Opioids remain the mainstay of treatments to ease pain, but over time, patients develop tolerance to the drugs, and so require higher doses to experience the same level of relief. In some cases, patients even experience more pain, a paradoxical phenomenon known as opioid-induced hyperalgesia (OIH).
Now, researchers led by Grégory Scherrer, Stanford University, US, report how tolerance and OIH arise in mice. In doing so, they also identify a strategy that could curb both side effects in patients.
Scherrer and colleagues show that tolerance and OIH can be traced to pain-sensing nerves in the body. Daily doses of morphine paired with the drug methynaltrexone bromide (MNB), which selectively targets a protein on those nerves, reduced these side effects in the animals, but spared morphine’s ability to quell pain.
MNB has already been approved by the Food and Drug Administration (FDA) for the treatment of another common opioid side effect, constipation, so researchers are hopeful that the combined drug strategy will be effective and safe in patients.
“What’s exciting about these findings is that clinical trials could be set up pretty much immediately,” says Howard Gutstein, University of Pittsburgh, US, who was not involved in the study.
The study was published online January 16 in the journal Nature Medicine.
The seed of the problem
Earlier studies had hinted that pain-sensing nerves are somehow involved in tolerance and OIH. To test this idea further, Scherrer and his colleagues took advantage of genetically modified mice, whose pain-sensing nerves lacked a protein that allows cells to respond to morphine. That protein is called the mu-opioid receptor.
In contrast to their normal counterparts, the genetically modified animals developed neither tolerance nor OIH when given daily injections of morphine. This suggested that these unwanted effects stem from mu-opioid receptors on a particular subset of nerves.
Yet the two groups of mice were alike in their levels of pain relief. For example, both had higher thresholds for detecting intense heat and pressure. That’s likely because morphine still activated mu-opioid receptors in the spinal cord and brain, which together make up the central nervous system).
Morphine plus MNB
Next, the researchers tried to achieve the same outcome—less tolerance and OIH, while preserving pain relief—by giving mice daily doses of morphine and MNB. MNB is a drug that blocks mu-opioid receptors, but its chemical structure restricts it to the body, so it doesn’t get into the central nervous system. As a result, it more selectively targets receptors present on peripheral nerves. That also means receptors in the central nervous system, including those that drive pain, are still available for morphine to act on.
The strategy worked: pairing the two drugs prevented tolerance and OIH in normal mice, without affecting pain relief. And, this approach also succeeded when mice had either a tibia fracture (a model of postsurgical pain) or nerve damage (a model of chronic pain).
This is not the first time that researchers have teased apart the desired and undesired effects of opioids. Last year, for example, a group identified a new compound called PZM21 that dulled pain as well as morphine, but did not slow breathing or appear to be rewarding, at least in mice (see related RELIEF story here).
But unlike PZM21, MNB has already been clinically approved, so the new strategy could soon find its way into clinical trials.
“I think our data put out there the possibility that we could improve [tolerance and OIH] with this peripherally restricted drug [MNB],” says Vivianne Tawfik, an anesthesiologist and pain medicine physician at Stanford University, and one of the lead authors of the current study.
Due to tolerance, patients who use opioids must often increase their dose to keep pain at bay. That, however, increases the risk of overdose and other health problems, says Tawfik.
“This strategy is not encouraging the use of opioids. But for people who are taking them, is there a way we can decrease the risks?” –Matthew Soleiman
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman