Approved by the FDA since the 1970s, naloxone is a very safe medication with the potential side effect of a theoretical risk of allergy that has never been documented. Its administration may result in acute opioid withdrawal (agitation, nausea, vomiting, diarrhea, "goose flesh", tearing, runny nose, and yawning). When victims experience these symptoms, they may become irritable and anxious. It is uncommon, however, for the revived victim to become violent or combative. Intranasal naloxone delivery is less likely to result in severe withdrawal symptoms than an injection.

On rare occasions, reviving an opioid overdose victim may restart existing health problems or uncover the effect of other drugs the victim had taken. This may result in heart palpitations or seizures. In all cases of overdose, it is critical victims be transferred to the care of medical professionals.