The death toll from the decades-long U.S. opioid crisis continues to climb as the toxic drugs are still used to treat chronic pain, but scientists have hit a milestone in developing an innovative alternative that involves inhibiting the body's pain-encoding gene.
A paper published Wednesday in Science Translational Medicine says one can measure the amount of inhibition necessary to modulate Nav1.7 — the ion channel that signals for pain — in humans by looking to results from primates. Such an ability would allow scientists to predict patient outcomes before administering the therapy.
"[The data demonstrates] that it is possible to measure Nav1.7 target modulation in nonhuman primates, and determine the plasma concentration required to produce a predetermined level of inhibition," study author Richard L. Kraus, a researcher at pharmaceutical company Merck & Co. Inc., told The Academic Times.
The work is a step forward for the novel pain-relief tactic because, of several clinical trials that have attempted to inhibit the gene for Nav1.7, Kraus says not a single one has provided relief that is efficient enough to make the therapy publicly available.
"It is unclear if the Nav1.7 inhibitors at the tested doses were engaging channels enough to impact pain signaling in humans," he explained. "Such a mechanistic translational approach will improve estimates of [the] dose required to modulate the target and achieve analgesia in the clinic."
Like many other researchers, including a team that successfully completed in vitro and in vivo implementations of Nav1.7 inhibition using a dead Cas9 approach — which targets and represses the ion channel via CRISPR gene editing — Kraus hopes to expedite the novel concept of Nav1.7 modulation toward public use because of the highly toxic nature of opioids.
These dangerous drugs are often prescribed for many types of chronic pain. A recent study found that 50.2 million Americans suffer from some sort of chronic pain, accounting for 20.5% of the adult population and resulting in close to $300 billion in lost productivity annually.
"There is a clear unmet medical need for new targeted options for the treatment of chronic pain as an alternative to opioids," Kraus said.
With the first wave beginning in the 1990s and the epidemic's rapid worsening since 1999, opioid-related fatalities continue to wreak havoc across the nation. According to the U.S. Centers for Disease Control and Prevention, there were 70,630 deaths from drug overdose in 2019, 70% of which involved an opioid.
The harsh reality of opioid use is that while the drug is potent and therefore effective in reducing pain quickly, it is also dangerous for the body — potentially leading to respiratory distress — and extremely addictive. What starts out as a need for pain relief can easily become an endless cycle of abuse for patients.
To avoid opioids, some patients have turned to a plant-based alternative called kratom for pain relief, even though it is not formally endorsed by the U.S. government or approved by the Food and Drug Administration.
The unique concept documented in the new study was first conceived when researchers identified patients who had natural mutations to the Nav1.7 gene.
"Humans with loss-of-function mutations in the Nav1.7 channel gene show profound insensitivity to pain," Kraus said. "Therefore, inhibition of the Nav1.7 channel with small molecules has been considered a promising approach for the treatment of various human pain conditions."
While noting that it is too early to speculate about which patients would be most suitable for the therapy or the potential duration of pain relief, Kraus said the data indicate that the small molecule Nav1.7 inhibitor as an isolated treatment was able to achieve analgesia, an inability to feel pain, in the team's nonhuman primate assays.
To measure Nav1.7 target modulation, these models tested for nerve conduction, which measures the speed at which an impulse moves through one's nerve; perception of a painful stimulus; and olfaction, or sense of smell. Both nerve conduction and perception of painful stimuli were inhibited depending on the dose administered, but the researchers also found that loss of olfaction was reported in Nav1.7-inhibited primates.
"We also know that Nav1.7 channels are also expressed in sympathetic fibers, which are important in cardiovascular function; we are evaluating the implications of this," Kraus noted. "Clinical success is dependent on seeing analgesia at well-tolerated doses."
The study, "Nav1.7 target modulation and efficacy can be measured in nonhuman primate assays," published May 19 in Science Translational Medicine, was authored by Richard L. Kraus, Fuqiang Zhao, Parul S. Pall, Dan Zhou, Joshua D. Vardigan, Andrew Danziger, Yuxing Li, Christopher Daley, Jeanine E. Ballard, Michelle K. Clements, Rebecca M. Klein, Marie A. Holahan, Thomas J. Greshock, Ronald M. Kim, Mark E. Layton, Christopher S. Burgey, Darrell A. Henze and Andrea K. Houghton, Merck & Co. Inc.; and Jordi Serra, King's College Hospital.