The Biology of Pain Relief Differs Between the Sexes

Discussion in 'Fibromyalgia Main Forum' started by matthewson, May 27, 2006.

  1. matthewson

    matthewson New Member

    SAN FRANCISCO -- Oct. 29, 1996 -- For women, treatment of moderate to severe pain can be provided with fewer side effects by a neglected class of opioid drugs, according to researchers at the University of California San Francisco.

    The recently developed drugs, called kappa-opioids, are commercially available but seldom prescribed for severe pain because they have been thought to be less effective than morphine or similar opioid drugs, called mu-opioids.

    The UCSF researchers studied 48 men and women in their early twenties for three hours following surgery to remove impacted third molars (wisdom teeth). They found that women experienced much greater and longer-lasting pain relief than men when both were treated with kappa opioids.

    According to Jon D. Levine, MD, PhD, professor of medicine and oral surgery at UCSF and the leader of the research effort, the use of kappa-opioids for women with nerve injury, labor pain, post-surgical pain, cancer pain or other moderate to severe pain should be re-evaluated in light of the UCSF group's recent research. Results of the work, which was funded by the National Institutes of Health, appear in the November issue of Nature Medicine.

    "Kappa-opioid agents appear to be of little clinical benefit for males but produce very satisfactory analgesia for females," Levine says. A more fundamental conclusion can be drawn from the UCSF research, according to Levine. "Our studies provide evidence that biologically, men and women do not obtain pain relief in the same way," he says. "It may be that the brain circuitry regulating pain relief differs between the sexes."

    Kappa-opioids are marketed as a substitute for mu-opioids such as morphine, codeine, oxycodone and methadone. Mu-opioids have been long regarded by doctors as the most powerful painkillers available, but they frequently cause nausea, sedation, confusion and constipation. Furthermore, patients can develop a tolerance and sometimes even an addiction to these drugs.

    Pharmaceutical companies had hoped to develop kappa-opioids as substitutes that would be as powerful as mu-opioids, but without the side effects. However, Levine explains, when the kappa opioids were clinically tested, primarily in men, they were found to lack the painkilling power of the older drugs. As a result, the kappa-opioids have generally been regarded as inferior to the mu-opioid drugs for relief of moderate to severe pain, according to Levine.

    For several years, Levine and his colleagues have used wisdom tooth extraction as a model for the study of pain and pain relief. His research team first discovered a difference in the amount of pain relief experienced by men and women last year.

    That finding was the unanticipated outcome of a study intended to compare the combined effects of pentazocine, a kappa-opioid, and diazepam, a sedative used to relax patients before molar extraction. To the researchers' surprise, statistical analysis indicated that virtually all of the differences in the patients' responses to the drug treatment could be attributed to gender, Levine says.

    Although, it is not clear why, it is well known among pain experts that women report more pain on average than men in response to the same painful situation -- a broken arm, for instance, Levine says. But apparently no research team had ever deliberately set out to investigate the possibility that men and women might also experience pain relief differently, he adds.

    "We have laboriously and exhaustively reviewed the published literature and we cannot find a single study comparing the responses of men and women for any type of painkiller," Levine says. "I have asked many other experts and not one has been able to cite a study that looked for differences."

    Levine's team designed the new study to determine if the discrepancy in pain relief might be due to the general action of kappa-opioid drugs. The researchers tested two different kappa-opioids, nalbuphine and butorphanol.

    Men and women were assigned randomly to be injected with one of the drugs after wisdom tooth extraction, and they did not know which drug they received. At 20-minute intervals over three hours, patients reported the amount of pain they were experiencing. On average, pain relief was greater for female participants and remained strong throughout the evaluation period.

    Levine expects to learn more about the physiological basis of the different responses to kappa-opioid drugs exhibited by men and women by studying female as well as male rats, and possibly through examination of autopsy specimens. In addition, more clinical studies are needed to compare the strength of pain relief provided to women and men by kappa-opioids, mu-opioids, and inactive placebo, Levine says.

    The names of the opioid classes, kappa and mu, correspond to the Greek-letter names assigned to two distinct but related receptor molecules to which the opioids attach at the surfaces of certain nerve cells. When an opioid drug or one of the body's own painkillers, called endorphins, attaches to one of these receptors, the likelihood that an electrical signal registering pain will be relayed from one nerve cell to the next is reduced. Molecules that stimulate the receptors to quell pain are called "agonists."

    Studies of male rats conducted in several laboratories have revealed that kappa and mu receptor molecules populate a different distribution of brain cells, suggesting that they may have different roles in pain perception, Levine says. The side effects of the mu-opioids are attributed to the fact that they sometimes activate a third type of opioid receptor, called the sigma receptor.

    "One possible explanation for our results is the effect of hormones," Levine says. "A male-related hormone, such as testosterone, might interact negatively with kappa-opioid agonists. It's also possible that female-related hormones, such as progesterone or estrogen, bolster the action of kappa-opioid agonists. However, differences unrelated to hormones might also be responsible for the differences in pain relief we have observed."

    Co-authors of the Nature Medicine study include Robert W. Gear, DDS, assistant clinical professor of restorative dentistry; Christine Miaskowski, PhD, RN, professor and chair of the Department of Physiological Nursing; Newton C. Gordon, DDS, clinical professor of oral surgery, and Steven M. Paul, PhD, senior statistician with the School of Nursing, all from UCSF; and Philip H. Heller, MD, PhD, a staff physician with the Kaiser Foundation Hospital, in Hayward, Calif. Heller is also a researcher for the UCSF Department of Oral Surgery.

    An interesting article I found surfing online.


  2. matthewson

    matthewson New Member

    I can attest to that theory since I have red hair! My son does too and another thing they have found with red heads is that they need more anesthesia than the general population. When I go to the dentist, they give me the maximum amount of novacaine (or lidocaine, not sure which one they use now) and I can still feel pain! My son is like that too.

    Redheads also bleed longer. Sometimes it's not much fun being a redhead!

    Take care, Sally

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