This article reviews the emerging class of peripherally acting mu-opioid receptor antagonists and provides insight on formulary considerations when evaluating these agents.
This article reviews the emerging class of peripherally acting mu-opioid receptor antagonists (PAMORAs) and provides insight on formulary considerations when evaluating these agents. PAMORAs provide pain relief for patients while minimizing the unwanted peripheral effects of opioids. Agents in this class include methylnaltrexone and alvimopan. Methylnaltrexone is FDA approved for opioid-induced constipation in palliative care patients with advanced illness; alvimopan is approved for use in postoperative ileus in patients who have had a bowel resection with anastamosis. Both agents are considered to have clinical, as well as economic, benefits.
Opioids have been used for more than 4,000 years and continue to be the most widely accepted medication for treating patients with moderate to severe acute and chronic pain.1 Opioids produce analgesic effects, suppress coughs, and relieve severe diarrhea by attaching to opioid receptors found in the brain, spinal cord, and gastrointestinal (GI) tract. Opioids may act centrally by activating receptors within the central nervous system, producing sedation, nausea, vomiting, and respiratory depression. They may also act peripherally by activating receptors outside the central nervous system, producing constipation, hypotension, and pruritis.
Opiate agonist agents produce analgesia by activating mu-opioid receptors found in the central and peripheral nervous systems. Activation of peripheral mu-opioid receptors can lead to the development of constipation and postoperative ileus (POI), a common surgical complication.2 Depression of GI motility largely depends on effects of mu receptors in the gut wall.1 In surgical patients receiving postoperative opioid analgesic therapy, mu-opioid receptors in the GI tract mediate reduced motility.3
The emergence of a new class of agents has introduced an opportunity for patients to receive effective pain relief while minimizing the unwanted peripheral effects of opioids. The peripherally acting mu-opioid receptor antagonists (PAMORAs) selectively block opioid effects that are mediated by mu receptors outside the central nervous system. Agents in this class include methylnaltrexone and alvimopan.1 Table 1 provides a summary of fundamental differences between the agents. This report provides an overview of the PAMORAs and gives insight on the impact of inclusion of these agents on a formulary.
METHYLNALTREXONE: OPIOID-INDUCED CONSTIPATION
Methylnaltrexone was approved by FDA in April 2008. It is a quaternary amine (methylnaltrexone bromide); therefore, penetration into the blood-brain barrier (BBB) is limited. This allows the agent to function as a PAMORA in tissues such as the GI tract, thereby decreasing the constipating effects of opioids without affecting opioid-mediated analgesic effects within the central nervous system or precipitating withdrawal symptoms.4
The most common adverse effect associated with opioids is constipation, which occurs in approximately 90% of patients treated. This issue can be problematic to patients that rely on opioids for pain relief associated with terminal illnesses such as cancer, acquired immunodeficiency syndrome, and end-stage diseases. To avoid constipation that sometimes becomes resistant to laxative treatment, patients may decrease their use of opioids, which can lead to additional pain.2
According to the National Comprehensive Cancer Network (NCCN), patients suffering with opioid-induced constipation (OIC) should first increase fluid and fiber intake, as well as physical activity, prior to pharmacologic intervention. If these lifestyle modifications do not provide relief, laxative therapy should be initiated. The NCCN also recommends that cancer patients utilize dual therapy of a stool softener with a stimulant laxative. Another option available includes the conversion of oral or IV opioid therapy to a transdermal alternative, such as fentanyl.5 Methylnaltrexone now provides another option for these patients, as it is FDA approved for OIC in patients with advanced illness receiving palliative care after unsuccessful treatment with laxatives.
Methylnaltrexone is usually scheduled as 1 dose every other day, as needed, but no more than 1 dose in 24 hours in the following dosages:
Safety and efficacy
Methylnaltrexone demonstrated efficacy in 2 double-blind trials, MNTX 301 and MNTX 302, both of which were pivotal to its FDA approval. Both trials evaluated subcutaneous methylnaltrexone for the treatment of OIC in advanced illness patients receiving palliative care. Table 2 provides a summary of these trials.
MNTX 301 compared a subcutaneous dose of 0.15 mg/kg or 0.30 mg/kg versus placebo given as needed over a 4-week dosing period. Study results demonstrated that patients achieved laxation within 4 hours of the first dose in 61.7% (0.15 mg/kg) and 58.2% (0.30 mg/kg) of patients. There were no statistically significant differences in efficacy among the dosages, although the 0.30 mg/kg dosage was associated with more GI adverse effects.4,6
In MNTX 302, patients received 0.15 to 0.30 mg/kg or placebo for 2 weeks. In the MNTX group, 48% of the patients had laxation within 4 hours after the first study dose in comparison to 15% in the placebo group. Additionally, the treatment did not appear to affect central analgesia or precipitate opioid withdrawal.7
The most common adverse effects experienced by patients in the clinical trials included GI disturbances such as abdominal pain, flatulence, diarrhea, and nausea. Additionally, dizziness was reported.6,7 Rare postmarketing adverse effects have included mild to moderate abdominal cramping prior to bowel movements, increase in body temperature, muscle spasms, and syncope.
There are no known drug interactions at this time. Methylnaltrexone is renally eliminated; therefore, patients with severe renal insufficiency (a creatinine clearance 4
A study was conducted of patients with a history of OIC receiving a single methylnaltrexone tablet at different dosage levels following an overnight fast. Forty-eight percent of subjects receiving 1 of the doses (n=25) laxated within 4 hours of treatment.8
Subcutaneous absorption occurs rapidly, with onset of action in 30 to 60 minutes.4 Methylnaltrexone is widely distributed with a steady-state volume of distribution of 1.1 L/kg. Protein binding is relatively low at approximately 11% to 15.3%.4
The primary pathways of metabolism are conversion to methyl-6-naltrexol isomers (5% of total) and methylnaltrexone sulfate (1.3% of total). N-demethylation of methylnaltrexone to produce naltrexone is not significant. Additional information indicates there is minor hepatic metabolism via the cytochrome P450 2D6 pathway, which is responsible for the breakdown of methylnaltrexone into methyl-6-naltrexol isomers, methylnaltrexone sulfate, and 3 other minor metabolites.4
Methylnaltrexone is eliminated primarily unchanged (85% of administered radioactivity), with about 50% of the dose excreted in the urine. It has an elimination half-life of approximately 8 hours.4
Contraindications/Warnings. This medication is contraindicated in patients with known or suspected mechanical GI obstruction. Patients should discontinue use and contact a physician immediately if they experience severe or persistent diarrhea. The use of methylnaltrexone has not been studied in patients with peritoneal catheters.4
Patient monitoring guidelines. Since methylnaltrexone alleviates OIC, monitoring should include evaluating the patient for constipation resolution. Due to the extensive renal excretion, patients should have their serum creatinine monitored to ensure renal function is not declining.4
Preparation, administration, and storage. Methylnaltrexone is available as 12 mg/0.6 mL solution for injection and should only be administered subcutaneously to the upper arm, abdomen, or thigh to achieve the maximum absorption. It should never be administered intravenously, and should be stored at room temperature and protected from light. Once a syringe is drawn, it can be stored at room temperature for no longer than 24 hours.4
ALVIMOPAN: POSTOPERATIVE ILEUS
Alvimopan was approved by FDA in May 2008 as a PAMORA and shares the same mechanism of action as methylnaltrexone. However, the product carries a different indication than methylnaltrexone. POI is an impairment of bowel function following surgery.9,10 Pathogenesis of POI is not fully understood, although autonomic nervous dysfunction appears to be at the root. The hyperactivity of the sympathetic nervous system postoperatively causes decreased release of acetylcholine and increased inhibition of motility.11 Other factors thought to inhibit colonic smooth muscle activity include increased levels of neurotransmitters such as norepinephrine and dopamine, and a decrease in motilin. These factors make management of POI difficult due to its multifactorial etiology ranging from neurogenic, inflammatory, hormonal, and pharmacologic components that arise from the use of opioid analgesics for perioperative pain management. Likely risk factors for development of POI include surgical procedures that trigger the release of endogenous opioids, which bind to mu-opioid receptors within the GI tract inhibiting motility.9
The challenge in identifying the etiology of POI requires a multimodal approach towards treatment. Techniques implemented to prevent POI include the use of minimally invasive procedures, preoperative preparation, and the decreased use of opioid analgesics.12 Supportive nonpharmacologic measures such as nasogastric intubation, early enteral feeding, and ambulation are used, as well as pharmacologic strategies. The clinician should also aim to maintain intravascular volume and if necessary restore fluid and electrolytes. Pharmacologic agents that have been used include neostigmine, prokinetics such as metoclopramide, beta-blockers, and lidocaine. Ideally, treatment of POI should be based on treating the underlying condition if applicable.11
Alvimopan is approved by FDA for the management of POI after major abdominal surgery. Alvimopan antagonizes the peripheral effects of opioids on GI motility and secretions, thus promoting GI motility. Alvimopan contains a charged quaternary structure that lowers its lipid solubility and in turn its ability to cross the blood-brain barrier. Therefore, its oral formulation is poorly absorbed and its effects are mostly concentrated in the GI tract. Due to its limited ability to cross the blood-brain barrier, it does not compromise the analgesic effects of opioid medications.13
The recommended dosage is 12 mg orally, administered 30 minutes to 5 hours before surgery, followed by 12 mg twice daily on the day after surgery for a maximum of 7 days or until discharge, whichever occurs first. Patients are not to receive more than 15 doses. The drug is for hospital use only and is distributed to hospitals that have been enrolled in the Entereg Access Support and Education (E.A.S.E.) program.14
Safety and efficacy
Five phase 3, randomized, double-blind, placebo-controlled, parallel-group, multi-site studies were conducted to review the safety and efficacy of alvimopan in POI. The end point of the studies was the time taken to recovery of GI function, defined as GI-3 and GI-2. Subjects were considered to have met GI-3 when they first tolerated solid food (an indicator of upper GI function recovery), and either passed flatus or experienced a bowel movement for the first time (an indicator of lower GI function). Due to variability in the measurement of flatus, a second composite end point, GI-2, was coined, which represents the later of either of the following-time that the patient first tolerated solid food, or the first bowel movement.9,10,12,15,16 Results from the various trials are included in Table 3.
In patients undergoing major abdominal surgery, including a partial colectomy, a simple or radical hysterectomy, or a laparotomy, and receiving the approved 12-mg oral dose, 4 studies showed that alvimopan accelerated GI recovery and time to hospital discharge order writing. The studies also showed that alvimopan was well tolerated.9,10,15,16 In the study conducted by Büchler et al, the results were not found to be significant.12
A randomized controlled trial was conducted by Webster et al investigating the use of alvimopan in the management of OIC. Subjects were randomly assigned in a 1:1:1:1 ratio to oral alvimopan 0.5 mg twice daily, 1 mg once daily, 1 mg twice daily, or placebo capsules. The primary efficacy end point was a change in weekly spontaneous bowel movement (SBM) frequency during the first 3 weeks of the 6-week treatment period. There was a statistically and clinically significant increase compared with placebo in mean weekly SBM frequency over the initial 3 weeks of treatment (primary end point) with alvimopan 0.5 mg twice daily (+1.71 mean SBMs/wk), alvimopan 1 mg once daily (+1.64 mean SBMs/wk), and alvimopan 1 mg twice daily (+2.52 mean SBMs/wk); P17
The most commonly reported adverse events in clinical trials in patients who received alvimopan were nausea, vomiting, abdominal distention, pruritis, post-procedural pain, pyrexia, urinary retention, hypotension, and hypertension.9,12,15,16
Alvimopan is absorbed in the small intestine and peaks after approximately 2 hours. The steady state volume of distribution is estimated to be 30+10 L. ADL 08-0011 is the primary active metabolite of alvimopan. Both alvimopan and ADL 08-0011 are bound to albumin. Alvimopan and its metabolite are p-glycoprotein substrates, but currently no studies on concomitant administration of strong inhibitors of p-glycoprotein and alvimopan have been conducted. Alvimopan is not a CYP450 substrate inhibitor or inducer; therefore, it is unlikely to alter metabolism of drugs metabolized via these pathways. The pharmacokinetics of alvimopan has not been shown to be affected by concomitant administration of acid blockers or antibiotics, although plasma concentrations of the metabolite were lower in patients receiving these medications. This does not require a dosage adjustment, since the metabolite is not required for efficacy. A high-fat meal decreases the extent and rate of absorption.14
While ADL 08-0011 is eliminated by glucuronidation, biliary secretion is considered the main pathway for elimination. Renal excretion accounts for 35% of the total clearance. In patients with mild to severe renal impairment, there is no need to adjust dosage. However, alvimopan is not recommended for patients with end-stage renal disease.14
Alvimopan has a boxed warning that states it is only available for short-term (15 doses) use in hospitalized patients. It is contraindicated in patients who have received therapeutic doses of opioids for more than 7 consecutive days immediately prior to undergoing surgery. Patients who have been recently exposed to opioids are expected to be more sensitive to alvimopan, and need to be closely monitored for side effects and intolerance.14
A long-term (12-month) clinical study of alvimopan in patients treated with opioids for chronic pain showed a numeric imbalance in the incidence of ischemic cardiovascular events. There were more reports of myocardial infarctions in patients treated with alvimopan 0.5 mg twice daily compared with placebo-treated patients during the first 4 months after the initiation of treatment. Although a causal relationship has not been confirmed with alvimopan, and this has not been observed in other studies, the manufacturer has taken precautions. 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:
Patient monitoring guidelines. Alvimopan should be used with caution in patients with cardiovascular disease. Although no clear relationship exists between alvimopan and cardiovascular complications, clinicians should monitor patients for any cardiovascular side effects, since a high incidence of myocardial infarctions in patients receiving alvimopan was observed in a phase 2 study.
Methylnaltrexone is the first FDA-approved peripherally selective opioid antagonist. Although it is not the only available opioid receptor antagonist, it is the only one indicated for patients with advanced illness who are receiving palliative care, when the response to laxative therapy has not been sufficient. The most beneficial environment for methylnaltrexone seems to be in settings with a population of terminally ill cancer patients or those that provide palliative care services, which may include hospitals, hospices, or organizations that provide home services. These environments should consider methylnaltrexone for their formulary using clinical criteria. This type of restriction allows availability for use by the medical staff after the patient has failed laxative therapy.
Based on clinical trial data, patients should meet the following criteria to receive therapy with methylnaltrexone:
A cost effectiveness analysis was conducted from a third-party payer perspective in the Netherlands to examine treating OIC with methylnaltrexone plus standard care compared with standard care alone in patients with advanced illness who receive long-term opioid therapy. It found that treatment with methylnaltrexone plus standard care was cost effective, resulting in more constipation symptom-free days. The cost of methylnaltrexone was offset by a reduction in other constipation-related costs.18
Alvimopan is the only FDA-approved agent for the management of POI. Such patients would include those undergoing bowel resection or other major abdominal surgeries associated with a high risk of POI. As mentioned in the contraindications/warnings section, hospitals must enroll in the E.A.S.E. program and comply with its criteria in order to acquire the drug.14 Restrictions may need to be placed on the use of alvimopan in patients with cardiovascular disease, recognizing the need for further research in this area. Alvimopan was not studied in opioid-dependent patients and may also be restricted in these groups of patients until additional safety data are available. The appropriate use of alvimopan could be achieved by modifying preoperative and postoperative protocols, policies, and procedures to ensure its optimal use, which will result in positive patient outcomes.3
Other than clinical adverse effects, POI can negatively impact patient satisfaction and increase the use of healthcare resources by prolonging the length of stay if a patient does not regain his/her full bowel function, since patient discharges are often postponed until POI resolves.19 Thus, an effort to minimize POI has the potential to improve length of stay for hospitals, resulting in reduced costs.
The overall incidence of POI is estimated to be 8.5% for abdominal surgeries, 14.9% in large-bowel resection, and 19.2% in small-bowel resection patients. The total cost to U.S. hospital systems is estimated to be $1.46 billion annually.20 These numbers may actually be conservative since an estimated 90% of POI cases go unreported due to the notion that POI is an unavoidable outcome following surgery.19 In a 2007 report, the average length of stay for patients with POI was 11.5 days with an average cost of hospitalization of $18,877, compared to 5.5 days and a cost of $9,460 in those who did not have POI.20 In a separate report of patients with prolonged POI, the average length of stay was 16.6 days and the total mean of hospitalization was $28,823, compared to 8.6 days and a cost of $16,407 for patients without prolonged POI.21
It has been noted that technologies that reduce length of stay such as stents after percutaneous coronary intervention have been shown to have economic benefits. Thus, the ability of alvimopan to reduce the occurrence of POI, thereby reducing the length of stay for patients, can be of benefit to the healthcare system.19
The approval of methylnaltrexone and alvimopan has introduced new therapeutic options in the management of OIC and POI. While it may be necessary to limit their use, this new class of agents may provide clinical benefits to patients and economic benefits to institutions.