Further evidence that endorphins figure importantly in pain control comes from a new look at some of the oldest and newest pain treatments. The new look frequently involves the use of a drug that prevents endorphins and morphine from working. Injections of this drug, naloxone, can result in a return of pain which had been relieved by morphine and certain other treatments. But, interestingly, some pain treatments are not affected by naloxone: Their success in controlling pain apparently does not depend on endorphins. Thus nature has provided us with more than one means of achieving pain relief.

• Acupuncture. Probably no therapy for pain has stirred more controversy in recent years than acupuncture, the 2,000-year-old Chinese technique of inserting fine needles under the skin at selected points in the body. The needles are agitated by the practitioner to produce pain relief which some individuals report lasts for hours, or even days. Does acupuncture really work? Opinion is divided. Many specialists agree that patients report benefit when the needles are placed near where it hurts, not at the body points indicated on traditional Chinese acupuncture charts. The case for acupuncture has been made by investigators who argue that local needling of the skin excites endorphin systems of pain control. Wiring the needles to stimulate nerve endings electrically (electroacupuncture) also activates endorphin systems, they believe. Further, some experiments have shown that there are higher levels of endorphins in cerebrospinal fluid following acupuncture.

  Those same investigators note that naloxone injections can block pain relief produced by acupuncture. Others have not been able to repeat those findings. Skeptics also cite long-term studies of chronic pain patients that showed no lasting benefit from acupuncture treatments. Current opinion is that more controlled trials are needed to define which pain conditions might be helped by acupuncture and which patients are most likely to benefit.

• Local electrical stimulation. Applying brief pulses of electricity to nerve endings under the skin, a procedure called transcutaneous electrical nerve stimulation (TENS), yields excellent pain relief in some chronic pain patients. The stimulation works best when applied to the skin near where the pain is felt and where other sensibilities like touch or pressure have not been damaged. Both the frequency and voltage of the electrical stimulation are important in obtaining pain relief.
• Brain stimulation. Another electrical method for controlling pain, especially the widespread and severe pain of advanced cancer, is through surgically implanted electrodes in the brain. The patient determines when and how much stimulation is needed by operating an external transmitter that beams electronic signals to a receiver under the skin that is connected to the electrodes. The brain sites where the electrodes are placed are areas known to be rich in opiate receptors and in endorphin-containing cells or fibers. Stimulation-produced analgesia (SPA) is a costly procedure that involves the risk of brain surgery. However, patients who have used this technique report that their pain "seems to melt away." The pain relief is also remarkably specific: The other senses remain intact, and there is no mental confusion or cloudiness as with opiate drugs. NINDS is currently supporting research on how SPA works and is also investigating problems of tolerance: Pain may return after repeated stimulation.
• Placebo effects. For years doctors have known that a harmless sugar pill or an injection of salt water can make many a patient feel better -- even after major surgery. The placebo effect, as it has been called, has been thought to be due to suggestion, distraction, the patient's optimism that something is being done, or the desire to please the doctor (placebo means "I will please" in Latin).

  Now experiments suggest that the placebo effect may be neurochemical, and that people who respond to a placebo for pain relief -- a remarkably consistent 35 percent in any experiment using placebos -- are able to tap into their brains' endorphin systems. To evaluate it, two NINDS- and NIDR-supported investigators at the University of California at San Francisco designed an ingenious experiment. They asked adults scheduled for wisdom teeth removal to volunteer in a pain experiment. Following surgery, some patients were given morphine, some naloxone, and some a placebo. As expected, about a third of those given the placebo reported pain relief. The investigators then gave these people naloxone. All reported a return of pain.

  How people who benefit from placebos gain access to pain control systems in the brain is not known. Scientists cannot even predict whether someone who responds to a placebo in one situation will respond in another. The San Francisco investigators suspect that stress may be a factor. Patients who are very anxious or under stress are more likely to react to a placebo for pain than those who are more calm, cool, and collected. But dental surgery itself may be sufficiently stressful to trigger the release of endorphins -- with or without the effects of placebo. For that reason, many specialists believe further studies are indicated to analyze the placebo effect.

As research continues to reveal the role of endorphins in the brain, neuroscientists have been able to draw more detailed brain maps of the areas and pathways important in pain perception and control. They have even found new members of the endorphin family: Dynorphin, the newest endorphin, is reported to be 10 times more potent a painkiller than morphine.

At the same time, clinical investigators have tested chronic pain patients and found that they often have lower-than-normal levels of endorphins in their spinal fluid. If you could just boost their stores with man-made endorphins, perhaps the problems of chronic pain patients could be solved.

Not so easy. Some endorphins are quickly broken down after release from nerve cells. Other endorphins are longer lasting, but there are problems in manufacturing the compounds in quantity and getting them into the right places in the brain or spinal cord. In a few promising studies, clinical investigators have injected an endorphin called beta-endorphin under the membranes surrounding the spinal cord. Patients reported excellent pain relief lasting for many hours. Morphine compounds injected in the same area are similarly effective in producing long-lasting pain relief.

But spinal cord injections or other techniques designed to raise the level of endorphins circulating in the brain require surgery and hospitalization. And even if less,drastic means of getting endorphins into the nervous system could be found, they are probably not the ideal answer to chronic pain. Endorphins are also involved in other nervous system activities such as controlling blood flow. Increasing the amount of endorphins might have undesirable effects on these other body activities. Endorphins also appear to share with morphine a potential for addiction or tolerance.

Meanwhile, chemists are synthesizing new analgesics and discovering painkilling virtues in drugs not normally prescribed for pain. Much of the drug research is aimed at developing nonnarcotic painkillers. The motivation for the research is not only to avoid introducing potentially addictive drugs on the market, but is based on the observation that narcotic drugs are simply not effective in treating a variety of chronic pain conditions. Developments in nondrug treatments are also progressing, ranging from new surgical techniques to physical and psychological therapies like exercise, hypnosis, and biofeedback.

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