NOAs include acetaminophen and the non-steroidal anti-inflammatory drugs (NSAIDs). They are the first choice for mild pain. NOAs also play an important opioid-sparing role in multimodal pain therapy for moderate to severe pain. Unlike opioids, all NOAs have a therapeutic ceiling beyond which the beneficial effects cannot be improved by increasing the dosage.

Selecting the appropriate NOA depends on the type of pain and the patient's risk for adverse effects.

• Acetaminophen provides a level of analgesia similar to aspirin without aspirin's side effects. It has very little effect in tissues outside of the central nervous system. It produces analgesia by blocking transmission of pain impulses within the brain. Unlike aspirin, acetaminophen has no peripheral anti-inflammatory effect and no effect on platelet aggregation. Acetaminophen is metabolized by the liver. Patients with liver disease should avoid acetaminophen due to potential for hepatotoxicity.
• NSAIDs produce analgesia by inhibiting the synthesis of pro-inflammatory prostaglandins that sensitize nerve cells. Prostaglandins are synthesized by two forms of the enzyme cyclooxygenase (COX):
  • COX type-1 exists in most cells. It synthesizes homeostatic prostaglandins necessary for normal physiologic functions including vasodilation, GI mucosal health, platelet aggregation and renal perfusion. Aspirin irreversibly inactivates platelet COX-1 which eliminates their ability to aggregate. Platelets are cell fragments which lack the ability to replace inactivated COX-1.
  • COX-2 is induced within cells by stress and tissue injury. It synthesizes pro-inflammatory prostaglandins that lower the activation threshold of nociceptors. COX-2 is also believed to promote synthesis of vascular protective prostacyclin by vascular endothelium.

Non-selective NSAIDs, like aspirin and ibuprophen, inhibit both COX-1 and COX-2, resulting in a greater variety of side effects. Selective NSAIDs primarily inhibit COX-2 prostaglandins. Because selective and non-selective NSAIDs both inhibit COX-2, they all produce a similar level of analgesia. While COX-2 inhibitors have less risk of GI ulceration and hemorrhage they have been found to increase the risk of thromboembolic events including stroke and myocardial infarction.

Therefore, acetaminophen may be the first choice analgesic for mild to moderate pain when inflammation is of little concern or when vascular or renal disease are present. NSAIDs may be preferred if inflammation is present or hepatotoxicity is a risk. Benefits of NSAIDs must be weighed against the risk of GI bleeding and cardiovascular side effects.

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