Serious life-threatening respiratory depression may occur with pharmacologic pain intervention. The nurse has an ethical and legal duty to provide safe, quality, and accountable pain management. The nurse must acquire self-efficacy for the administration of pain medications for critically ill patients to prevent serious side effects and adverse reactions. This article presents a clinical toolkit for acute pain pharmacologic management by presenting professional guidelines, evidence-based pain assessment tools, common pain medication therapy, and focused monitoring specific to the drug. Medical adjustments owing to special populations is also discussed. Case reports demonstrate application of clinical reasoning skills needed for pain management.