To review the effects of naltrexone on withdrawal-related adverse events (AEs) and euphoria-related effects, and the relationship between plasma naltrexone concentrations and withdrawal across EMBEDA (MSN; extended-release morphine sulfate with sequestered naltrexone) studies. Five studies in pain patients and a safety review summarizing AE reports during the first year following approval of MSN were assessed for withdrawal reports. Three of these studies also assessed Clinical Opiate Withdrawal Scale (COWS) scores. Plasma naltrexone concentrations of MSN-treated individuals were summarized. Abuse potential was assessed in four studies in non-dependent recreational opioid users. Withdrawal AEs occurred in 13/1781 patients across five MSN studies, and 25/182 cases involving withdrawal were reported in the safety review. In three of these studies, 11/964 patients experienced moderate withdrawal (COWS score = 13-24) and 1/964 patients experienced moderately severe withdrawal (score = 28); all were either non-compliant with study drug, had undetectable plasma naltrexone concentrations, or were tapering to placebo. In ≥89% of plasma naltrexone concentration samples from patients who took MSN (n = 166), naltrexone was below the limit of quantification (4.0 pg/mL). In four studies with non-dependent recreational opioid users (n = 118), crushed MSN was associated with significantly lower scores of drug liking, high, and take drug again than crushed morphine sulfate (p ≤ 0.005). When taken intact as directed, naltrexone in MSN does not precipitate withdrawal. However, when MSN is crushed, naltrexone mitigates, but does not eliminate, the euphorigenic effects of crushed morphine sulfate.