How NSAIDs work

NSAIDs reduce inflammatory pain by blocking the action of certain enzymes called cyclooxygenase (Cox) 1 and 2.

Cox-1 is normally expressed in the stomach, where it protects against acid damage. It is also availble in platelets, where it is involved in clotting.

Cox-2, while not normally found in the skin or joints, is produced in these sites after inflammation occurs. Cox-2 is necessary in manufacturing a chemical called prostaglandin E2 (PGE2), which increases the sensitivity of nerves to pain. Inhibition of PGE2 at the site of inflammation had been thought to account for both the anti-inflammatory and pain-killing actions of NSAIDs.

When Cox-2 is produced at the site of inflammation, it also begins to be expressed in nerve cells in many regions of the spinal cord and brain.

PGE2 increases the excitability of nerve cells, a phenomenon known as "central sensitization. Central sensitization alters the processing of pain messages so that normally nonpainful stimuli such as moving a joint becomes painful, and a stimulus such as a pin prick becomes even more painful. It also explains the widespread tenderness that surrounds damaged or inflamed tissue.

Pain from inflammation occurs when peripheral inflammation stimulates production of a molecule called interleukin 1 beta (IL-1b ). IL-1b acts as the trigger that signals nerve cells to switch on the Cox-2 gene. This expression of Cox-2 in turn causes the production of PGE2, which excites nerve cells and leads to pain.

This chain of events can be interrupted at several points along the way to limit the sensation of pain. Drugs targeted at blocking production of IL-1b by inhibiting IL-1b -converting enzymes or ICE, as well as agents that inhibit Cox-2 expression can break this cycle and provide effective pain relief. Also drugs delivered directly into the spinal cord required significantly lower doses than drugs administered elsewhere.

The widespread presence of Cox-2 in the central nervous system may help address the question of why symptoms such as aches and pains, appetite loss and depression are often associated with infection and inflammation.

Recent Cox-2 inhibiting drugs are designed to achieve the analgesic benefits of aspirin and aspirin-like products without the well-known side effects of gastric irritation and bleeding that are associated with NSAIDs that inhibit both Cox-1 and Cox-2.