When people die from overdoses of opioids, whether prescription pain medications or street drugs, it is the suppression of breath- ing that almost always kills them. The drugs act on neuronal recep-
tors to dull pain, but those in the brain stem
also control breathing. When activated, they
can signal respiration to slow, and then stop.
The results are well-known: an epidemic of
deaths—about 64,000 people in the United
States alone last year.
Countering this lethal side effect without
losing opioids’ potent pain relief is a challenge that has enticed drug developers for
years. Now, for the first time, the U.S. Food
and Drug Administration (FDA) in Silver
Spring, Maryland, is considering whether
to approve an opioid that is as effective as
morphine at relieving pain and poses less
risk of depressing breathing.
Trevena, a firm based in Chesterbrook,
Pennsylvania, announced on 2 November
that it has submitted oliceridine, an intravenous opioid meant for use in hospitalized
patients, to FDA for marketing approval.
The drug, which would be marketed under
the name Olinvo, is the most advanced of
what scientists predict will be a growing
crop of pain-relieving “biased agonists”—so
called because, in binding a key opioid re-
ceptor in the central nervous system, they
nudge it into a conformation that promotes
a signaling cascade that kills pain over one
that suppresses breathing (see graphic,
p. 848). And in a paper out this week in Cell,
a veteran opioid researcher and her col-
leagues unveil new biased opioid agonists
that could surpass oliceridine, though they
haven’t been tested in people yet.
“There are many groups creating [such]
The competition aims to catch up quickly.
biased agonists. And one of them is going
to get it right,” says Bryan Roth, a molecular
pharmacologist at the University of North
Carolina in Chapel Hill. “To have a drug
you can’t die of an overdose with would
be a huge lifesaver for tens of thousands of
people every year.”
Trevana’s compound is by far the clos-
est to the finish line, having been through
clinical trials. The firm has had setbacks,
however. In phase III trials in postsurgical
patients reported in February, oliceridine
proved to be as effective a painkiller as
morphine, and quicker to act. But although
a low dose of it caused less respiratory sup-
pression and fewer other side effects than
morphine, those improvements didn’t reach
statistical significance for higher doses.
Last month, Mebias Discovery in Philadelphia, Pennsylvania, presented data on two
new biased opioids that protected breathing in rats even at four times the effective
painkilling dose. It hopes to begin human
trials of one of them as soon as 2019.
For most of these early-stage drugs, de-
But the Cell study this week has done both,
velopers haven’t assessed just how selec-
tively they trigger the painkilling pathway
over respiratory suppression. Nor have they
shown conclusively that the molecular bias
matters—that the more biased a compound
toward triggering the painkilling pathway,
the less the risk of respiratory suppression.
at least in mice.
In that work, neuroscientists Laura Bohn,
Cullen Schmid, Thomas Bannister, and their
colleagues at the Scripps Research Institute
in Jupiter, Florida, developed several pain-killing-biased compounds from among scores
that bind the µ-opioid receptor. Activating
this protein, which is embedded in neuronal
cell membranes, leads to either pain relief
or respiratory depression depending on the
brain circuit to which it belongs. The molecule is known as a G protein–coupled receptor because it triggers so-called G proteins to
bind to the inner side of a receptor and start
a signal cascade.
When traditional opioids—such as morphine, fentanyl, and heroin—activate
the receptor, that also attracts an intracellular protein called b-arrestin2. It tamps
down G-protein signaling, so that the message doesn’t remain indefinitely “on.” But
b-arrestin2 also helps produce the respira-
tory suppression and constipation that are
hallmark side effects of opioids.
Beginning 18 years ago, Bohn and her col-
leagues showed that, in mice engineered to
lack b-arrestin2, morphine’s pain relief was
stronger and longer-lasting and its main
By Meredith Wadman
‘Biased’ opioids could yield safer pain relief
New compounds activate opioid receptor in a way that protects breathing
Because opioids can shut
down breathing, overdoses
are often fatal without