Misadventure with pharmaceutical oral medication has been on the rise, with the opioid crisis playing a major part. Drug overdose related to opioids has become such an issue, that it has been labelled a worldwide crisis. This review explores the mitigation strategies currently in place to prevent accidental overdose from oral pharmaceuticals, categorising the options based on whether they are relevant before, during or after the consumption of a toxic drug dose. To prophylactically prevent an overdose before consumption, governments and medical boards provide guidelines and implement policy, such as prescription monitoring, for the use of heavily abused medication. Some opioids have also been formulated as abuse deterrent formulations (ADF) which make it difficult for an individual to tamper with the medication. However, this does not prevent accidental overdose and only a few novel formulations were found to have multi-dose preventative properties. After an overdose has occurred, the situation is usually dealt with by first responders and hospitals using antidotes or medical procedures to limit the absorption of the drug. As pharmaceutical scientists, therein lies an opportunity to produce novel formulations that could limit the chances of accidental overdose. One approach could be to harness the physiological properties within the gastrointestinal tract (GIT), especially the enzymatic degradation of macromolecular matrix formulations. The ideal formulation will deliver a therapeutic dose but prevent or limit further release from consequent dose forms if a toxic quantity of drug is consumed.