Chronic neck and low back pain are common in the society, leading to activity limitation and labor loss. Non-steroidal anti-inflammatory (NSAI) drugs and acetaminophen are used as the first option in the treatment of many painful conditions. However, the efficacy and safety of these drugs in chronic neck and low back pain is not clear. The mechanisms of action of these drugs are still unclear. In this article, the mechanisms of action of NSAI drugs and paracetamol, their usage at chronic neck and low back pain treatment, and the side effect profiles are reviewed.