AbstractMethadone is currently the only opioid available for the pharmacotherapy of opioid dependence. Cross‐tolerance between methadone and other opioids constitutes the pharmacological basis for substitution and attenuating the effects of illicit opioid use. However, these principles limit the utility of methadone. Potential alternative opioids include long‐acting partial agonists such as buprenorphine and pure antagonists such as naltrexone. Buprenorphine is an alternative to methadone with intermediate intrinsic efficacy. It has a large margin of safety, yet displays some agonist actions similar to methadone. It has greater potential than methadone to safely and effectively block the actions of illicit opioids. Naltrexone is a safe, convenient opioid‐antagonist for use following detoxification from opioid agonists. Its main use is to block the actions of other opioids, thereby attenuating or eliminating illicit use during treatment. However, it is poorly accepted by many clients, limiting its application to a sub‐group who are highly motivated to detoxify. The distinct pharmacological properties of these opioids can overcome some of the drawbacks of methadone, but other limitations may emerge. Non‐opioid adjuncts such as α2‐adrenoceptor agonists can also have a role during detoxification. These drugs might be of use for specific groups of opioid users, providing therapists with the flexibility to tailor pharmacotherapy to the individual need