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NIDA. (1996, April 1). Scientists Explore Novel Approaches to Pain Control. Retrieved from

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April 01, 1996
John A. Bowersox

Two recent studies conducted by scientists in NIDA's Division of Intramural Research (DIR) at the Addiction Research Center (ARC) in Baltimore add to the variety of possible alternative methods of pain control. One study examined whether a medication used primarily for heart problems might also be useful for treating pain; the other investigated a pain-relief pathway that is controlled by sensory nerves in the 's periphery and thus does not involve the central nervous system.

In the first study, Drs. Bruce Vaupel, W. Robert Lange, and Edythe D. London of the DIR demonstrated that the medication verapamil boosted the analgesic effect of morphine and moderated the "high" that is a common side effect of morphine and other opiates.

A calcium channel blocker, verapamil closes the passageways through which calcium enters and exits cells. Manipulating calcium channels with medications can serve a variety of therapeutic purposes. Physicians often prescribe verapamil and other calcium channel blockers to treat high blood pressure, irregular heartbeat, and chest pain caused by heart disease. In animal experiments, calcium channel blockers also have been shown to increase the pain-relieving effect of morphine.

Calcium channel blockers, which are used primarily to treat high blood pressure and other heart problems, have been shown to increase the pain-relieving effect of morphine in animals.

In their study, which was the first demonstration of this effect in humans, Dr. Vaupel and his colleagues found that individuals who received a combination of morphine and verapamil had a higher pain threshold than did individuals who received only morphine. "Verapamil could allow greater pain relief with smaller doses of morphine" and thus be of clinical benefit, says Dr. Vaupel. Another potential therapeutic application of the verapamil-morphine combination could be to control pain in patients who do not respond to opiates alone, he adds. Such patients might respond to the enhanced analgesia promoted by verapamil.

Dr. Vaupel notes that the most novel finding, however, was that the euphoria and other pleasant feelings associated with the morphine high that were reported by the study subjects declined more rapidly in individuals who received verapamil than in those who received morphine only. This effect also could help reduce the dependence liability of analgesic or pain-relieving doses of morphine.

This study involved volunteers with histories of heroin abuse who were subsequently offered referrals to drug abuse treatment programs. Verapamil's effect on morphine-induced analgesia may be even more pronounced in nondrug-abusing patients, says Dr. Vaupel. "Because each individual in the study had a history of heroin abuse, each may have had a tolerance for morphine," he says. Drug-tolerant individuals require more of a drug to experience the same effects that lower doses cause in drug-naive subjects.

"We may be underestimating the effect," Dr. Vaupel says. If so, the verapamil-morphine combination might produce even greater analgesia in nondrug-abusing patients. Further research is necessary to determine verapamil's effects in drug-naive populations, he adds.

Animal experiments conducted for the second study at the ARC suggest the possibility of developing a new generation of analgesics that function by stimulating injured tissue to release endogenous opioids, naturally occurring painkillers produced by the body.

The study, which was conducted by Dr. Christoph Stein and Dr. Michael Schäfer, found that two immune system substances, interleukin-1 (IL-1) and corticotropin-releasing factor (CRF), inhibited pain when injected into inflamed tissue in rats. IL-1 and CRF did not inhibit pain in noninflamed tissue.

The researchers suspected that the pain-relieving effects of IL-1 and CRF were related to the presence of endogenous opioids, also known as endorphins, in the inflamed tissue. Three experiments confirmed their predictions. IL-1 and CRF failed to produce analgesia when antibodies that bind to and inactivate endorphins were injected into the inflamed tissue. Pain relief also was blocked by injecting opioid receptor antagonists into the tissue. Opioid antagonists neutralize endorphins by blocking the sensory nerve cell receptors to which they bind. Finally, the researchers measured the release of endorphin from immune cells grown in the laboratory.

Based on these findings, Dr. Stein, an associate professor of anesthesiology at the Johns Hopkins School of Medicine, hypothesizes that IL-1 and CRF relieve pain by releasing endorphins from inflamed tissue. These endogenous opioids then bind chemically to opioid receptors located on sensory nerve terminals in the inflamed tissue to produce potent analgesia.

The findings, say Dr. Stein and Dr. Schäfer, clearly suggest the existence of a functional link between the immune and sensory nervous systems. The study findings also suggest that it may be possible to develop a new generation of analgesics that would promote the local release of endorphins following injury. By binding to opioid receptors on sensory nerve cells at the site of injury, locally acting endorphin analgesics would not cause unpleasant side effects, such as nausea, sedation, confusion, and breathing difficulties, which can result from the use of opioids that bind to receptors in the brain.


  • Schäfer, M.; Carter, L.; and Stein, C. Interleukin-1 b and corticotropin-releasing factor inhibit pain by releasing opioids from immune cells in inflamed tissue. Proceedings of the National Academy of Sciences 91:4219-4223, 1994.
  • Vaupel, D.B.; Lange, W.R.; and London, E.D. Effects of verapamil on morphine-induced euphoria, analgesia, and respiratory depression in humans. The Journal of Pharmacology and Experimental Therapeutics 267:1386-1394, 1993.