by Dana Alliance for Brain Initiatives

January, 2006

Romilly Lockyer / Brand X Pictures

Blood pressure, pulse, respiration, and temperature are the vital signs that help doctors measure a person’s physical condition. Many doctors now consider pain to be equally important. While there is no objective test for measuring it, an individual’s perception of pain can indicate his or her state of health and well-being. In 2005, pain researchers continued their quest to determine the mechanisms of pain and to develop more effective ways to treat it.

Two studies found that certain drug combinations are effective treatment regimens for pain resulting from injury to peripheral nerves and for severe pain. Another investigation found that activating certain cells in the body eliminates pain by releasing substances that affect how some neurons respond to noxious stimuli. Scientists also discovered a genetic basis for variations in pain perception and the development of a common musculoskeletal pain condition. And, while nearly 45 percent of Americans will seek treatment for pain at some point in their lives, a team of researchers found that only 1 percent of grants funded by the National Institutes of Health had pain as a primary focus.

A Drug Combination to Treat Neuropathic Pain

Neuropathic pain is pain that arises from nerve disease or damage and is a common complication of diabetes, cancer, human immunodeficiency virus, herpes zoster (shingles), and neurodegenerative diseases. The burning, searing nature of neuropathic pain can have a profound impact on quality of life. The drugs to treat neuropathic pain, however, are not totally effective and have dose-limiting side effects.

In an effort to find more effective ways to treat neuropathic pain, researchers at Queen’s University in Canada discovered that combining two drugs commonly used to treat painful diabetic neuropathy and acute nerve pain resulting from herpes can significantly reduce pain more than either drug given individually. In the March 31 issue of the New England Journal of Medicine, 1 Ian Gilron and colleagues reported that treating patients with a combination of gabapentin and morphine reduced their neuropathic pain more than treatment with either drug as a single agent. Gabapentin, which quells the acute radiating spasms of neuralgia, is a first-line treatment for painful neuropathy. Morphine is a powerful narcotic used to treat other kinds of moderate and severe pain.

Forty-one of 57 patients—35 with diabetic neuropathy, 22 with postherpetic neuralgia—completed the trial. Using a pain scale from 0 to 10 (the higher the number, the more severe the pain), the patients reported a mean daily pain score of 5.72 before treatment and, at the highest tolerated dose, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination.

In addition, the highest tolerated doses of gabapentin and morphine were considerably lower when given in combination than when either was used as a single agent, suggesting an additive interaction between the drugs. The researchers also discovered that the gabapentin-morphine combination resulted in fewer adverse effects (such as constipation, sedation, and dry mouth) than either drug caused individually.

Gilron and his team say that, in view of the potential benefits of drug-combination therapies such as this one, trials are needed that will study other combinations of pain fighters and compare them to the use of drugs as single agents for the treatment of neuropathic pain.

Suppressing Pain Outside the Brain

Researchers have found that drugs that mimic the action of natural pain-relief processes in the body are promising candidates for the treatment of acute, inflammatory, and neuropathic pain. Reporting in the February 22 issue of the Proceedings of the National Academy of Sciences, 2 the University of Arizona researchers wrote that they developed a drug that activates the “CB2” receptor—one of a frequently studied group called “cannabinoid” receptors because they respond to the active ingredient of marijuana, or cannabis. Activation of the CB2 receptor, the researchers reported, stimulates the release of a substance that acts on the neurons that send signals from sensory receptors—skin, eyes, ears, nose, and tongue—to the central nervous system to eliminate pain.

Researchers have found that drugs that mimic the action of natural pain-relief processes in the body are promising candidates for the treatment of acute, inflammatory, and neuropathic pain.

More important, the researchers say, is that drugs targeting CB2 cannabinoid receptors do not act widely in the central nervous system, primarily because CB2 receptors are not found there. Because multiple nervous system effects limit many current pain therapies, the narrow range of action is an important feature of this of drugs.

Treating Severe Pain

Researchers at Memorial Sloan-Kettering Cancer Center identified more effective therapies for moderate and severe pain by combining nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, with more powerful painkilling drugs. Used alone, NSAIDs have limited effect in managing moderate-to-severe pain conditions.

In a study published in the March 2 issue of Brain Research, 3 the researchers sought to evaluate the effectiveness of certain combinations of NSAIDs and narcotics in a model of moderate-to-severe pain. By applying heat to the tails of mice to elicit a response to painful stimuli, the researchers found that certain NSAIDs greatly increase the pain-relieving effect of two widely prescribed narcotic drugs, hydrocodone and oxycodone, while other combinations have little utility in combating moderate-tosevere pain. For example, ibuprofen increases pain relief from hydrocodone and oxycodone, but another NSAID does not boost hydrocodone’s effect, and ibuprofen does not increase the pain relief of the narcotics fentanyl and morphine.

NSAIDs suppress the activity of a specific enzyme, cyclo-oxygenase. Two forms of the enzyme—Cox-1 and Cox-2—are known to promote inflammation. The researchers say that more studies are needed to determine how potential combinations of NSAIDs and narcotics interact with Cox-1 and Cox-2 to inhibit inflammation and pain responses. The researchers say that testing different combinations in the clinical setting may help identify better pain-control therapies.

Genetic Basis for Pain Perception

Significant numbers of people develop chronic pain conditions characterized by increased sensitivity to pain. Seeking why some people and not others become especially pain-sensitive, scientists at the University of North Carolina have found that subtle variations in genes can make people less sensitive to painful stimuli and protect them from developing a common, debilitating pain condition called chronic temporomandibular joint disorder (TMJ).

The researchers, led by Luda Diatchenko of UNC’s Comprehensive Center for Inflammatory Disorders, examined 202 healthy women ages 18 to 34 over five years to determine their relationship between pain sensitivity and the development of TMJ, which is characterized by such symptoms as headache, earache, and jaw and facial pain.

Focusing on the genetics of an enzyme called catecholamine-O-methyltransferase (COMT), which controls certain chemicals related to stress response, the researchers conducted molecular biology, cell culture, and animal behavior experiments to demonstrate how COMT and pain sensitivity are related. (Researchers also are studying COMT in relation to schizophrenia; see page 64.)

The findings, reported in the January issue of Human Molecular Genetics, 4 showed that individuals with lower levels of COMT were more sensitive to pain and more likely to develop temporomandibular joint disorder. Slight differences in the gene that produces the COMT enzyme, they found, can predict the risk of developing TMJ, which affects nearly 10 percent of the U.S. population. The UNC researchers believe their findings may also apply to other chronic pain conditions, including fibromyalgia, irritable bowel syndrome, and certain chronic sensory disorders.

Slight genetic differences, significant effects

People with lower levels of a certain enzyme were more sensitive to pain and more likely to develop a debilitating pain disorder. Graph courtesy of Luda Diatchenko

Diatchenko and her colleagues say their findings have ramifications for the development of genetic markers of pain conditions, as well as strategies for treating pain. Based on their findings, they are now investigating new drug therapies for TMJ and related disorders.

Pain Research Database to Identify Underfunded Areas

An estimated 50 million Americans suffer from persistent pain and nearly 45 percent of the U.S. population seeks medical care for pain at some point in their lifetime. In the May issue of the Journal of Pain, 5 with this prevalence of pain in mind, researchers from the University of Utah issued the first-ever classification of pain-research spending by the National Institutes of Health  (NIH). They found that in 2003, the year for which they compiled and analyzed data, the NIH funded 518 pain-related grants. Although these grants totaled $170 million, they accounted for only 1 percent of all NIH funding in 2003.

An estimated 50 million Americans suffer from persistent pain and nearly 45 percent of the U.S. population seeks medical care for pain at some point in their lifetime.

The researchers classified pain grants as either primary or secondary. Primary grants involved research with a main focus on advancing knowledge about pain, reducing pain symptoms, or treating pain, while secondary grants involved studies of pain as a symptom of a specific disease but contributed little to the understanding of pain.

 Using these findings, the researchers developed the Pain and Related Conditions Database (PRCD) to identify underfunded areas of pain research. This interactive database, the researchers say, provides objective and verifiable information about NIH funding patterns for pain research.

The University of Utah researchers say their findings will aid federal and state policymakers, professional pain organizations, researchers and clinicians, as well as those responsible for future pain research.

An accompanying editorial argues that, in addition to helping to determine whether clinical conditions associated with pain are being overlooked by scientists and funding agencies, the PRCD’s strength is its ability to classify research projects by a study’s level of focus on pain. The current NIH research database (called CRISP, for Computer Retrieval of Information of Scientific Projects) does not provide this level of detail.