MGH Researchers Shed New Light On How Pain Killers Work

The study, published in the March 22, 2001 issue of Nature, has important implications for improving the way that pain may be treated in the future and for developing safer, more effective pain-killing medications and delivery systems.

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, and 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. This 1970s discovery, in fact, earned a Nobel Prize for John Vane of London.

In the recent study, MGH researchers Clifford Woolf, MD, PhD, director of the Neural Plasticity Research Group in the Department of Anesthesia and Critical Care, Tarek Samad, PhD, a research fellow in Anesthesia, and their colleagues, showed that even as 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. This previously unknown centralized expression results in the production of PGE2 throughout the central nervous system.

PGE2 increases the excitability of nerve cells, a phenomenon known as "central sensitization," which was discovered by Woolf in 1983. 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.

"There clearly is a major central nervous system component in the way that the body responds to inflammation and this has a key role in the production of pain," says Woolf. "Now that we are starting to understand how local inflammation acts centrally, we need to go down a parallel track and find ways to manage pain hypersensitivity more effectively."

In the study, Woolf and his team also shed light on the complex pathway from inflammation to pain. The journey begins 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.

Researchers determined that this chain of events could 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. The researchers also found that because of the central nervous system involvement, drugs delivered directly into the spinal cord required significantly lower doses than drugs administered systemically.

Finally, the research team reported that data from the study indicate that 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.

Woolf says that he is hopeful his team’s findings will help lead to faster, more effective pain-killing drugs that have fewer side effects. He points to last year’s introduction of two Cox-2 selective drugs, which have been highly successful "blockbuster" pain relievers, as the possible beginning of a new era in pain relief. These 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.

"We believe that to have the maximum efficacy, the next generation of pain killers will need to focus on inhibiting central as well as peripheral production of PGE2," Woolf says. "We’re tremendously excited about the potential to relieve suffering more effectively for millions of people around the world."

The study was funded by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health. The Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $300 million and major research centers in AIDS, the neurosciences, cardiovascular research, cancer, cutaneous biology, transplantation biology and photo-medicine. In 1994, the MGH joined with Brigham and Women’s Hospital to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.