Table 1.

Adverse Events in Studies of Methylnatrexone for the Treatment of OIC. All Patients in These Trials Had OIC

Study Drug	Patient Population	Safety Results	AE Severity	Comments
Anissian 201121 SQ MTX 12 mg QD RCT	33 pt with acute OIC following orthopedic surgery	AEs reported in 33% of MTX and 27% of placebo pt Most common AEs possibly related to study drug: nausea, abdominal pain, diarrhea GI adverse events occurred in 17% of MTX and 7% of placebo pt	No serious AEs occurred	2 pt in MTX group discontinued the drug No changes in analgesia No signs of OWS
Bull 201513 SQ MTX 8 or 12 mg/kg QOD Placebo-controlled with OLE	230 patients with advanced illness in DB study and 149 entered OLE	AEs occurred in 82% of MTX and 74% of placebo pt in RCT and in 90.6% of OLE pt Most common AE in MTX pt was abdominal pain, 33% vs 17% in RCT In OLE most common AEs (≥ 5 pt) deemed at least possibly related to MTX were abdominal pain (15%), diarrhea (7%), and flatulence (3%)	No serious AEs in the RCT or OLE were considered related to MTX Most side effects were mild to moderate	No clinically meaningful changes in pain, analgesia reported in RCT or OLE OWS results not reported
Chamberlain 200916 SQ Methylnaltrexone 0.15 mg/kg every other day for 2 wk RCT	71 patients with advanced illness	Abdominal pain, flatulence, nausea, increased body temperature, dizziness occurred in ≥ 5% more MTX pt than placebo patients Most common AEs were abdominal pain, flatulence, vomiting	Most AEs in both groups were mild to moderate Serious AEs occurred in both active and control groups but all were deemed related to the underlying illness	On the Himmelsbach Withdrawal Scale, ≤4% of patients in either group had a change from none to mild to moderate 1 pt taking MTX had severe OWS at day 14
Lipman 201110 SQ MTX 0.15 mg/kg as needed with dosing adjustments possible up to 0.3 mg/kg or 0.075 mg/kg OLE	82 pt with advanced illness who had previously participated in the study reported below under Thomas 2008	Every pt experienced at least 1 AE with most common AEs: abdominal pain (30.5%), cancer progression (24.4%), nausea (20.7%) and vomiting (19.5%) 57/82 pt had GI AEs of which 31 were possibly or probably or definitely related to MTX and 26/82 AEs were not	Serious AEs occurred in 43.9% of pt but the most common related to the underlying disease (neoplasm progression) Serious AE deemed possibly related to MTX occurred in 1 pt (muscle spasms)	6 pt discontinued MTX because of AEs No pt reported clinically meaningful changes in analgesia or pain intensity Most pt had no signs or mild signs of OWS
Mori 201715 SQ MTX Single-dose (not stated) Observational	12 cancer patients	No severe AEs at 4 h 1 severe AE at 24 h (nausea) 1 severe AE at 48 h (abdominal pain) Most frequent AEs at 4, 24, and 48 h: mild to moderate flatulence No reports of injection site reaction.	Most AEs were mild to moderate	No signs of OWS
Nalamachu 201524 SQ MTX Pooled analysis from 2 RCTs	165 pt with advanced illness	Any AE for MTX: 0.15 mg/kg: 77% 0.30 mg/kg: 82% Pooled: 79% Placebo: 68% Most common AEs for MTX were abdominal pain (28% vs 10% placebo), flatulence (7% vs 12% placebo), vomiting (9% vs 8% placebo), restlessness (7% MTX and placebo), peripheral edema (4% vs 7% placebo), abdominal distension (2% vs 6% placebo), and fall (2% vs 6% placebo)	Most AEs were mild to moderate, 10% were serious and the most common of which was neoplasm progression (unrelated to study drug).	Analgesia and OWS not reported No discontinuations reported
Rauck 201723 Oral MTX (150, 300, or 450 mg) QD for 4 wk then PRN for 8 wk RCT	803 chronic noncancer pain pt	Over 12 wk, abdominal pain occurred in 11% MTX vs 9% placebo pt; nausea 6% vs 9%; diarrhea 8% vs 4%. AEs were similar by dose to placebo: MTX 150: 86% MTX 300: 87% MTX 450: 86% Placebo: 86%	Most AEs were mild to moderate. Serious AEs occurred in 3% of MTX groups (pooled) vs 4% of placebo	Those who discontinued the drug were similar by group: MTX 150: 1% MTX 300: 3% MTX 450: 0 Placebo: 2% Analgesia remained similar across all groups for 12 wk OWS not reported
Thomas 200817 SQ MTX 0.15 mg/kg every other day for 2 wk Placebo controlled In the extension phase, doses could increase, as needed, max 0.3 mg/kg	133 pt with advanced illness	Most commonly reported AEs in both groups (≥5% or more of pt affected): abdominal pain, flatulence, nausea, increased body temperature, and dizziness but were reported more in the MTX than placebo group Falls and hypotension occurred more often in the placebo group	Most AEs were mild to moderate Serious and severe AE occurred in 17% and 8% of MTX pt respectively and 28% and 13% of placebo patients, most of which were related to the underlying disease Life-threatening AE occurred in 16% of MTX and 15% of placebo patients, all of which were deemed related to the underlying illness 6% of MTX and 7% of placebo patients discontinued the study drug during the study	The extension phase of this study is reported as Lipman
Viscusi 201619 SQ MTX (12 mg QD, 12 mg QOD) in RCT for 4 wk	460 patients with noncancer pain in the RCT, of whom 134 entered the OLE and crossed over to SQ MTX 12 mg PRN	33% of RCT and 43% of OLE pt had an AE. In the OLE, the most common AEs were abdominal pain, nausea, and urinary tract infections	Serious AEs were reported by 1 pt in RCT and 4 pt in OLE, none of which were considered MTX related	Abdominal pain typically decreased over time Analgesia changes and OWS not reported
Webster 201722 SQ MT 12 mg QD, 48 wk Open-Label	1034 pt with noncancer pain	79% of pt reported an AE, most AEs were GI (24% abdominal pain, 16% diarrhea, 7% vomiting, 7% upper abdominal pain, 6% flatulence) 11% reported a psychiatric disorder (anxiety, depression, insomnia)	Most mild to moderate with 6% severe. The most common severe AE was abdominal pain (4%). 10% reported serious AEs of which four patients had AEs possibly related to MTX	15% of pt discontinued because of AEs 1.5% reported a cardiac AE but no clear causal link to MTX could be found No sign of OWS Analgesia changes not reported

Note: Data from these studies.10,13,15–18,21−24

Abbreviations: AE, adverse event; GI, gastrointestinal; h, hour; max, maximum; mg, milligram; mg/kg, milligram per kilogram; MTX, methylnaltrexone; OLE, open-label extension (study); OWS, opioid withdrawal syndrome; pt, patient(s); QD, once a day; QOD, once every other day; RCT, randomized clinical trial; SQ, subcutaneous; wk, week.