David Daniels, Ph.D., a synthetic chemist at the University of Minnesota,
says he has a lofty dream. "I want to develop the perfect
analgesic"—that is, a drug that relieves pain, but that will not
cause tolerance or dependence.
He announced his quest at a recent conference titled "Pain, Opioids,
and Addiction: An Urgent Problem for Doctors and Patients." It was
cosponsored by the National Institute on Drug Abuse (NIDA) and the AMA.
The conference was also the perfect setting for Daniels' announcement since
Nora Volkow, M.D., director of NIDA, had brought scientists on both sides of
the divide—pain control and addiction— together. "For many
years, the two fields did not talk with each other," she said.
But until Daniels' perfect analgesic, or at least until safer analgesics
than the current opioids, are developed, physicians using opioids to treat
pain are faced with a tough balancing act, conference speakers
stressed—relieving patients' pain while avoiding opioid tolerance or
This neuroimage shows where mu opioid receptors are located in the
brain. Opioid drugs produce their analgesic effects by acting on these
receptors, among others. Some scientists have also developed a series of
potent opioid analgesics that target complexes of the mu receptors and delta
opioid receptors, but that do not produce tolerance and dependence as the
currently available opioids can.
Credit: Jon-Kar Zubieta, M.D., Ph.D.
At first glance, the opioid analgesics seem to be wonder drugs, Nathaniel
Katz, M.D., an adjunct assistant professor in analgesic research at Tufts
University, reported. Some 30 randomized, placebo-controlled trials have found
that they can counter numerous types of pain, but patients may develop
tolerance to them. Yet virtually no research has explored this putative
danger, Katz pointed out. So if patients ask whether an opioid is going to
lose its pain-relieving effects over time, physicians should reply that they
honestly don't know, he advised.
Even if the opioids relieve patients' pain without tolerance developing,
there is the risk of dependence on them. However, only two prospective studies
have been published that attempted to determine the magnit ude of dependence
risk in an opioid-analgesic-using population, Katz said. And the studies came
up with markedly different answers—2.5 percent to 5 percent in one and
32 percent in another.
The study that found a 2.5 percent to 5 percent opioid-dependence risk,
Katz explained, was based on a very large sample size (more than 11,000
patients taking opioids for pain), but the diagnosis of opioid dependence was
based on a nonvalidated, telephone survey, "so this is possibly why the
estimate may have been on the low side," he said.
The study that found a 32 percent risk, he noted, was a carefully designed
prospective clinical trial in which patients were followed with urine
toxicology, checked for doctor shopping, and other outcome measures. The
reason why its opioid-dependence risk estimate was much higher than that of
the other study, he speculated, may have been because of its excellent
follow-up or because the "patients may have been at high risk to begin
with, or otherwise they would not have been referred to the clinic in which
the study was being done."
In any event, yet a third prospective investigation to determine the degree
of opioid abuse/dependence was reported at the pain-opioid conference by Mark
Sullivan, M.D., a professor of psychiatry at the University of Washington. Its
estimate of opioid-dependence risk was 2 percent, that is, close to what one
of the two previous investigations found. But like the two previous studies,
it too had its strengths and weaknesses, Sullivan pointed out. For example, it
was based on a very large sample size (15,000 veterans taking opioid
medications for pain relief), but automated diagnostic records were used to
assess opioid abuse/dependence, so some cases may have been missed.
But even if the risk of opioid dependence is as low as 2 percent,
physicians may worry that their patients might be among that percentage,
conference speakers said. One possible red flag is depression, Sullivan
indicated. In their prospective study of veterans, he said, "a diagnosis
of depression while receiving opioid therapy predicted opioid dependence even
when possibly confounding factors were taken into consideration."
Another predictor of dependence is euphoria, Katz pointed out. In an
unpublished study of 40 subjects taking opioids for pain, he and his coworkers
found that those who initially experienced euphoria went on to become
So Daniels' dream—an opioid that relieves pain without causing
tolerance or dependence—would indeed be a windfall for pain patients and
the physicians who treat them. But how realistic is it?
Actually quite realistic, Daniels believes. He and his colleagues have
developed a series of potent opioid analgesics that target complexes of mu
opioid receptors and delta opioid receptors (two of the three types of opioid
receptors identified to date). Several of these compounds do not produce
tolerance or dependence. The University of Minnesota is in the process of
patenting them, and two drug companies have approached the university about
Yet another approach to creating an opioid that relieves pain without
producing dependence is being explored by Christopher Evans, Ph.D., a
professor at the University of California at Los Angeles's Center for Study of
Opioid Receptors and Drugs of Abuse. The tactic consists of separating the
rewarding effects of opioids from their analgesic effects. For example, he is
interested in combining opioid analgesics with antagonists of the cannabinoid
system, which seems to be involved in the rewarding aspects of opioids.
In fact, new types of pain medications that are just as potent as the
opioids and without the danger of dependence may become available during the
next few years. For example, Ze'ev Seltzer, D.M.D., a scientist at the
University of Toronto's Center for the Study of Pain, and his colleagues have
amassed evidence that pain in both animals and humans has a strong genetic
basis and have identified one of the genes involved. By 2010, he predicted, he
and others in the field of pain genetics will have identified a number of
important pain genes, and this identification will lead to the design of
painkillers that are as effective as, but safer than, currently available
Nonmedical pain treatments, and thus purportedly without dependence
problems, are being explored as well. R. Christopher deCharms, Ph.D., chief
executive officer of Omneuron Inc. in Menlo Park, Calif., and his colleagues
are using neuroimaging to train subjects to activate certain areas of their
brains that are involved in suppressing pain. This activation, they hope, will
then lead to pain relief. Results in a small number of patients suggest that
such brain control is feasible and that it can counter both experimental pain
and chronic pain over the short term.
"We are now doing studies to see whether [with this method] we can
reduce chronic pain long term," he said. "We have [studied] 21
patients to date. We are seeing a decrease in pain ratings thus far. But we do
not yet have a placebo group in place." ▪