The National Institute on Drug Abuse estimates more than two million Americans suffer from substance abuse disorders related to prescription opioids. For thousands of them, what started as relief granted by trusted providers turned into dependence. In some cases, this results in addiction to heroin and other narcotics. In some instance, patients will forego pain relief out of fear they could become dependent on the drugs or that the prescriptions will fall into the hands of their children who might misuse them. The opioid crisis is more visible now than ever before, and that has some groups racing to develop an alternative.
Steve Doberstein, PhD, vice president and chief scientific officer of San Francisco-based Nektar Therapeutics, believes his firm has an answer. In setting out to develop a new opioid, one that could deliver the pain relief but none of the addictive properties of commonly used and abused opioids, Nektar invented a new molecule, according to Dr. Doberstein.
"The important thing to understand about NKTR-181 is it's a brand new opioid molecule," Dr. Doberstein says. "It's the first one that's been developed in quite a while that isn't a formulation of an old-fashioned opioid we already know."
The difficulty of designing an opioid that works but doesn't trigger dependency is enabling the molecule to cross the blood-brain barrier, but to do so with a slow rate of entry, Dr. Doberstein says. When medicine crosses that barrier, it triggers a burst of dopamine that causes pleasure and euphoria — the feelings and chemical that underlie addiction. Cocaine, amphetamines and nicotine all trigger that dopamine release at a fast rate of entry. Nektar set out to make a molecule that separated the pain-control properties of opioids out from the euphoria-causing properties that lead to abuse.
Dr. Doberstein says one early attempt to combat abuse was locking up painkillers such as oxycodone into time released formulations like Oxycontin. These opioids concentrate large quantities of their active pain-killing ingredient into an extended release pill, giving patients the ability to take just one over the course of an entire day, as opposed to something like Percocet, which patients may take 3-4 times per day. However, the molecules themselves don't move across the blood-brain barrier any more slowly, even if the pill takes a much longer time to be released into the body.
Clinical trial evidence shows that NKTR-181 as a molecule has an inherently slower rate of entry into the brain, Dr. Doberstein says. Those trials have not only shown that it offers patients effective pain relief, but that patients suffering from opioid addiction don't receive the same kind of euphoric rush they do when abusing traditional prescription painkillers.
"We asked healthy patients in a phase I clinical trial to put their arms in an ice water bath to test their capacity for pain either on a placebo or on a dose of NKTR-181," Dr. Doberstein says. "In all of the NKTR-181 cases we were able to see an extended period of time, so they're experiencing less pain, which is the kind of evidence of analgesic effect you'd expect to see with an opioid [chemical]."
Before testing anonymous individuals who recreationally abuse opioids, researchers were also able to measure the rate of entry into the brain based on the rate that the phase I participants' pupils shrank. This is an indicator of how quickly an opioid induces a dopamine-releasing effect. They found the rate NKTR-181 entered participants' brains was slower than what would be expected when taking a traditional opioid like oxycodone or hydrocodone, according to Dr. Doberstein.
When the researchers compared NKTR-181's euphoric effects against opioids like oxycodone or a placebo in individuals who abuse painkillers to get high, there was also a stark difference in outcomes.
"On a euphoria scale of one to 100, those participants would typically rate a dose of oxycodone at about an 80," Dr. Doberstein says. "We gave them three separate dose levels of NKTR-181 and found that for the bottom two, 100 milligrams and 200 milligrams, there was essentially no difference in euphoria from the placebo."
For the highest dose of NKTR-181 (400 milligrams) study participants reported euphoria peaked around 20 on a scale of 100. For Dr. Doberstein, this signals that Nektar has developed a drug that inherently has a slow rate of entry into the brain and offers good pain control by triggering the same receptor that traditional opioids target. "And we know that in a population of drug abusers, [NKTR-181 as a] drug is not well-liked," he says. "In fact it's not liked at all."
Nektar's next step is to determine what other characteristics, good or bad, their new drug might have. There is some anecdotal evidence, Dr. Doberstein says, that NKTR-181 might be less sedating than other opioids. If true, the drug could also make it feasible for pain patients to return to work, or at least offer an alternative to the symptoms of sluggishness and lethargy associated with traditional opioid use. But future clinical trials will need to bear that out.
"By molecularly separating the side effect mechanism from the analgesic mechanism, we're hoping we may have made a drug that patients and doctors can use and prescribe with much more confidence of low rates of diversion," Dr. Doberstein says. "Many patients don't even want to take opioids the first time — that's a big problem. You've got a whole bunch of patients who have chronic pain but who won't take their pain medications. We'd like to give them an option they can feel safer in using."