Methylnaltrexone for Reversal of Constipation Due to Chronic Methadone Use

Yuan, Chun Su; Foss, Joseph F.; OʼConnor, Michael; Osinski, Joachim; Karrison, Theodore; Moss, Jonathan; Roizen, Michael F.

doi:10.1001/jama.283.3.367

Cited by 290 publications

(195 citation statements)

References 30 publications

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“…Despite numerous attempts at regulating doses, A-opioid antagonists have proven unsuitable for patients receiving opiates for pain management because of analgesia reversal and breakthrough pain (33). MNTX is a quaternary derivative of the tertiary A-opiate antagonist naltrexone (34). The addition of the methyl group to naltrexone at the amine in the ring forms the compound N-MNTX with greater polarity and lower lipid solubility.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Singleton

Garcia

Moss

2008

Molecular Cancer Therapeutics

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Many patients with cancer receive combinations of drug treatments that include 5-fluorouracil (5-FU) and bevacizumab. Therapeutic doses of 5-FU are often associated with unwanted side effects, and bevacizumab is costly. Therefore, we explored potential agents that can reduce the therapeutic concentration of these drugs. Our data indicate that methylnaltrexone (MNTX), a peripheral antagonist of the M-opioid receptor, exerts a synergistic effect with 5-FU and bevacizumab on inhibition of vascular endothelial growth factor (VEGF) -induced human pulmonary microvascular endothelial cell (EC) proliferation and migration, two key components in cancer-associated angiogenesis. MNTX inhibited EC proliferation with an IC 50 of f100 nmol/L. Adding 100 nmol/L MNTX to EC shifted the IC 50 of 5-FU from f5 Mmol/L to f7 nmol/L. Further, adding 50 ng/mL MNTX shifted the IC 50 of bevacizumab on inhibition of EC migration from f25 to f6 ng/mL. These synergistic effects were not observed with naltrexone, a tertiary M-opioid receptor antagonist. On a mechanistic level, we observed that treatment of human EC with MNTX, but not naltrexone, increased receptor protein tyrosine phosphatase M activity, which was independent of M-opioid receptor expression. Silencing receptor protein tyrosine phosphatase M expression (small interfering RNA) in human EC inhibited both synergy between MNTX and bevacizumab or 5-FU and increased VEGF-induced tyrosine phosphorylation of Src and p190 RhoGAP with enhanced activation of Akt and the actin cytoskeletal regulatory protein, RhoA, whereas silencing Src, Akt, or RhoA blocked VEGF-induced angiogenic events. Therefore, addition of MNTX could potentially lower the therapeutic doses of 5-FU and bevacizumab, which could improve index.

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Section: Discussionmentioning

confidence: 99%

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Singleton

Garcia

Moss

2008

Molecular Cancer Therapeutics

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“…Only the pharmacist was unblinded at each site; the patients and investigators remained blinded during the study. The dose of 0.3 mg/kg methylnaltrexone was selected based on previous studies15,16. The first dose of study drug was administered within 90 min after the end of the surgical procedure.…”

Section: Methodsmentioning

confidence: 99%

Randomized placebo-controlled study of intravenous methylnaltrexone in postoperative ileus

Viscusi

Rathmell

Fichera

et al. 2013

Journal of Drug Assessment

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ObjectiveThis phase 2 study evaluated the safety and activity of intravenous methylnaltrexone on the duration of postoperative ileus in patients undergoing segmental colectomy.MethodsAdults (aged 18 years or older) with American Society of Anesthesiologists physical status of I, II, or III who underwent segmental colectomy, including partial colectomy, sigmoidectomy, cecectomy, or anterior proctosigmoidectomy, via laparotomy with general anesthesia, received intravenous methylnaltrexone 0.30 mg/kg or placebo every 6 h beginning within 90 min after end of surgery. Treatment continued until 24 h after the patient tolerated solid foods, was discharged, or for 7 d maximum. Efficacy endpoints included measures of gastrointestinal recovery and time to discharge eligibility.ResultsA total of 65 patients (methylnaltrexone, n = 33; placebo, n = 32) were randomized. Mean time to first bowel movement was accelerated by 20 h (p = 0.038) and time to discharge eligibility was accelerated by 33 h (p = 0.049) with methylnaltrexone vs placebo. Opioid use was similar between groups until postoperative day 4, then fluctuated in the placebo group. Methylnaltrexone was generally well tolerated.ConclusionsIn this study, intravenous methylnaltrexone significantly decreased time to postoperative bowel recovery and eligibility for hospital discharge by ∼1 d, with an adverse event profile similar to placebo. These were two of several exploratory endpoints; not all efficacy endpoints showed a significant difference between methylnaltrexone and placebo. The efficacy results in this trial were not seen in two subsequent large-scale studies.

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“…[11][12][13] Further studies of methylnaltrexone for the treatment of constipation due to methadone use demonstrated rapid laxation response. [14][15][16] Two randomized, doubleblind, placebo-controlled studies of methylnaltrexone in 288 patients with advanced illness and OIC showed that methylnaltrexone rapidly induced laxation without compromising analgesia. 17,18 Methylnaltrexone is currently approved for the treatment of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.…”

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confidence: 99%

Subcutaneous methylnaltrexone for treatment of acute opioid‐induced constipation: Phase 2 study in rehabilitation after orthopedic surgery

Anissian

Schwartz

Vincent

et al. 2011

Journal of Hospital Medicine

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Methylnaltrexone for Reversal of Constipation Due to Chronic Methadone Use

Abstract: Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.

Cited by 290 publications

References 30 publications

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Synergistic effects of methylnaltrexone with 5-fluorouracil and bevacizumab on inhibition of vascular endothelial growth factor–induced angiogenesis

Randomized placebo-controlled study of intravenous methylnaltrexone in postoperative ileus

Subcutaneous methylnaltrexone for treatment of acute opioid‐induced constipation: Phase 2 study in rehabilitation after orthopedic surgery

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