Evidence supports the use of opioids for treating acute pain. However, the evidence is limited for the use of chronic opioid therapy for chronic pain. Furthermore, the risks of chronic therapy are significant and may outweigh any potential benefits. When considering chronic opioid therapy, physicians should weigh the risks against any possible benefits throughout the therapy, including assessing for the risks of opioid misuse, opioid use disorder, and overdose. When initiating opioid therapy, physicians should consider buprenorphine for patients at risk of opioid misuse, opioid use disorder, and overdose. If and when opioid misuse is detected, opioids do not necessarily need to be discontinued, but misuse should be noted on the problem list and interventions should be performed to change the patient’s behavior. If aberrant behavior continues, opioid use disorder should be diagnosed and treated accordingly. When patients are discontinuing opioid therapy, the dosage should be decreased slowly, especially in those who have intolerable withdrawal. It is not unreasonable for discontinuation of chronic opioid therapy to take many months. Benzodiazepines should not be coprescribed during chronic opioid therapy or when tapering, because some patients may develop cross-dependence. For patients at risk of overdose, naloxone should be offered to the patient and to others who may be in a position to witness and reverse opioid overdose.