This Is Why It's Nearly Impossible to Study Pain

This Is Why It's Nearly Impossible to Study Pain

Jeremy Delahanty

The authors discuss tests that look at reflexive responses to potentially harmful stimuli like too much pressure or excessive heat. The hind paw is the location best understood and most often stimulated for investigating these reflexes in animals. The idea is that there is a certain amount of "painful" stimuli an animal can tolerate and, when that threshold is reached, the animal quickly withdraws its limb. Regardless of what test is used, it's important to find a baseline threshold that causes a reflex behavior.

Once the baseline is found, the researcher then induces an injury and the tests are performed again. In response to the injury, the threshold drops. This new, lower threshold is a condition known as allodynia. The IASP defines it as "pain due to a stimulus that does not normally provoke pain." Think of a pleasant shower becoming painful after getting sunburned. The successful treatment of this condition is one of the foremost foundations upon which all new pain relieving treatments are built upon.

Finally, a treatment, such as a new drug or exercise therapy, is given and the tests are performed one last time. If the threshold rises back to baseline or near baseline levels, the therapy has alleviated the paw's allodynia and therefore successfully treated a key component of pain perception. But treating pain in animals does not necessarily treat it in humans. For example, a couple of decades ago, a class of compounds called NK1 receptor antagonists were found to be effective in rodents and hailed as a potential breakthrough in pain care. When clinical trials were performed, however, Merck Pharmaceutical researchers that helped develop the drug were dismayed to find that "the outcome from clinical trials [was] extremely disappointing with no clear analgesic efficacy." The drugs simply failed in humans.

Well that's all very creepy...

This Is Why It's Nearly Impossible to Study Pain

Jeremy Delahanty




Well that's all very creepy...

This reminds me of Conolidine, discovered as a non-opioid extract of the bark of a tropical flowering plant used in traditional Chinese, Ayurvedic and Thai medicine, Tabernaemontana divaricata. Despite its use in traditional medicine, no therapeutically relevant properties of conolidine had previously been reported. Back in 2011 researchers nevertheless investigated its analgesic pain-relieving properties using the standard mouse model techniques, and found that with the mouse model it was a powerful non-opioid painkiller on par with morphine in its effect on pain, but as far as they could tell using mice, with none of the bad side effects of morphine such as addiction, drowsiness and constipation. A practical means of synthesizing the alkaloid compound was found, since the natural source is at extremely low concentration in the plant. A summary article is at https://www.painresearchforum.org/news/6...s-pain-how .

It all looked good for commercial exploitation of it.

Unfortunately in the intervening years practically nothing has happened, beyond selling of a very low concentration extract by an obscure nutritional supplement company Pharm Origins. The primary reason is that it just doesn't seem to work in  humans. With humans, most of its very moderate effects can be traced to placebo effect and suggestion. On top of this the socioeconomics are wrong for commercial exploitation - first, the mechanism of action does not use the brain's opioid receptors and is unknown (making it unpopular in a lot of quarters where this is required to pass it on safety and other factors). Second, and probably the real killer, is that commercial exploitation would very adversely affect the profit margins of some big pharmaceutical companies.