Examining pain in mice versus man

Animal research remains the only way to get causal information, but it’s challenging to gather scientific information from one species and apply it to another species, said Jeffrey Mogil, PhD, at the 2019 Institute for Functional Medicine Annual International Conference in San Antonio, Texas.

In recent years, there has been an explosion of knowledge in the biological mechanisms related to pain. However, we’re not in a good place in the pain treatment world, Mogil said. Many compounds are studied, but are never approved due to “lack of efficacy,” which means it may have worked in animals, but didn’t work in humans. This is a catastrophe, Mogil said.

Some experts put the blame for this error in translation on the pre-clinical side (generalizability, species differences, and dependent measures in animal models), while others put the blame on the clinical side (changing participants, trial design, and placebo effect).

Currently, we only do pain research on two species, the rat and the mouse. Within these species, we only use one type or rat and one type of mouse. These genetic differences react differently to pain. However, in addition to having quantitative variability, Mogil said, there is also qualitative variability. Since it is not cost-effective to conduct tests on multiple meta strains, researchers settle for results that may not be entirely true.

Species also have significant difference in expression genes, Mogil said. “All species are different from each other, and that’s our problem,” he said. “There’s a lot more individuality between species than we have assumed.”

While the issues with genetics in pain research likely cannot be solved, problems with sex can, Mogil said. Women are more likely to endorse having chronic pain than men. In fact, 70 percent of chronic pain patients in the U.S. are women.

According to a 2015 paper published in the Journal of Pain, in 79 percent of studies using rats or mice, only male mice or male rats are used. Essentially, male mice and rats are standing in for human women. This is not okay, Mogil said.

Mogil used an example of Morphidex. In the late 80s and early 90s, the medical community was excited about this new drug and its potential to treat chronic pain. In animal models, every study but one was done in male mice. However, the only study in female mice found the drug was ineffective. When the drug moved to a Phase 2 clinical trial in humans, it failed. Studies conducted in humans are required to use both male and female subjects, but that it not the case for animal studies. Mogil said it is possible that this trial could have failed sooner, saving both significant time and money, had the researchers been required to use both male and female mice.

Measurement of pain is another limitation in animal models, Mogil said. The challenge is that pain researchers are simply studying the “wrong” symptoms.

The symptoms of chronic pain include superficial pain, deep pain, ongoing pain, intermittent pain episodes, series of consecutive pain episodes, evoked pain, aftersensations, trigger zones, activity-evoked pain, touch-evoked pain, pain evoked by moving stimuli, pressure-evoked pain, warmth-evoked pain, and cold-evoked pain. A 2009 study published in PLOS Medicine ranked each symptom based on their occurrence in patient populations. Pre-clinical pain researchers typically measure mechanical allodynia and thermal hyperalgesia, or touch-evoked pain and warmth-evoked pain, which ranked as two of the lowest symptoms. However, spontaneous pain, or ongoing pain, was ranked as the second highest, and is only measured 10 percent of the time.

It is challenging to measure spontaneous pain in rodents, but the pain research landscape has been changing rapidly, and new methods have proposed in the last couple of decades to try to measure spontaneous pain, including operant conditioning, burrowing, ultrasonic vocalization, classical conditioning, and wheel running.

Mogil and colleagues also created the Mouse Grimace Scale, which is developed from a scale that helps physicians measure pain in babies. This turned out to be very useful, especially for measuring pain in postoperative veterinary treatment. Many animals now have their own grimace scale now, Mogil said.

So, is there an “irreproducibility crisis” in science? Mogil said the hypothesized causes of irreproducibility include low sample size, lack of power analyses, poor reporting practices, no blinding or randomization, and poor incentives. He said we need to do better, but it’s not the cause of this crisis.

“The problem is we greatly underestimated the potential sources of variability in the laboratory environment,” said Mogil. “This is challenging, but it’s possible to fix." 

Editor’s note: This article is part of Integrative Practitioner’s live coverage of the 2019 Institute for Functional Medicine Annual International Conference. For a full list of coverage, click here.