With the opioid crisis in North America, opioid addiction has come in the spotlight and reveals the weakness of the current treatments. Two main opioid substitution therapies (OST) exist: buprenorphine and methadone. These two molecules are mu opioid receptor agonists but with different pharmacodynamic and pharmacokinetic properties. In this review, we will go through these properties and see how they could explain why these medications are recognized for their efficacy in treating opioid addiction but also if they could account for the side effects especially for a long-term use. From this critical analysis, we will try to delineate some guidelines for the design of future OST.