June 13, 2000 UCSF researchers have discovered a pain relief strategy that could provide a long-sought alternative to morphine, without the drug's addictive quality. The finding, the latest in a series of revelations regarding a class of drugs known as kappa-opioids, illuminates just how intricately wired and discriminating the human brain is.
Kappa-opioids have been clinically available for 40 years, but have long been dismissed as ineffective pain killers. Published studies have suggested that women prefer kappa-opioids to morphine during labor and delivery, but current clinical wisdom dictates that they are ineffective, and the pharmaceutical industry's assessment of their effectiveness has been lukewarm at best.
During the last five years, UCSF researchers have revealed a more complex picture of the drug. Their findings have hinted that the drug's full potential has not been tapped. The findings have also provided a window into the complex way in which opioids, including kappa-opioids, act on the pain-modulating circuitry in the body. And these discoveries, in turn, have provided insights into the way men and women experience pain.
In their new study, published in the June 9 issue of Journal of Pain, the researchers appear to have discovered a way to tap kappa-opioid's full potential -- in men and women.
"The potential implications of this finding are really incredible," says the senior author of the study, Jon Levine, MD, PhD, UCSF professor of Oral and Maxillofacial Surgery and Medicine and director of the NIH Pain Center at UCSF. Morphine is the painkiller most often used for severe pain, but it can have limitations -- over time, people can develop tolerance to the drug and/or become dependent on it, and the drug can cause severe constipation.
Low to moderate doses of kappa-opioids, by contrast, have minimal addictive effects. Tolerance is only a minimal problem, and the drugs do not cause constipation.
The finding builds on two previous kappa-opioid studies by the team that showed that men and women experience pain differently.
In their breakthrough study, in 1996, the UCSF researchers discovered that kappa-opioids do, in fact, provide substantial pain relief in women, though not men. Their study, conducted in 48 patients following jaw surgery, provided the first biological evidence that men and women respond differently to potent narcotic analgesics. The finding highlighted the limitation of traditional drug studies -- until the early 1990s, only men were included in most clinical trials.
Last year, the researchers discovered that a low dose of one form of kappa-opioid, known as nalbuphine, actually causes a marked increase in pain in men. The dose-response study, conducted in patients with moderate to severe pain following extraction of impacted wisdom teeth, showed that as the dose was increased, the pain disappeared and a weak, short-lived analgesic effect set in. The low dose had no effect in women, while a higher dose of the drug had a strong and lasting analgesic effect.
In the current study, involving 56 patients following dental surgery, the researchers report that administration of a low dose of nalbuphine, in conjunction with naloxone -- a drug that normally blocks the effects of opioids -- not only prevents the increase in pain in men, but causes profound, prolonged pain relief -- in men and women.
The discovery provides further evidence that men and women respond differently to kappa-opioids, and that naloxone somehow eliminates this difference. The finding also indicates, says Levine, that administering naloxone in conjunction with a low to moderate dose of the nalbuphine may provide a substantial analgesia for moderate to severe pain in both men and women, with minimal side effects, providing a significant alternative to morphine.
The researchers do not know what mechanism allows naloxone to reverse the heightened pain experienced by men receiving low dose nalbuphine, nor how the drug combination causes a powerful analgesic effect in both men and women. But the answer lies somewhere in the opioid pain-modulating system through which kappa-opioids act.
Kappa-opioids have remained of intense interest to UCSF pain researchers, despite their bad reputation as analgesics, because the opioid pain-modulating system has proven, over thousands of years, to be exquisitely designed to relieve pain.
Opioids, which also include heroin, are synthetic versions of drugs originally derived from the juice of the opium poppy plant. They mimic the body's naturally occurring opioids -- the neurotransmitters known as endorphins and enkephalins. Both the drugs and the neurotransmitters attenuate signals of pain by latching on to opioid receptors on cells that normally receive and transmit pain signals.
Morphine acts at so-called mu receptors. Nalbuphine is believed to act predominantly at kappa receptors. Others opioids work at delta receptors. But within each class there are subtypes of receptors and scientists are still working to tease out the impact the individual drugs have at each receptor. There are three clinically available forms of kappa-opioids, nalbuphine, pentazocine and butorphanol.
One possible explanation for the new finding lies in the hypothesis that kappa-opioids have anti-analgesic effects as well as analgesic effects. Previous research has suggested this may be the case. Under this scenario, while the drug may cause analgesia at one receptor subtype, it could be causing anti-analgesic effects at another.
If this were the case, the kappa receptors that mediate the anti-analgesic effect of nalbuphine might be more sensitive to naloxone antagonism than those that mediate its analgesic effect. Thus, naloxone may unmask the analgesic effect of nalbuphine by antagonizing its anti-analgesic effect.
It is also possible, the researchers say, that the profound analgesia produced by the drug combination results in part from an enhancement of a latent capacity for naloxone to produce analgesia itself, though the researchers doubt this is the explanation.
"What is the naloxone reversing? That's what we have to get our hands on," says Levine. "We are trying to design the experiment to make that next step."
Co-authors of the study were Robert W. Gear, DDS, PhD, UCSF assistant clinical professor of Oral and Maxillofacial Surgery in the NIH Pain Center at UCSF; Christine Miaskowski, RN, PhD, UCSF professor and chair of the Department of Physiological Nursing; Newton C. Gordon, DDA, MS, UCSF professor of oral surgery in the Departments of Oral and Maxillofacial Surgery; Steven M. Paul, PhD, associate dean in the School of Nursing and the departments of epidemiology and biostatistics; and Philip H. Heller, MD, PhD, UCSF assistant research professor of physiology.
The study was funded by the National Institutes of Nursing Research and the Kaiser Community Services Program.
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