DRUG FIRMS TRYING TO MAKE PAINKILLERS LESS ABUSABLE

Efforts Include More Tamper-Proof Pills And Compounds That Suppress the 'High'

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."