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Stroke is a leading cause of death and disability, and novel treatments need to be found, particularly drugs with neuroprotective and restorative effects. Lately, there has been an increased interest in the relationship between opioids and ischemic stroke. To further appreciate this association between opioids and stroke, we conducted a systematic review to investigate anti-opioid medication's effectiveness in treating ischemic stroke. We used PubMed advanced-strategy and Google Scholar searches and only included full-text clinical trials on humans and written in the English language. After applying the inclusion/exclusion criteria, seven clinical trials were reviewed. Only one of the naloxone and nalmefene clinical trials showed statistically favorable results. Overall, the nalmefene clinical trials used more updated measures (NIHSS, GOS) to evaluate recovery and functional status in ischemic stroke patients than the naloxone clinical trials. There was less bias in the nalmefene clinical trials. Animal and in vitro studies have showed promising results. Additional research should be conducted with new clinical trials of both drugs with larger samples in patients less than 70 years old and moderate to severe infarcts. [ABSTRACT FROM AUTHOR]