Rats, Depression and Chronic Pain

By Pat Anson, Editor

An unusual study involving rats, depression and chronic pain is making headlines – the latest in a long line of flawed research studies being used to debunk the effectiveness of opioid pain medication.

“NIH study suggests opioid therapy not effective against chronic pain,” is the headline in UPI.

“Pain-induced changes in the brain explain the limited effectiveness of opioid therapy,” is how the Tech Explorist put it.

At issue is a small study by the National Institutes of Health (NIH) and McGill University in Montreal on pain-induced changes in 17 laboratory rats. That's right, 17 rats. The study findings, published in the journal Pain, concluded that chronic pain reduced the number of opioid receptors – the molecules that opioids bind to -- in the rats’ brains. In theory at least, that would make the rats less responsive to opioid pain medication.

Note that the research did not include any people, the rats were not given any opioids, and the effectiveness of opioids wasn't even measured in the rats. But that didn’t stop the NIH from drawing some sweeping conclusions.

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“These results provide insights into why we see limited effectiveness of opioid therapy in chronic pain and the mechanism of the depression that may accompany it,” said David Shurtleff, PhD, acting director at the National Center for Complementary and Integrative Health (NCCIH).

“These basic research findings support NIH’s efforts to better understand chronic pain and comorbid symptoms and to develop better ways to help chronic pain patients effectively manage their pain.”

McGill University was more cautious, saying further studies were needed in humans to confirm the study findings.

“Although the study… was conducted in rats, and the results of animal studies may not be directly applicable to people, the findings provide new insights into how the brain may respond to pain and opioids,” a McGill press release states. “These findings, if confirmed in people, will enhance the understanding of the impact of chronic pain on the brain, its relation to depression, and the effects of opioids.”

Researchers have many theories about the origins and treatment of chronic pain, but conducting tests on humans to prove them is problematic. Laboratory animals are often used as an imperfect substitute.

In the NIH/McGill study, 17 rats had brain surgeries to produce a nerve injury that causes chronic pain, while another group of rats had sham surgeries (a similar procedure that did not cause chronic pain). Three months later, PET scan imaging showed opioid receptors had decreased in multiple regions of the brain in the nerve-injured rats, but no changes occurred in the sham-surgery rats.

These results suggest that pain itself, not treatment or pre-existing trauma, altered the brain’s opioid system. Other tests showed a weaker link between chronic pain and depression in the nerve-injured rats.

How did researchers determine the rats were depressed? 

When given a choice, healthy rats will normally drink water sweetened with sugar rather than plain water. But animals with a decreased ability to experience pleasure, a recognized symptom of depression, may not. The rats in the study with chronic pain showed a decreased preference for sugar water over plain water, while rats in the sham group still showed a preference for sweetened water. This, the researchers believe, was enough evidence to conclude the nerve-injured rates were depressed.

“It’s well known that there’s a link between chronic pain and depression,” explained co-author M. Catherine Bushnell, PhD, scientific director of NCCIH’s Division of Intramural Research.  “The results of this study indicate that pain-induced changes in the brain’s opioid system may play a role in this association. Animals with the greatest decrease in opioid receptor availability showed the greatest increase in depression-like symptoms after experiencing chronic pain.”

While intriguing, the results of this rat study are far from definitive and do not prove that opioids are an ineffective treatment for chronic pain in people. What they do show is that we need more and better research about opioids and chronic pain, not more misleading headlines and statements from the NIH.