The use of pharmacological treatments for opioid use disorders, including methadone, buprenorphine and naltrexone has been associated with a reduction in mortality compared with illicit opioid use. However, these treatments can also contribute significantly to the risk of death. The opioid agonists methadone and buprenorphine achieve clinical efficacy in patients with an opioid use disorder through suppressing craving and diminishing the effectiveness of illicit opioid doses, while the antagonist naltrexone blocks the action of opioids. Pharmacological differences between opioid pharmacotherapies then create different temporal patterns of protection and mortality risk, different risks of relapse to illicit opioid use, and variations in direct and indirect toxicity, which are revealed in clinical and epidemiological studies. Induction onto methadone and the cessation of oral naltrexone treatment are associated with an elevated risk of opioid poisoning, which is not apparent in patients treated with buprenorphine or sustained-release naltrexone. Beyond drug-related mortality, these pharmacotherapies can impact a participant’s risk of death. Buprenorphine may also have some advantages over methadone in patients with depressive disorders or cardiovascular abnormalities. Naltrexone, which is also commonly prescribed to manage problem alcohol use, may reduce deaths in chronic co-alcohol users. Understanding these pharmacologically driven patterns then guides the judicious choice of drug and dosing schedule and the proactive risk management that is crucial to minimising the risk of death in treatment.