The progression of aging and the increase in musculoskeletal diseases have led to an increase in invasive treatment methods, including various surgical methods, but conservative treatment should be attempted before surgical treatment in musculoskeletal diseases. Medication for pain control, such as acetaminophen, non-steroidal anti-inflammatory drugs, steroid, opioids, antidepressants, etc., is one of the most popular methods for pain control. If the pain receptors on peripheral organ are stimulated, pain is transmitted to the brain by the ascending pathway, and the brain then secretes endogenous opioids, such as endorphin, by the descending pathway for pain control. Opioids are substances that act on the opioid receptors, and there are three receptors for opioids. The affinity for each receptor varies according to the tissue and the patient's systemic status. Antidepressants work on the synapses in the central nervous system and its main mechanism is regulation of the ascending pathway. This is mainly effective in chronic pain and neuropathic pain, which is similar in effectiveness to opioids. This review focuses on the effectiveness, method of use, and side effects of opioids and antidepressants.