In the painkiller arena, there's always room for one more, and right now there's easily room for two or three.

Vioxx was withdrawn from the market in 2004 and could conceivably ruin Whitehouse, N.J.-based Merck & Co. Inc.; a jury initially awarded damages of $235.4 million in the first Vioxx lawsuit to reach the courts, despite that fact that the patient in question died from a condition - arrhythmia - that has not been linked to Vioxx use.

Other drugs in Vioxx's class, while not as much of a legal headache for their makers, do bear similar risks for cardiovascular disease.

In the meantime, chronic pain patients are suffering; some have said that an increased risk of cardiovascular disease in the future is a price they are willing to pay for avoiding total disability in the present. There is a need for new approaches to controlling pain.

At least in the near term, it won't be locally administered opioids, though.

Opioids are both the oldest the strongest type of painkillers on the market. However, side effects range from constipation to addiction.

In a paper published in the October 2005 issue of Arthritis and Rheumatism, researchers from the University of Calgary in Alberta tested whether local administration of the opioid receptor agonist endomorphin would alleviate arthritis pain while avoiding some of the side effects of systemic administration. Instead, they found that in a model of long-term arthritis, mu opioid receptors are down-regulated, and local administration of receptor agonists ceases to be effective.

"We were hoping it would work in [chronic inflammation], because it works to control pain in normal and acutely inflamed joints," senior author James McDougall told BioWorld Today. But electrophysiological studies of the neural response to pain in chronically inflamed joints showed that endomorphin "didn't control the pain as well as it should have," based on acute studies.

As usual, "long term" in an experimental study is not as long term as outside of it; the researchers investigated the consequences of arthritis-like swelling for a maximum of three weeks.

Still, that time period was sufficient for mu opioid receptors, the main type of receptor that endomorphin binds to, to be down-regulated. In fact, immunohistochemistry and PCR follow-up studies showed that mu opioid receptors were down-regulated by one week after inflammation began.

McDougall is far from conceding defeat at this point.

"It opens up the possibility to study why these receptors are disappearing in chronic inflammation and what interventions we could use to prevent that loss," he told BioWorld Today, adding that his group is working on a number of approaches toward that goal.

In the meantime, new findings reported in another paper add evidence that a type of calcium channel might be a good target for painkillers. In the Sept. 21, 2005, issue of Journal of Neuroscience, researchers from the University of Virginia report that a subpopulation of pain-sensing neurons is highly enriched in T-type calcium channels.

T calcium channels are not new, but "in typical pain-sensing neurons, they have a very low density," senior author Slobodan Todorovic told BioWorld Today. For that reason, when the channels were first discovered, scientists assumed that they were involved in sensory perception, but not in pain.

However, further studies showed that T-channel antagonists could act as painkillers. In the new research, Todorovic and his colleagues show that not only do T-calcium channels exist on the sensory neurons responsible for pain transmission, but also that on some of those neurons they are the only way for calcium to enter the cell. Todorovic described his lab's discovery as "a new cell subtype based on function."

Todorovic said he hopes that T-channel antagonists ultimately will help control both normal and abnormal pain. Because they are involved in sensitization, there is a possibility that they could be used to treat neuropathic pain, a process in which previously normal stimuli become painful. His lab is currently looking for specific T-channel blockers.