Adjuvants and co-analgesics are quickly becoming a mainstay of therapy for the treatment of persistent pain. Anesthetics, antidepressants, and anticonvulsants are a few of the pharmacotherapeutic options. While many of these agents have proven efficacious for pain, adverse effects are common and self-discontinuation of these agents by patients are a frequent barrier to care. Here the most common adverse effects will be discussed to assist in the appropriate selection based on patient-specific variables. Monitoring and recommendations for discontinuation will also be discussed.