Brand Name: Relistor®
Generic Name: methylnaltrexone bromide
Manufacturer: Wyeth Pharmaceuticals
Drug Class1: Gastrointestinal Agent
Opioid Antagonist
Uses1,3:
Labeled: Opioid-induced constipation, in adult patients with advanced illness receiving
palliative care after failing laxative therapy
Unlabeled: Opioid-induced constipation
Mechanism of Action1,2:
Methylnaltrexone bromide is a peripherally acting mu-opioid receptor antagonist. It is a quaternary derivative of naltrexone. Methylnaltrexone selectively targets receptors in peripheral tissues without diminishing the opioid affects in the central nervous system. The addition of the methyl group to the ring nitrogen of naltrexone creates a quaternary amine that carries a permanent positive charge. The charge gives methynaltrexone its peripheral receptor selectivity since the molecule has greater polarity and lower lipid solubility, which lowers the molecules ability to cross the blood brain barrier.
Pharmacokinetics1,3:
Tmax |
0.5 hr |
Vd |
1.1 L/kg |
t ½ |
~8 hr |
Cl |
Not Reported |
Protein Binding |
11.0% – 15.3% |
Bioavailability |
Not Reported |
Metabolism1,3: The primary pathways of methylnaltrexone bromide metabolism are conversion to the methyl- 6-naltrexol isomers and methylnaltrexone sulfate. N-demethylation to naltrexone does not appear to play a large role in the metabolism of the drug.
Elimination3: Approximately 85% of a methylnaltrexone bromide dose is excreted unchanged. About 50% of a dose is excreted in the urine with lesser amounts being excreted in the feces.
Efficacy4,5,6:
Yuan CS, Wei G, Foss JF, O'Connor M, Karrison T, Osinski J. Effects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: a double-blind randomized placebo-controlled trial. J Pharmacol Exp Ther. 2002 Jan;300(1):118-23.
Study Design: Double-blind, randomized, cross-over, placebo-controlled trial
Description of Study: The purpose of the study was to assess the effect of subcutaneously administered methylnaltrexone bromide on morphine-induced delays in oral-cecal transit time and on morphine-induced subjective effects, such as dizziness, headache, nausea, dry mouth, warmth, tingling, and itching. Twelve subjects were randomized and divided into two groups of six. The study consisted of three separate blinded sessions. Patients received each treatment regimen once over the course of the study. In session 1 both groups were administered a combination of placebo plus placebo to obtain baseline levels. In sessions 2 and 3 subjects were given, in random order, either placebo plus 0.05 mg/kg IV morphine or SQ methylnaltrexone (0.1 mg/kg in group one and 0.3 mg/kg in group two) plus 0.05 mg/kg IV morphine. In group one, morphine plus placebo increased transit time from 85 ± 20.5 min at baseline to 155 ± 27.9 min (P <0.01). Administration of 0.1 mg/kg methylnaltrexone plus morphine showed a transit time increase to 110 ± 41.0 min. In group two, morphine plus placebo increased transit time from 98 ± 49.1 min at baseline to 140 ± 58.2 min (P < 0.01). Administration of 0.3mg/kg methylnaltrexone plus morphine increased transit time to 108 ± 59.6 min (P <0.05). Morphine plus placebo showed increased morphine-induced subjective effects 20 min after the start of the IV infusion in both groups (P < 0.01 for both). Both methylnaltrexone dosages showed significant reductions in morphine-induced subjective effects (P < 0.05 in 0.1 mg/kg group, P < 0.01 in 0.3 mg/kg group). Laxation response was not reported in this study. No adverse events were observed in the study.
Limitations: Major limitations of this study included the small sample size and no reported power. The study subjects were healthy individuals who do not represent the population the drug is approved to treat. Only one dose of the drug was given which does not indicate anything about safety or efficacy of multiple doses. A cross-over design was used. A few of the authors stood to benefit financially from the success of the study medication.
Conclusion: Despite the limitations, the study did show that co-administration of methylnaltrexone plus morphine decreased oral-cecal transit times compared to morphine administration alone. The drug also showed a greater ability to reduce morphine-induced subjective effects compared to placebo. Methylnaltrexone may be an alternative to treat morphine-induced constipation; however, larger scale studies of longer duration and better study design need to be conducted to verify these findings.
Portenoy RK, Thomas J, Moehl Boatwright ML, Tran D, Galasso FL, Stambler N, et al.
Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in
patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. J Pain Symptom Manage. 2008 May;35(5):458-68.
Study Design: Multicenter, randomized, parallel group, repeated dose, dose-ranging trial, consisting of a one week double-blind phase and an additional three week open- label phase.
Description of Study: The purpose of the study was to assess the safety and efficacy of subcutaneous methylnaltrexone on opioid-induced constipation in patients with terminal illnesses. Thirty-three subjects who were receiving palliative care with chronic opioid therapy for a terminal or end-stage illness were included. Patients were initially randomized to receive either 1 mg, 5 mg, or 12.5 mg doses of methylnaltrexone. The dose range was extended to include 20mg after completion of the preliminary blinded assessment. Patients received doses on days 1, 3, and 5 during the double-blind phase, and as often as every other day during the open-label phase. The primary outcome measure was laxation response, defined as a bowel movement within four hours of the initial dose. Secondary outcome measures included laxation responses within four hours of subsequent doses, and within 24 hours after each drug administration. Primary outcome data from the double-blind phase showed that 1 out of 10 patients responded to the 1 mg treatment, 3 out of 7 to the 5 mg treatment, 6 out of 10 to the 12.5 mg treatment, and 2 out of 6 to the 20 mg treatment. This data showed no dose-response relationship among the three higher doses (P = 0.05), however a significant difference was seen between 5 mg vs. 1 mg (P = 0.05) and 12.5 mg vs. 1 mg (P = 0.06). The data showed no significant difference in secondary outcomes between treatments, but a positive trend was seen when the higher doses were collectively compared to the 1 mg dose. Eighteen subjects took part in the open-label phase of the study. One hundred total doses were administered during this phase, with the majority being in the 5 – 12.5 mg range. Similar results were obtained during this phase to those obtained in the double-blind phase. Laxation response ranged between 49% and 63%. All patients experienced at least one adverse event, but the majority of these were attributed to factors other than the drug. One subject experienced drug related syncope.
Limitations: The study contained several limitations, including a small sample size, a large number of drop-outs, and a lack of a control group. Funding was provided by the company that manufactures methylnaltrexone.
Conclusion: The significance of the data obtained in this study could be discredited due to some of study limitations. However, methylnaltrexone doses between 5 mg and 12.5mg were shown to increase laxation response. Although this study has shown that certain doses of methylnaltrexone can significantly reduce the effects experienced with opioid- induced constipation, further studies need to be conducted to determine if these doses are optimal.
Yuan CS, Foss JF, O'Connor M, Toledano A, Roizen MF, Moss J. Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther. 1996 Apr;59(4):469-75.
Study Design: Double-blind, randomized, placebo-controlled trial
Description of the Study: The purpose of the study was to assess the effects of methylnaltrexone on analgesia and morphine-induced delays in gastrointestinal motility. Only the effects on analgesia will be discussed in this monograph due to the fact that IV methylnaltrexone was used in this study and its effects on gastrointestinal motility may not translate to the subcutaneous formulation. Fourteen subjects, aged 18 to 43, were enrolled in the study. The study consisted of three separate blinded sessions. Patients received each treatment regimen one time over the course of the study. Patients were administered a combination of placebo plus placebo in session 1. In sessions 2 and 3 subjects were given, in random order, either placebo plus 0.05 mg/kg IV morphine or 0.45 mg/kg IV methylnaltrexone plus 0.05 mg/kg IV morphine. Methylnaltrexone’s effect on analgesia was assessed by the cold-pressor test, which consist of patients immersing their forearm in a tub of ice water. Pain intensity and pain bothersomeness were assessed at different intervals by a subjective rating scale ranging from 0 to 10, 10 representing extreme pain/bothersomeness. This test was conducted during each of the 3 sessions. The study showed that the ability of methylnaltrexone plus morphine to reduce the pain intensity ratings was not significantly different to the effect of morphine alone (P = 0.78). The methylnaltrexone and morphine combination did not produce a lesser reduction in pain bothersomeness either (P < 0.01).
Limitations: The study was conducted on healthy individuals who were not on chronic opioid therapy. These parameters don’t represent the population this drug is intended to treat. The study had a small sample size.
Conclusion: The study did show that methlynaltrexone does not antagonize the analgesic effects of morphine. Since the cold-pressor is a widely used and accepted test to analyze the analgesic effects of drugs, the information obtained from this test can be validated. The data obtained shows methlynaltrexone’s potential ability to limit the peripheral side effects seen with opioid therapy without affecting the analgesic effects of the drug. However, tests need to be conducted to further assess the drug’s central antagonizing effects on different subsets of the population. Tests also need to be conducted using the commercially available subcutaneous formulation to confirm the results obtained from using the IV formulation.
Contraindications1,3:
Patients with known or suspected mechanical gastrointestinal obstruction.
Precautions1,3:
Discontinue therapy if severe or persistent diarrhea occurs; Dosage adjustment required for severe renal impairment.
Adverse Effects1,3:
Abdominal pain (28.5%)
Flatulence (13.3%)
Nausea (11.5%)
Dizziness (7.3%)
Diarrhea (5.5%)
*Rates based on clinical trial data and may not translate to rates seen in the practice setting
Drug Interactions3: No significant interactions have been reported.
Dosing/Administration1,3:
Usual Dose: One dose (wt. based) given SQ every other day as needed. Max of one dose in a 24-hour period. See the table below for correct weight-based dose.
Patient Weight |
Dose |
Injection Volume |
< 38 kg (< 84 lb) |
0.15 mg/kg |
*See Below |
38 – 61 kg (84 – 135 lb) |
8 mg |
0.4 mL |
62 – 114 kg (136 – 251 lb) |
12 mg |
0.6 mL |
> 114 kg (> 251 lb) |
0.15 mg/kg |
*See Below |
* Injection volume should be calculated as follows:
- Patient wt in kilograms multiplied by 0.0075 and round up the volume to the nearest 0.1 mL
- Patient wt in pounds multiplied by 0.0034 and round up the volume to the nearest 0.1 mL
Geriatric dose: No adjustment is necessary
Pediatric dose: Safety and efficacy have not been established
Renal impairment dose:
Mild to Moderate: No adjustment is necessary
Severe (CrCl < 30 mL/min): Reduce weight-based dose by one-half
Patients on Dialysis: Data not available
Hepatic impairment dose:
Mild to Moderate: No adjustment is necessary
Severe: Data not available
Use in special circumstances1,3:
Pregnancy: Category B
Breast feeding: Animal studies have concluded that methylnaltrexone bromide is excreted in the milk of lactating rats. No human data is available.
Conclusion: Methylnaltrexone bromide has the potential to be a very useful drug in the treatment of opioid-induced constipation and other opioid related side effects. Studies have shown its ability to reduce these types of symptoms without antagonizing the analgesic properties of these drugs. Methylnaltrexone is currently only approved to treat a small subset of the population so its current role in this arena is limited. Due to the availability and affordability of other laxative medications, methylnaltrexone is currently used as a last-line treatment. Though its use will continue to be reserved, further investigation may expand its value to include a larger demographic.
References:
Prepared by: Chris Costelnock, Doctor of Pharmacy Candidate.