Neuroscientists from the University of Colorado have found a peculiar and paradoxical effect in rats subject to morphine treatment: They tend to experience pain longer. In rat subjects suffering from what's known as a chronic constriction injury (CCI), even just a few days of morphine administration led to an extension of chronic pain lasting for months after discontinuation. The group's work is published this week in the Proceedings of the National Academy of Sciences.
The CCI is a rat model of chronic neuropathic pain in humans—a broad condition resulting from damage to the central and-or peripheral nervous system. Its symptoms are vast and varied, including but not limited to burning and shocking sensations, abnormal and uncomfortable sensations when touching things, painful reactions to non-painful stimuli, and a general amplification of normal pain. It's very often accompanied by depression and insomnia. You don't really want to know how this is simulated in lab rats, but it's plenty effective.
It's worth emphasizing that neuropathic pain is a very specific variety of pain for the simple reason that it originates within the nervous system itself. And the counterproductivity of opioid painkillers in managing it is not a new idea. Generally, this is known as the "two-hit hypothesis," in which a neuropathic injury triggers overactivity in neural-support cells known as glial cells, which are then triggered again by the introduction of the painkiller.
"Short-term decision to take such opioids can have devastating consequences of making pain worse and longer lasting"
The result is a signalling cascade driven by a protein called interleukin-1beta (IL-1b), with the effect being an increase in the activity of pain-responsive nerve cells sensitivity. In rat models, this increase persisted for months.
"Opioids superimposed on CNS neuroinflammation may have far-ranging consequences beyond pain," the PNAS study suggests. "For example, opioids may also serve as a second hit for glia primed by aging or inflammation/trauma and may lead to cognitive decline in the elderly, postoperative cognitive decline, and impaired recovery of motor function after spinal cord injury. Whether the mechanistic underpinnings revealed in the current series of studies will prove to generalize to such opioid-related phenomena remains to be defined."
The study makes the obvious point that opioids are dangerously overused, and, sure, we could probably avoid some of this if we prescribed them less. "The implications for people taking opioids like morphine, oxycodone and methadone are great, since we show the short-term decision to take such opioids can have devastating consequences of making pain worse and longer lasting," notes Linda Watkins, the CU research group's leader, in a statement. "This is a very ugly side to opioids that had not been recognized before."
But in many cases just not prescribing the drugs winds up being a pretty fake solution. Neuropathic (nerve) pain, in particular, is often only marginally treatable and otherwise miserable and frequently disabling. (Neuropathy is usually found in concert with diabetes or other conditions.)
In cases where narcotic painkillers really are needed, Watkins and her group offer at least some good news. Using a designer drug technology known rather unfortunately as DREADD, they were able to come up with a way of blocking receptors on the inflammatory glial cells.
"These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal," the paper notes.
In any case, we're still talking about rats and the clinical significance for humans remains to be demonstrated. In the meantime, we have plenty of other reasons to be concerned about the "silent epidemic" of opiode painkiller overuse.