Millions of Americans suffer from intense but poorly treated pain that could be helped by today's broad array of morphine-based prescription painkillers. Millions of others abuse prescription narcotics, using them to get high rather than to ease pain, and many become addicted.

This dilemma -- that legal painkillers are both under-used and abused -- has become a pressing issue since the introduction in the mid-1990s of the extended-release opioid OxyContin. The drug has provided enormous relief to many pain sufferers and could help many more, but it has also become a drug of choice for many addicts, who promptly discovered how to disable the extended-release aspect of the drug to get high on the enhanced dose.

With the problem now clearly identified, dozens of researchers have embarked on a difficult and high-stakes race to find ways to keep the benefits of prescription painkillers available to pain sufferers while eliminating or reducing the possibility for abuse.

Officials at Purdue Pharma, the makers of OxyContin, say they and at least 19 other companies are actively working on ways to make nonaddictive or less addictive pain relievers. Some are working on compounds other than opioids, but most are trying to reformulate the large array of prescription narcotics already available.

Charles Grudzinskas, who has worked on these issues with industry and then the National Institute on Drug Abuse, said his recent search of patent applications found 450 issued since 1998 for ways to reduce the abuse potential of pain-killing drugs.

"There's a whole biology we're starting to pull apart," said Grudzinskas, who will chair a session this week on the "Quest for Non-Abusable Opioid Analgesics" at the annual meeting in Puerto Rico of the College on Problems of Drug Dependence, a group that has focused on addiction and pain relief since the 1930s. "We're making progress, but this is very hard -- like trying to thread a needle without any glasses on," he said.

The reason is the unique set of demands placed on potential drug producers seeking a less abusable painkiller. Drugs based on morphine, which is derived from the poppy plant, are the gold standard for relieving severe post-operative and chronic pain, and recent research has increasingly found that when used properly by pain sufferers, addiction is seldom a problem. Researchers and drug makers do not want to reduce the effectiveness of the drugs as they make them more abuse-resistant; in fact, they say, it would be unethical to do so.

Individuals respond quite differently to opioids, however, and with even greater variability to opioids that have been combined with another compound. As a result, some combination drugs that might reduce the abuse potential of painkillers are also likely to reduce their effectiveness.

And finally, any effort to make OxyContin or Lortab or other painkillers less prone to abuse has to make them unappealing to addicts while not causing them undue harm. It is a challenge unlike any other in drug formulation.

Nonetheless, industry, the federal government and academic researchers are actively involved in the effort because the need -- and potential profit -- is so great. With doctors increasingly wary of prescribing painkillers to patients because of the possibility of abuse -- and the growing fear that the Drug Enforcement Administration will come after them if they prescribe the high dosages that some doctors now believe are appropriate -- that need is only expected to grow.

Purdue Pharma of Stamford, Conn., for instance, has concentrated on adding a compound that blocks the brain receptors that normally capture the opioids and relay their effects onward in the brain. The compound would be added in contained, or "sequestered," form and would pass inertly through a patient taking the painkiller properly, but it would become an active antidote to the opioid if the pill were opened and crushed for a quick high. The added compound would, in effect, cause the abuser to go into withdrawal rather than feeling euphoric.

"We are very committed to making pain relief that can't be tampered with and abused," said David Haddox, Purdue Pharma's vice president for health policy. "It's our number one priority."

Harvard Medical School professor Clifford Woolf has proposed adding capsaicin, the substance that makes chili peppers hot, to the painkiller in sequestered form. The drug would deliver the expected relief, but it would give an abuser snorting, chewing or injecting it a very unpleasant surprise.

Officials at Endo Pharmaceuticals of Chadds Ford, Pa., another major producer of painkillers, said they are experimenting with new ways to chemically encapsulate the opioids in their painkillers to make it far more difficult for abusers to extract the narcotic.

"We call it the Fort Knox approach," said Endo senior medical officer Bradley Galer. "We want to tweak the formulation, so if the abuser crushes a pill and takes some of the powder, the opioid would still be in extended release form and there would be no sudden burst of drug."

A variation on that idea, under development by a company that wants to remain anonymous, would reformulate painkillers into hard-to-open, gummy pills that squish, rather than split open, when hammered or cut. If perfected, they would deny abusers the narcotics they seek.

Frank Vocci of the National Institute on Drug Abuse said his agency is actively supporting further research into the basic science of how opioids work in the brain, and how they and other analgesics can be made less susceptible to abuse.

Another line of research supported by NIDA involves efforts to create a synthetic cannabinoid (the family that includes marijuana) that relieves pain but does not produce euphoria. The research, led by Alexandros Makriyannis of the University of Connecticut, was reported last year in the Proceedings of the National Academy of Sciences. Other efforts are underway to develop nonaddictive, and potentially very powerful, painkilling agents from puffer fish and sea snails and other shellfish.

Despite the money and effort going to this kind of research, experts doubt any breakthroughs are imminent. "To have a medication that's devoid of abuse potential and has good analgesic effect is highly desirable, but I know nothing at this point that would do it," said Vocci of NIDA. "We hope compounds will become available with reduced abuse liability, and that they will push the more abusable compounds out of the market. But this is such a complicated field that I see no single, absolute solution or silver bullet."

"If this was easy to do," said Martin Adler, executive director of the College on Problems of Drug Dependence, "it would have been done long ago."