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10 Articles in Volume 15, Issue #10
2015 Has Been a Good Year for Clinical Progress
Addison’s Original 1855 Cases Reveal Stories of Chronic Pain
Can We Prevent Chronic Pain?
Letters to the Editor: Nerve Fiber Testing, Fibromyalgia
Medication Guide for Pain—A Short Primer for Primary Care
Odd Pet Behavior During SCS Trial—Case Report
Opioid-Induced Constipation: New and Emerging Therapies—Update 2015
Palliative Care: Dying With Dignity
PPM Editorial Board: Year in Pain Management 2015
QT Intervals and Antidepressants

Opioid-Induced Constipation: New and Emerging Therapies—Update 2015

Approximately 50% of patients on opioid therapy will experience constipation. New and emerging therapies are targeting the root cause of opioid-induced constipation and providing real relief to patients.

Severe chronic pain affects more than physical or mental function, it impacts quality of life and productivity, which “imposes a significant financial burden on affected individuals, as well as their families, their employers, their friends, their communities, and the nation as a whole.”1,2

Almost all patients requiring chronic opioid therapy develop side effects, the most common of which affect the gastrointestinal (GI) and central nervous systems (CNS).3,4 Although tolerance develops to many of the CNS side effects over time (ie, sedation), resolution of opioid-induced bowel dysfunction (OIBD), and more specifically opioid-induced constipation (OIC), does not occur with continued use.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.5 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 non-cancer pain ranged between 40% and 50%.6

In addition to being a common side effect, OIC significantly affects a patient’s quality of life.7 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 (equivalent of 14 hours of lost productivity per week), and 38% activity impairment.8

To appreciate the impact OIC has on patients, the authors conducted an informal survey of their patients. Here are actual quotes about OIC from pain patients:

  • “I have to get off of my opioid pain medications because of my plumbing bills…I keep clogging the toilet.”
  • “I have had many surgeries and injuries in my life and nothing compares to the pain of severe constipation.”
  • “Coming to the emergency room for disimpaction was the most embarrassing experience in my life.”
  • “My constipation was so bad I thought I was going to die…actually, I wanted to die.”
  • “I’d much rather live with pain than the side effect of severe constipation.”
  • “I’d rather give birth again with no anesthesia than go through a bout of constipation from my medications.”

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.9

Effect of Opioids on the GI Tract

Multiple mechanisms influence the occurrence of OIC. In fact, the very mechanisms that allow opioids to be effective pain medications are also involved in causing OIC. Opioid agonists mitigate pain by binding to opioid receptors that are located in the central and peripheral nervous systems. Mu-opioid receptors, and to a lesser extent kappa- and delta-opioid receptors, are located throughout the GI tract. Here opioids reduce contractility and tone leading to increased transit time.3

Specifically, they exert their effects in the neuronal plexi, located between the longitudinal and circular muscle layers (myenteric plexus) and within the submucosa (submucosal plexus),9 and indirectly through the central nervous system via intrathecal administration of opioids, decreasing GI motility and intestinal secretion.10

Passive absorption of fluids is increased and intestinal secretions are reduced in the GI tract with opioids due to increased frequency and strength of circular muscle contractions that cause non-propulsive contractions.3 Within the myenteric plexus, opioids stimulate relaxation of the longitudinal smooth-muscle layer, thus increasing tonicity in the circular smooth-muscle layer. The mechanism of this action is believed to occur through inhibition of acetylcholine release and inhibition of vasoactive intestinal peptide and nitric oxide release.

Ultimately, this results in an increase in segmental contraction, while peristaltic activity is decreased, inducing constipation. 6 Reduced propulsive contractions of longitudinal muscles also contributes to hard and dry stools.4 Rectal stool evacuation is decreased by an increased threshold for triggering of the anorectal reflex.3,11

Diagnosis of OIC

Opioids affect the entire gut, from the mouth to the anus, and OIBD refers to the constellation of GI effects.4 This includes gastroparesis, gastroesophageal reflux disease (GERD), and other GI-related disorders.12 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.3,11,13,14

According to the American College of Gastroenterology definition, constipation is defined as unsatisfactory defecation with infrequent bowel movements, difficult stool passage, or both.11,15 Functional constipation, as outlined by the Rome III criteria, requires 2 or more of the following symptoms to occur no less than 25% of the time in the past 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.16 Even though this definition is not restricted to opioid-induced constipation, the Rome III criteria is often used to describe this condition (Table 1).11,17

Treatment Options

There are a variety of non-pharmacologic treatments and over-the-counter options for management of constipation, including increasing dietary fiber intake, increasing fluid intake, and increasing physical activity.3 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.3

Perhaps overlooked in the discussions with patients is positional strategies (ie, squatting) that can help ameliorate constipation.18 When sitting on the toilet, the position of the puborectalis muscle chokes off 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 (Figure 1).
When dietary strategies are ineffective, laxatives, stool softeners, enemas, suppositories or even manual disimpaction are often employed. Stimulant laxatives are often used due to their low cost and efficacy despite not correcting the underlying mechanism.3,13 Table 2 describes categories of laxative agents.

Stimulant laxatives, including senna and bisacodyl, work by increasing muscle contractions. Patients, however, may develop tolerance and dependence to stimulant laxatives.3 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.19

Docusate, a surfactant stool softener, does not assist with muscle contractility but is non-habit forming.3 Bulk-forming laxatives, for example psyllium, may lead to increased abdominal pain and bowel obstruction.3 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.3,11,13,15 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.

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 one 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 central nervous system or precipitating withdrawal symptoms (Table 3).4,20

Alvimopan

The first available medication in this class was alvimopan (Entereg), which is indicated to accelerate the time to upper and lower gastrointestinal recovery following surgeries that include partial bowel resection with primary anastomosis.21

Although not specifically approved for OIC, alvimopan has been studied in 522 patients with OIC.22 The patients, who were all receiving 30 mg per day of morphine equivalent, were randomly assigned to receive oral alvimopan at three doses (0.5 mg twice daily, 1 mg once daily, 1 mg twice daily), or placebo for 6 weeks. When compared with placebo, alvimopan significantly increased the mean weekly frequency of spontaneous bowel movements (SBM) over the initial 3 weeks of treatment: 0.5 mg twice daily (+1.71 mean SBMs per week), 1 mg once daily (+1.64), and 1 mg twice daily (+2.52) (P < 0.001 for all comparisons). The increased frequency of SBMs and additional treatment effects (less straining, incomplete evacuation, abdominal bloating or discomfort; more stool consistency; and better appetite) were sustained for more than 6 weeks.22

In a study employing alvimopan (0.5 mg twice daily) for patients with chronic non-cancer pain (CNCP) on opioids, alvimopan was associated with an increased risk of myocardial infarction compared to placebo, leading to the issuance of a boxed warning and REMS program.21 The manufacturer requires hospitals to enroll in the E.A.S.E. program to be able to acquire alvimopan. A hospital in the E.A.S.E. program must acknowledge the following:

  • Hospital staff who prescribe, dispense, or administer the product have been provided the educational materials on the need to limit the use to short-term, inpatient use.
  • Patients will not receive more than 15 doses.
  • The product will not be dispensed to patients after they have been discharged from the hospital.13

Methylnaltrexone 

The next PAMORA introduced to the market was methylnaltrexone bromide (Relistor). In 2010, methylnaltrexone subcutaneous injection was FDA-approved for the treatment of OIC in patients with advanced illness receiving palliative care. More recently, the agent was approved for the treatment of OIC in adult patients with CNCP.23 Methylnaltrexone bromide is a quaternary amine with limited penetration through the blood-brain barrier.

The clinical trials leading to methylnaltrexone’s 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 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.23

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 methlynaltrexone. Two open-label extension studies suggested the laxation response appeared to be maintained over the course of 3 to 4 months.24

According to the Prescribing Information, methylnaltrexone is available in single-use vials and single use pre-filled syringes. The dosage for CNCP is 12 mg, similar to those patients with OIC in advanced illness weighing 62-114 kg; patients weighing 38-62 kg should receive 8 mg. Outside of this range, dosing is recommended at 0.15 mg/kg. Administration for CNCP is daily, with the caveat to discontinue all maintenance laxative therapy prior to starting injections; 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.23

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 1300 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 last 4 weeks.

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 last 4 weeks.25 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 2.25

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 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%-21%), diarrhea (6%-9%), nausea, and flatulence.26 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.26

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. 

Emerging Therapies

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

Axelopran

Axelopran (formerly TD 1211) is an oral, once-daily peripherally selective, multivalent inhibitor of the mu-opioid receptor.27 It successfully completed a Phase 2b study that demonstrated a sustained increase in bowel movement frequency in patients regardless of duration of OIC.28 As of September 2014, Phase 3 studies were pending.

At the 2015 PAINWeek meeting, 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.”29

Twenty-eight healthy subjects were enrolled in an open-label, randomized, four-period crossover study to determine the effect of axelopran on oxycodone exposure. Subjects received either axelopran alone, oxycodone alone, axelopran and oxycodone co-administered as two 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.”29

Bevenopran

Another emerging PAMORA currently in Phase 3 of development is bevenopran. The latest trial planned is a multicenter, double-blind, placebo-controlled, parallel-group study in subjects with OIC taking opioid therapy for CNCP. Patients will be randomized to receive either oral 0.25 mg bevenopran twice daily or placebo for the 12-week treatment period, followed by a 4-week follow-up period.

According to the independent Web site Avarex, “all subjects will be followed for 16 weeks regardless of when they discontinue study medication.”30 The primary outcome measure is overall SBM rates over the 12-week double-blind treatment period.

Naldemedine

Another emerging PAMORA currently in Phase 3 of development is naldemedine. The drug’s developer, Shionogi Inc., reported that naldemedine met its primary and secondary endpoints in three phase III studies (COMPOSE I, II and IV, the latter study was conducted in Japan).

Study results showed that naldemedine (0.2 mg once daily) statistically significantly improved the frequency of spontaneous bowel movement (SBM) compared with placebo over 12 weeks. The agent was found to be generally well-tolerated, with the most commonly reported side effects being gastrointestinal disorders.31

According to Shionogi’s website, naldemedine “may prove more favorable than existing treatments, given its efficacy at lower doses in alleviating not just opioid-induced constipation but also nausea and vomiting.”32

Prucalopride

Prucalopride (Resolor; Shire Pharmaceuticals) is currently being evaluated in 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, which showed improved spontaneous complete bowel movement at a dose of 2 mg a day.33

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 three pivotal clinical trials of prucalopride did not demonstrate any relevant electrocardiographic changes.33

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 IBS-C. It 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 responded to treatment, compared with only 13.9% and 22.6% of patient given placebo, respectively (P < 0.0001).33 The pain responder criterion of the FDA end point 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.33

Combination Product

A combination of prolonged-release oxycodone and naloxone (Targiniq; Purdue Pharmaceuticals) was approved by the FDA in 2014 for the treatment of patients with severe pain.34 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 III trials in patients with moderate to severe, chronic, non-malignant pain, plus a prospectively planned pooled analysis of 2 of these studies, demonstrated that oxycodone/naloxone PR improved bowel function, as measured by the bowel function index, compared with oxycodone alone. Additionally, oxycodone/naloxone PR relieved pain more effectively than placebo and no less effectively than oxycodone PR after 12 weeks.35

Cardiovascular Risk

A potential cardiovascular safety signal observed in the development program for alvimopan has raised questions regarding the amount and type of clinical safety data necessary to support approval of other opioid antagonists intended to treat OIC. In June 2014, a majority of FDA committee members voted that the FDA should not require cardiovascular outcomes trials for PAMORAs being developed for the treatment of OIC in patients with CNCP. Following a clarification of the vote, the majority of the committee members suggested continued post-approval data collection for cardiovascular safety.36

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. Non-pharmacological 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 gastrointestinal perforation.

Last updated on: December 8, 2015
Continue Reading:
Medication Guide for Pain—A Short Primer for Primary Care

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