EDITOR'S NOTE: For this Inaugural Forum, Jeffrey Mogil of McGill University raises the question why have the fruits of basic research in the pain field not translated into new treatments? Read Jeff's introductory text and then share your opinion.
Despite greatly increased academic and industry resources aimed at basic, translational and clinical pain research over the past few decades, and despite an explosion in pain “targets” (my PainGenes Database currently lists 334 genes implicated causally in pain or analgesia based on null mutant studies alone), only a tiny handful of drugs acting at novel targets have been approved for use as analgesics. Why is this? It strikes me that there are at least five possibilities:
1. Non-predictivity of preclinical (animal) pain models: The “validity” of the models is not really the question, but rather their relevance. We all now seem to agree that the hot-plate test is probably of low relevance to human clinical pain. But what about chronic constriction injury (CCI), spared nerve injury (SNI), spinal nerve ligation (SNL), and complete Freund’s adjuvant inflammation (CFA)? Criticisms abound, involving either the assays themselves or the measures currently used within them (i.e., mechanical allodynia, heat hyperalgesia, and cold allodynia):
- Measures in animal models are mostly withdrawal reflexes.
- Human clinical pain is largely spontaneous (non-evoked) in nature; measures in animal models are largely evoked.
- Human clinical pain involves emotional and cognitive modulatory factors not often (or not effectively) measured in animals.
- Human clinical pain involves “quality-of-life” reductions not often (or not effectively) measured in animals.
- Human clinical pain lasts for years; measured changes in animal models often resolve in days or weeks.
- Existing animal models are not etiologically valid. (CCI may be a decent model of causalgia, but causalgia is rare. Is it a useful model of post-herpetic neuralgia, or painful diabetic neuropathy?)
2. Species differences between rodents and humans: Is there a “right” model in animals at all?
- Human pain biology is fundamentally different than rodent pain biology, even at "lower" levels. Drugs developed in the rat will therefore work in the rat, but not in humans.
- Human pain biology is so much more complex than rodent pain biology, that drugs developed in rats don't make enough of a difference.
3. Failure of clinical trials to show efficacy: The failure of a clinical trial to show analgesic efficacy is either a failure of the drug (i.e., it’s not efficacious) or a failure of the trial. A number of recent negative Phase 3 trials of previously approved medications widely thought to be efficacious (and, of course previously shown to be efficacious in Phase 3 trials leading to their approval) have led some to wonder whether it is now more difficult to demonstrate analgesic benefit in a clinical trial than in the past. This could be for a number of reasons:
- More and more clinical trials are being run by for-profit organizations than in the past, when they largely occurred in academic medical centers.
- The overall number of clinical trials of analgesics is also increasing, such that more marginal analgesic compounds might be making it into trials.
- Given the larger number of available analgesics now, patients willing to enroll in clinical trials might be more likely to be refractory to all treatments.
- The larger number of available efficacious analgesics may be increasing the placebo response over time, making it harder to “beat” the placebo effect.
4. Barriers at the regulatory level: Is the “deck stacked against” analgesics at the FDA and EMEA?
- It’s too hard to prove efficacy of analgesics.
- Acceptable side-effect profiles of analgesics (as opposed to, say, anticancer drugs) are impossible to achieve.
5. Pain is not unique: Translation has been poor in all neurological disorders. The problem is that they’re harder than other diseases.
Which of the above do you believe is most responsible for the lack of translation in the pain field? Have I missed any major factors?