Are Painless Painkillers Possible?

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Are Painless Painkillers Possible?

By Jeanene Swanson 03/29/15

There are about a dozen drugs being developed to replace addictive painkillers.


Opioid painkillers have become, in a word, a bane. Some facts:

The estimated total number of opioid analgesic prescriptions in the United States increased by 104% from 2000 to 2010, totaling 207 million in 2013. In 2012, it was estimated that about 2.1 million Americans are addicted to prescription opioid painkillers. The number of overdose deaths from these meds has more than quadrupled in the U.S. since 1999. And, there is mounting evidence suggesting a link between increased non-medical use of opioid analgesics and heroin abuse.

In the face of what has become a prescription opioid and heroin epidemic, states across the country are looking to legislate against these drugs, limiting or even eliminating their use. That might bode well for acute pain sufferers, but not for those with chronic pain. Fortunately, scientists are working hard to find more efficacious, and less addicting, drugs to treat pain.

History of using opioids to treat pain

The opium poppy has been used to treat pain for over 3,000 years, and it’s the best medication we have for acute pain—anything that lasts from a few seconds to a few weeks. “Most of the analgesics employed today are opioids related to morphine that were developed over 50 years ago,” says Dr. Philip Portoghese, a medicinal chemist at the University of Minnesota. “They are effective in reducing acute pain, but upon prolonged exposure, tolerance and dependence develops—thus, they are not ideal medications for treatment of chronic pain.”

Chronic pain is a different animal. Chronic pain can last for months, years, or a lifetime. The problem with using opioid-based drugs to treat chronic, or lasting, pain is that the accompanying high can become addictive over long-term use. And, the longer you use opioids, the more you need to use because you become tolerant to the drug’s effect—which in turn promotes dependence and addiction. Chronic use of opioid medications can also cause one to become more sensitive to pain, thus perpetuating increased need for these drugs.

“This is becoming ever more apparent as our population is aging, increasing the number of people with arthritis, chronic back pain, etc.,” says Dr. Ajay Yekkirala of Children’s Hospital Boston and Harvard Medical School. “All of these problems require a new paradigm for pain therapy—drugs that are devoid of [these] side effects.”

How do current opioid medications work?

Opioids actually occur naturally in humans, and these endogenous molecules act on opioid receptors in the nerve cells in the brain, spinal cord, gastrointestinal tract, and other organs in the body. The receptors come in three major subtypes—mu, kappa, and delta—a fact that affects how the opioid binds and therefore, the effect it elicits. Our current synthetic opioid painkillers are mu agonists, which means the drug mimics the effect of an endogenous opioid molecule by binding to the mu receptor, activating it, and sending a signal to the body that reduces the effect of a painful stimulus.

The side effects seen using today’s synthetic painkilling drugs—which are based on “the prototypical analgesic, morphine,” Portoghese says—are because they activate the mu receptor. However, kappa and delta receptors have their problems, too. While they provide relief and are considered better in terms of not promoting as much of an addictive response, patients can experience “dysphoria or psychotomimetic effects—where patients hallucinate and many complain of feeling like they are dying,” Yekkirala says. “Several delta ligands also produce tolerance which leads to dose escalation and a slew of other problems,” says Portoghese. “Analgesics that target delta selectivity have been reported, but none are presently clinically employed.”

While there have been steps to reformulate existing drugs—FDA approved an “abuse-deterrent” version of OxyContin in 2013 that is slow release, and Pfizer now sells a short-acting version that has been designed to burn the nose if snorted—this is only sidestepping a larger problem. “Abuse deterrent formulations do have a huge impact on their abuse: It will minimize—[but] never eliminate—abuse of the prescription meds,” says Dr. Andrew Coop, chair of the department of pharmaceutical sciences at the University of Maryland School of Pharmacy. “The downside, as is already being seen, is the rise in heroin use again.” Yekkirala says that this approach feels more akin to a “Band-Aid, while coming up with a drug that is completely devoid of the addictive potential to begin with seems to be the superior long-term approach.”

New targets

There are several ways that research is targeting new drugs. One is by designing variants of the opioid receptor. In this method, mutations leading to opioid receptors that are formed slightly differently—called splice variants—can bind opioids differently. However, these are early days, and they are not well understood.

Another method is targeting not mu, but delta and kappa opioid receptors. Unfortunately, there are side effects, and in some ways, Yekkirala says, they’re “not as effective as mu ligands for analgesia.”

A third is targeting multiple receptor subtypes (turning one on, the other off). Portoghese was one of the first to show that activating mu while blocking delta reduces the development of tolerance. “That’s my approach,” Coop says, whose team has developed a drug, UMB 425, that does just that. “[It] appears to be strictly mu agonist, delta antagonist.” Simultaneously giving a delta antagonist reduces the development of tolerance to the mu ligand. Kappa, he says, doesn’t seem to have an effect on mu.

Portoghese’s work also shows that opioids’ effects are more complex than imagined. Not only can opioids bind complexes that consist of two opioid receptor subtypes (mu and delta, for example), but they can also bind complexes that consist of multiple receptors. Hence, a fourth new method is targeting multiple receptors that are not necessarily opioid. Promising pre-clinical studies have shown that targeting the mu receptor bound to either the metabotropic glutamate receptor 5 or the cannabinoid receptor type 1 can effectively diminish pain.

A fifth is called functional selectivity, or agonist trafficking. “It’s where all agonists are not the same” in terms of what signaling message is sent through the cell. “An agonist binds to the outside of a receptor, passes a message, which activates second messengers inside the cell,” Coop says. “If the agonists activate different second messengers, then they will have different effects.” There is much research looking into this method.

Less conventional, but still promising, approaches are targeting glial cells (which are found in the brain and act as immune cells, not neurons), cannabinoid receptors, capsaicin receptors, as well as the sodium and calcium channels that are embedded in the cell membrane. “Each has benefits and major issues,” Yekkirala says.

New drugs in the pipeline

Currently, there are about a dozen drugs being developed to replace addictive, painkillers like OxyContin. One of the most well publicized is Cara Therapeutics’ CR845, which works on kappa instead of mu opioid receptors. The Connecticut-based company recently released research showing its opioid drug is far less likely to cause patients to feel high. What’s different about CR845 is that the drug is “peripherally restricted,” or, it’s too big to cross the blood-brain barrier. “That way you can get pain relief in the extremities, but will not get the dysphoria usually elicited by kappa receptors in the brain,” Yekkirala says. While it’s a “great idea in theory, the jury is out on how effective this approach will be for various types of pain, especially because chronic pain usually involves something called “central sensitization,” Yekkirala says, which occurs in the central nervous system (brain and spinal cord). “It will not treat severe pain,” Coop says, citing another drawback.

Coop’s own lab has come up with UMB 425, which is a drug that works as an agonist on the mu receptor and an antagonist on the delta receptor. He says it’s been shown to both reduce tolerance in mice taking morphine chronically, which contributes to less side effects, and reduce dependence, “which has huge implications for becoming addicted to the drug.” They are currently repeating the studies in rats, along with looking at UMB 425’s ability to cause dependence. “This compound has the potential to replace all other opioids on the market, with no need for abuse-deterrent formulation as it would not have potential for abuse,” Coop says.

Portoghese’s lab has developed two notable compounds, MMG22 and NNTA. MMG22 works on a mu opioid-metabotropic glutamate receptor 5 (mGluR5) complex, which has “great potential” for lower tolerance, Coop says. The compound is meant to activate mu and turn off mGluR5. It has been shown to block pain associated with bone cancer and treatment of bone cancer in mice. “MMG22 has unprecedented potency and does not produce tolerance,” Portoghese says.

NNTA works on both the mu and kappa opioid receptors and is meant to bind specifically to this complex. 

“I think these ligands bear testimony to the fact [that] targeting such receptor complexes can make effective painkillers without some of the major side effects,” Yekkirala says. “For instance, NNTA is 50 times more potent than morphine and produces no physical dependence or drug-seeking behaviors in rodents.” They are actively developing a version of these drugs that can be used clinically. (Yekkirala first-authored the NNTA paper with Portoghese, and he is currently in the process of co-founding a startup around NNTA and other non-addictive pain medications.)

Future focus

All interviewed believe that doctors will eventually end up prescribing pain medications based on genetic makeup. Predicting who will respond and how he or she will respond to a particular drug is the holy grail of personalized medicine, and it seems especially useful in the context of how to treat pain in an addict or recovering addict. 

Some recent findings of mutations for pain tolerance and neuropathic pain, “[give] us an idea for what to look for in individuals,” Yekkirala says. “Lots more to unfold and understand here, though—I wouldn’t hold my breath. But rest assured, this may very well be how future approaches will go.”

Jeanene Swanson is a regular contributor to The Fix. She last wrote about how horses and dolphins can help you get sober and 5 Things You Need to Know About Your Liver.

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