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While mechanical approaches (e.g. splinting) are important in managing sprain, strain, and fracture (SSF) pain, pharmacotherapy retains an important position for orthopedic analgesia. Systemic analgesics used for SSF include acetaminophen (paracetamol), NSAIDs, and opioids. This chapter focuses on systemically active analgesics. Pain relief for SSF can often be facilitated with local or regional injection of local anesthetics. Opioids have long been effectively used for severe SSF pain. Intravenous opioids (e.g. morphine) remain the most effective means for achieving both rapid analgesia and sustained relief (e.g. using patient-controlled analgesia) in most SSF conditions when combined with acetaminophen, the mixed-mechanism opioid tramadol is found to be equally efficacious to hydrocodone for relieving SSF pain. Many combination products are available and often include an opioid and a weaker analgesic such as acetaminophen or aspirin. However, few studies have rigorously evaluated their performance against alternative approaches such as opioid monotherapy.