatment of cancer-induced constipation and irritable bowel syndrome with constipation IBS-C. It’s efficacy for the management of IBS-C was based on the results of 2 randomized trials. At a daily dose of 290 mcg, 33.7% and 47.6% of patients with IBS-C responded to treatment, compared with only 13.9% and 22.6% of patients given placebo, respectively (P < 0.0001). The pain responder criterion of the FDA endpoint was met by 48.9% of linaclotide-treated patients vs 34.5% of placebo-treated patients. The most common adverse effects were GI-related, of which diarrhea had the highest incidence.45

Conclusion

OIC is the most common adverse effect of chronic opioid therapy. It occurs as a natural response to opioid binding at mu receptors throughout the GI tract. Nonpharmacological strategies and laxatives are commonly employed to combat OIC; however, these strategies often fall short in efficacy. To avoid constipation resistant to laxative treatment, patients may decrease their use of opioids, which can lead to poorly controlled pain. For those failing first-line options, PAMORAs represent a reliable treatment option that targets the underlying cause of OIC. The emergence of this new class of agents has provided an opportunity for patients to receive effective pain relief while minimizing the unwanted peripheral effects of opioids. Clinicians need to understand the indications, limitations, and contraindications—especially in patients with risk of GI perforation.

Last updated on: January 11, 2017
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