Pain remains a global health challenge. For decades, clinicians have been primarily relying on μ-opioid receptor (MOR) agonists and nonsteroidal anti-inflammatory drugs (NSAIDs) for pain management. MOR agonists remain the most efficacious analgesics available; however, adverse effects related to MOR agonists use are severe which often lead to forced drug discontinuation and inadequate pain relief. The recent opioid overdose epidemic urges the development of safer analgesics. Combination therapy is a well-established clinical pharmacotherapeutic strategy for the treatment of various clinical disorders. The combination of MOR agonists with non-MOR agonists may increase the analgesic potency of MOR agonists, reduce the development of tolerance and dependence, reduce the diversion and abuse, overdose, and reduce other clinically significant side effects associated with prolonged opioid use such as constipation. Overall, the combination therapy approach could substantially improve the therapeutic profile of MOR agonists. This review summarizes some recent developments in this field.