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The Quest for Pain Relief

) was headed toward extinction.

By | March 28, 2005

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Courtesy of the John C. Liebeskind History of Pain Collection, History & Special Collections Division, Louise M. Darling Biomedical Library, UCLA

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In the 19th century, the European beaver (Castor fiber) was headed toward extinction. The search for pain relief was one of the reasons why. Beavers were hunted for, among other things, castoreum – a smelly secretion known to have analgesic and anti-inflammatory properties. Castoreum's benefits, subsequent analysis has shown, came from salicin derived from the willow bark in the beaver's diet. For those interested in improving modalities of pain relief today, it's perhaps galling to see just how just how little the field has progressed beyond hunting beavers. In light of the huge global burden of under-treated pain, a question worth asking is where the best hope lies for developing better pain treatment modalities.

THERAPEUTIC FAMILY TREE

Since the time of Hippocrates, physicians have known about the analgesic powers of willow bark, although it wasn't until the 19th century that Johann Buchner at the University of Munich isolated pure salicin from willow bark. In 1897, Felix Hoffmann, working for Friedrich Bayer & Co., derivatized one of the hydroxyl functional groups in salicylic acid with an acetyl group (forming the acetyl ester) to reduce side effects. In doing so, he created aspirin.

John R. Vane revealed the mechanism of acetylsalicylic acid in 1971, showing that it suppresses prostaglandins and thromboxanes by inhibiting cyclooxygenase. That work garnered him a Nobel Prize and a knighthood, and it opened the door for the development of the whole class of nonsteroidal anti-inflammatory drugs (NSAIDs), including, more recently, selective Cox-2 inhibitors.

If willow bark is the root of one branch of the pain-relief tree, the other is the poppy. Papaver somniferum was first classified by Linnaeus in 1753, although the drug first appeared in Greek pharmacopoeia during the 5th century BC and in Chinese medical writings during the 8th century AD.

Opium – the dried juice of the opium seedpod – is a mix of sugars, proteins, ammonia, latex, gums, and alkaloids. In fact, it contains more than 50 alkaloids – the most important of which are morphine, noscapine, papaverine, codeine, and thebaine. In 1803, Friedrich Wilhelm Serturner, a German pharmacist, identified and isolated the main ingredient of opium, morphine. He called this alkaloid "morphia," after Morpheus, the Greek God of Dreams. Codeine was first isolated from opium by Pierre-Jean Robiquet in 1832.

And that, to some extent, is where the analgesic train derailed. Efforts to develop new classes of analgesics to add to the salicylate and opioid families have borne little fruit in recent decades. "The benchmark for opioids is still morphine, which is a natural derivative, and the Egyptians knew about that 3000 years ago. And the NSAIDs are basically derivatives of willow bark," says Douglas Justins from the Pain Management Centre at London's St. Thomas' Hospital. "So we haven't really advanced that far, despite the protestations of some of the drug companies."

Justins notes that analgesics targeted at other receptors, such as bradykinin inhibitors and other opioid receptors, have not really come to clinical fruition. "In most hospitals around the world, you'll find that people are using old-fashioned opioids, and they are using NSAIDs in one form or another, and perhaps paracetamol (acetaminophen), which is the new boy on the block."

"That's the cynic's view of the conventional analgesics," says Justins, but he's not alone in holding it. As Henry McQuay from the Oxford Pain Relief Trust puts it: "There's really been very little significantly new in my working lifetime."

Unfortunately, neither opioid drugs nor NSAIDs are without their problems. The issues of addiction and dependency have plagued morphine and its cousins. Negative gastrointestinal effects have troubled traditional NSAIDs, and the cardiovascular effects of the more specific Cox-2 inhibitors are coming under closer and closer scrutiny.

So where does the field go from here? Unfortunately, that's a difficult question to answer, says McQuay. "In most things in medicine, the revolutionary things come out of left field, rather than through a desperately logical approach." "I haven't seen evidence of anything revolutionary in the pipeline," says McQuay. "Presumably one will come.... The question is whether the approach being taken by the pharmaceutical industry is yielding dividends."

GETTING MORE OUT OF NATURE

Considering that analgesia's origins lie in the willow and poppy, one logical place to start looking for new modalities would seem to be back in nature. The toxins of Conus sea snails are one example of a successful new drug from the natural pharmacopoeia, says John Loeser, from the University of Washington, former president of the International Association for the Study of Pain.

"There is a huge need for drugs that make use of nonopioid receptors," Loeser says. Drugs evolving from Conus toxins are genuinely new, and "our hope is that we'll be able to help people for whom opioids haven't been effective," he says. It remains to be seen, however, whether large numbers of patients will be able to handle the side effects of the drugs, he adds.

From a broader perspective, Loeser says that the search for new pain drugs in plants and animals will continue to be a hit-and-miss affair until science has a better understanding of the underlying mechanisms of pain. "If I was the tsar of the drug research world, I would put all my time and effort into better understanding the process," he says. "Until we have a better understanding of the mechanisms, it's a shotgun approach because there isn't any way of looking at the molecular anatomy and saying that product is affecting this mechanism."

Andrew Rice, from London's Imperial College, says he can understand Loeser's perspective, but notes that a decade or so of intensive basic research into the mechanisms of pain have yet to yield many results in the clinic. "There are an awful lot of pointers from basic science as to interesting drug targets," he says. "But by and large, those that have been tested in clinical trials have not worked out."

But Rice is optimistic that there is potential for developing new pharmacological treatments for pain – although in his view, the search will be made easier if the field addresses two major areas. One issue that needs attention is the value of animal models currently used in research. "Do the animal models really replicate model pain?" he asks. "We need to look at our animal models much more critically."

The second issue is that "the way we look for targets hasn't been particularly systematic," Rice says. "It's possible that gene and protein microarrays may be helpful in that regard," he adds, noting that pharmaceutical firms and organizations like the London Pain Consortium are moving down that route.

Rice himself has been closely involved in the development of another emerging class of pain drugs – cannabinoids. He sees them as an example of nonsystematic drug development. "The patients were telling us they worked, so then we went and looked at what their mechanisms might be."

There are suggestions that cannabinoids may have utility in neuropathic pain, although Rice points out that there are still hurdles to overcome. The first relates to drug-delivery methods, as the molecules are not conventionally orally available. The second problem resides in the short-term cognitive side effects of the compounds. "Obviously, some people desire some of these some of the time," he says, but they're not so desirable if you're taking a drug all the time. And thirdly, there's the vexed question of whether they impart any long-term effect on mental illness.

OLD DRUGS, NEW TRICKS

Drugs whose original uses lie in other therapeutic areas have also been a boon for treating pain in recent years. Epilepsy drugs, or anticonvulsants, and tricyclic antidepressants now have extensive use in the pain world. "In chronic pain clinics, and that's where I work most of the time, the big classes of drugs are the antidepressants, and there the drugs that have the most evidence for efficacy are the old-style tricyclics, of which the best example is amitriptyline," says Justins.

Among anticonvulsants, used alongside antidepressants for treating neuropathic pain, there are some new developments, says Justins. "Gabapentin, which is very popular at the moment, has evidence that it is effective," he notes. Add to this pregabalin, a gabapentinoid that he calls "son of gabapentin."

Gabapentin is one new drug in recent years that has been a success, says Rice. But in terms of developing new drugs along the same lines, Loeser says too little is known about fundamental mechanisms. "As new anti-epileptic drugs came along, people said, 'Hey, they're anticonvulsants, so maybe they'll have some effect on neuropathic pain, too,"' he says. "As the newer ones come along, they get plugged because of the preexisting drugs, but no-one has any idea of why they work for pain."

Rice points out, however, that not all anticonvulsants are the same. "The term 'anticonvulsants' is misleading," he says. "They're simply drugs that happen to be useful in epilepsy and in neuropathic pain. To lump them all together as anticonvulsants obscures an opportunity to examine their different modes of action."

SPECIAL DELIVERY

In the clinic, acute pain control has been revolutionized by new methods for delivering conventional drugs. But the relevance for new drug-delivery methods in chronic pain is not so great. "In acute pain and cancer pain, the existing drugs delivered in innovative ways has been a huge advance," says Justins. "But the new drug-delivery systems don't make a lot of difference for chronic pain."

For Loeser, the general issue of newer drug-delivery systems is something the field will see more of in the future. "In particular, the intrathecal route is ripe for development. It is possible that drugs we already have could have more benefit if they are delivered straight to the spinal cord," he says.

On a related subject, experts also feel there is also room for improvement in the way that existing drugs are used. "How do you improve things? The answer is through the education of both patients and health-care professionals to use what they have better. I don't think that's just fiddling at the edges," says McQuay.

It's a principle that has global implications, notes Justins. "A lot of people think that the biggest single advance in pain management worldwide would be to get the regulatory control of morphine relaxed in a lot of countries," he says. "In sub-Saharan Africa and a lot of Islamic countries, morphine is virtually unobtainable. Patients with severe cancer pain are being treated with paracetamol."

NONDRUG APPROACHES

With drug development slowed to a crawl, many clinicians feel that multidisciplinary approaches to treating and managing pain are where the biggest advances are being made. "And that's where a lot of people feel that more of the effort should be put anyway," says Justins.

These approaches put drugs in a matrix of physical, psychological, and other treatments. For example, at the Pain Management Unit in the United Kingdom's University of Bath, the main thrust of the treatment program is nonpharmacological, focusing largely on cognitive approaches. "We're not necessarily anti-drug, but we educate patients to take them appropriately," says research coordinator Catherine Sourbut. "It's to do with de-medicalizing and empowering the patients to manage their pain, as opposed to feeling like they need to get a solution from a medic."

For Sourbut, nondrug pain management is the best bet – short of a miraculous breakthrough. "I'm not aware of any imminent, huge breakthroughs in the pharmaceutical side of things that are suddenly going to mean that pain patients don't have pain any more," she says. "There's always going to be a place for medicine to take the edge of the pain and help people to function better, but it's never going to take the problem away."

Loeser agrees. Multidisciplinary pain management involving cognitive behavioral approaches "is a tremendously undertreated and underrecognized set of issues," he says. "There's good data on their efficacy; there are multiple metaanalyses of randomized clinical trials."

Andrew Rice says he also values multidisciplinary approaches in the clinic, but adds a caveat. "I also think that a lot of it is dealing with the consequences of people not having the right drugs," he says. "It may be that finding different drugs may remove the need for complicated multidisciplinary treatment models."

But as far as Loeser is concerned, the most successful approach to pain treatment will continue to be a matter of tailoring to the individual's needs. "It is very unlikely that we will wake up one day and have a pill or a procedure that will cure all pain," says Loeser. "I think that's beyond hope."

"Well..." he says, pausing, "there is one.... As I've told many a patient, decapitation cures all pain."

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