AT-121: A Promising Alternative to Opioid Pain Medications

By Eric Sarlin, M.Ed., M.A.
NIDA Notes Contributing Writer
National Institute on Drug Abuse

Dr. Eric Sarlin’s recent research reveals an experimental compound with a dual action at two opioid receptors which may provide powerful pain relief without many of the usual harmful opioid side effects. The compound may also have potential as a treatment for opioid addiction.

The reason AT-121 is promising is because it provides pain relief without producing the side-effect of euphoria.

This is a novel compound representing potential advancement toward the goal of non-addictive pain medications that are at least as effective as opioids but without typical opioid liabilities. The new compound—called AT-121—may also have potential as a treatment alternative for opioid addiction. Most of the potent analgesics currently in use act through mu-opioid receptors. AT-121 seems to relieve pain in monkeys without causing physical dependence. Most pain medications work by activating a receptor in the neurons the mu-opiate receptor. Mei-Chuan Ko, a professor of physiology and pharmacology at the Wake Forest School of Medicine, says “Oxycodone, morphine, fentanyl, heroin—they all work through the mu-receptor.” Ko is one of the authors of the study.

Dr. Nurulain Zaveri and colleages at Astraea Therapeutics, manufacturer of AT-121, used medicinal chemistry, computer modeling, and structure-based drug design to create and develop AT-121. Like opioids—such as morphine and oxycodone—AT-121 also binds to the mu-opioid receptor. Unlike those opioids, AT-121 also binds to another opioid receptor called the nociceptin/orphanin FQ peptide receptor. According to Dr. Zaveri, this interaction with the NOP receptor enhances AT-121’s analgesic effect and blocks unwanted side effects often seen with current opioid medications.

References

NIDA. (February 12, 2019). “A Promising Alternative to Opioid Pain Medications.”

Fentanyl Becomes Deadly Force

Some Excerpts taken from an article By Eric Scicchitano
The Daily Item
July 10, 2017

Fentanyl

The deadly heroin and opioid epidemic is expected to become even deadlier with the increasing presence of Fentanyl in America. According to the DEA, Fentanyl is 50 to 100 times more powerful than morphine, and substantially more potent than heroin. As little as 2 grams of Fentanyl can be deadly. Alarmingly, it is fast becoming the most prevalent active ingredient in counterfeit drugs like Adderall, Xanax, and OxyContin being sold on the streets. During the first quarter of 2017, heroin combined with Fentanyl was detected in 61% of opioids seized for evidence and inspected in DEA labs. It is also frequently laced into marijuana and smoked.

The DEA’s Philadelphia Division warns that Fentanyl is on the rise, with seizures of shipments more than doubling from 167 kilos in 2015 to 365 kilos in 2016. Investigators are trying to determine if an outbreak of Fentanyl is responsible for 51 overdoses which occurred in Williamsport (Pennsylvania) in forty-eight hours. [See my post 51 overdoses in 48 hours] Three of those cases ended in death. According to the National Institute on Drug Abuse (NIDA), heroin and opioids killed an estimated 280,000 people nationwide between 2002 and 2015. Based upon preliminary figures put together through state coroners, more than 4,800 people died of an overdose in Pennsylvania last year. Experts are concerned that the next chapter in the opioid crisis could dwarf what we’ve seen so far. Their concern is based on the proliferation of Fentanyl.

Fentanyl Deaths Map

Let’s take a few moments to discuss Fentanyl. It is a man-made (synthetic) opioid, meaning it is manufactured in a laboratory, but it acts on the mu-opioid receptors in our brain and spinal column in the same manner as the morphine molecule found naturally in opium. Typically, these receptor sites are meant for naturally-occurring endorphins, our “feel good” chemical released by the pituitary gland. Fentanyl is usually prescribed to patients suffering from intractable cancer-related pain and, in some cases, debilitating back pain. My father was given Fentanyl patches for compression fractures near the end of this life. Initially, it was believed Fentanyl would not be abused. Unfortunately, addicts decided to start opening the patch in order to scrape out the medicine and abuse it.

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As if that were not enough, Fentanyl is being illegally manufactured in labs (primarily in China). It is produced in powder form, and is also pressed into pills, and smuggled into the United States. These knock-off pills are catching users off guard. Fentanyl is 50 to 100 times more powerful than morphine. DEA and border patrol seized more than 10,000 counterfeit pills containing Fentanyl in 2015. An amount as small as 2 milligrams can be deadly. First responders and ER physicians have to use extreme caution in order to avoid accidental exposure. According to the article in The Daily Item, an Ohio police officer accidentally overdosed in May of this year after brushing Fentanyl powder from his uniform during an arrest.

After the recent overdose surge in Lycoming County (Pennsylvania), Todd Owens, Mount Carmel police chief and head of the Northumberland County Drug Task Force, advised first responders to take measures to protect themselves. Chief Owens said his own department stocks medical masks, coveralls and heavy-grade gloves in their cruisers to be worn in the event they encounter heroin.

Heroin Fentanyl and Carfentanil Pics

The above is an illustration of potency betwen heroin, Fentanyl, and Carfentanil.

Carfentanil

Carfentanil is an extremely powerful derivative of Fentanyl. While Fentanyl is up to 100 times more potent than morphine, Carfentanil is 100 times more powerul than Fentanyl. In other words, it is 10,000 times more powerful than morphine. It is not approved for use in humans; rather, it is used in veterinary medicine to sedate large animals, primarily elephants. Yes, elephants! Carfentanil is so powerful that when veterinarians handle it, they use protective gear to avoid breathing it in or absorbing it through their skin. The amount of Carfentanil that can be safely administered to a human is 0.1 mg., compared to 13 mg. needed to sedate an elephant. It is obviously rather easy for an addict to accidentally take too much Carfentanil.

Interestinly, there are no statistics showing Carfentanil leading to addiction. That’s because even in the case of a seasoned addict a dose the size of a grain of salt can rapidly lead to an overdose and death. Frighteningly, drug dealers have begun cutting heroin with Carfentanil because it is extremely cheap to acquire. Even more disturbing is the fact that addicts in search of the ultimate high are deliberately trying this deadly drug. Rangers at Yellowstone National Park have recently begun issuing warnings to avoid eating the meat of bison killed in the park because the bison might have been sedated with Carfentanil for tagging or medical treatment. The drug can easily enter the bloodstream of those who eat the bison meat. It is most chilling to note that Carfentanil rapidly latches on to the mu-opioid receptors in humans, causing overdose almost immediately.

Moving Forward

Fentanyl moved up the rankings, from the 9th most common drug involved in overdose deaths in 2013, to the 5th most common drug involved in overdose deaths in 2014. The singer-songwriter Prince died of an overdose of Fentanyl in April 2016, according to officials in Minnesota. Philip Seymour Hoffman, a very successful indie film star (and one of my favorites), died of a heroin overdose on February 2, 2014. Although he had a drug problem while in college, he was clean for twenty years. No doubt his system was not able to handle the strength of today’s heroin.

Reports from the Centers for Disease Control (CDC) and the Food and Drug Administration (FDA) showed that deaths from heroin more than tripled during a five-year period, from 3,020 deaths in 2010, to 10,863 deaths in 2014. These deaths are yet another symptom of the broader epidemic of opioid addiction. Just as deaths from AIDS are due to untreated HIV, deaths from overdose are frequently due to untreated addiction. I know of many addicts attending 12-step meetings who are positive for hepatitis-C secondary to sharing needles while injecting heroin. Prince’s death is a reminder that opioid addiction is a disease that can and does affect people from all economic classes and all walks of life.

References

Scicchitano, E. (July 10, 2017). Fentanyl Becomes Deadly Force. Daily Item. Sunbury, PA.

Wakeman, S. (Aug. 5, 2016). Fentanyl: The Dangers of this Potent “Man-Made” Opioid. [Web Blog Comment.] Retrieved from: http://www.health.harvard.edu/blog/fentanyl-dangers-potent-man-made-opioid-2016080510141

Rettner, R. (Dec. 20, 2016). Deaths From Fentanyl Overdoses Double in a Single Year. LiveScience.com. Retrieved from: https://www.livescience.com/57268-fentanyl-overdose-deaths-double.html

 

The Molecule

Andy Coop very nearly spent his career watching paint dry. The son of a machinist and school cafeteria worker, Coop hailed from Halifax in Northern England. He finished his undergraduate work in chemistry at Oxford University in 1991. He was given a choice of where to continue his studies. At Cardiff University was a professor whose specialty was the chemistry of paint. Industry at the time was aiming to find a new paint that dried at a certain temperature. At the University of Bristol was John Lewis, who studied the chemistry of drugs and addiction. In the 1960s, Lewis had discovered buprenorphine, an opiate that he later helped develop into a treatment for heroin addicts.

Coop didn’t remember giving the choice much thought. Drugs sounded more interesting than paint, so off to Bristol and John Lewis he went. It was there, in 1991, in a lab at Bristol, that Andy Coop encountered the morphine molecule – the essential element in all opiates. In time, Andy Coop got hooked on the morphine molecule – figuratively, of course, for he only once took a drug that contained it, and that was following surgery.

Like no other particle on Earth, the morphine molecule seemed to possess heaven and hell. It allowed for modern surgery, saving and improving too many lives to count. It stunted and ended too many lives to count with addiction and overdose. Discussing it, you could invoke some of humankind’s greatest cultural creations and deepest questions: Faust, Dr. Jekyll and Mr. Hyde, discussions on the fundamental nature of man and human behavior, of free will and slavery, of God and evolution. Studying the molecule, you naturally wandered into questions like, Can mankind achieve happiness without pain? Would that happiness even be worth it? Can we have it all?

In heroin addicts, there is a certain debasement that comes from the loss of free will and enslavement to what amounts to an idea: permanent pleasure, numbness, and the avoidance of pain. But man’s decay has always begun as soon as he has it all, and is free of friction, pain, and the deprivation that temper his behavior. In fact, the United States achieved something like this state of affairs during the last decade of the twentieth century and the first decade of the twenty-first century. It was first observable in widespread obesity. It wasn’t just people. Everything seemed obese and excessive. Massive Hummers and SUVs were cars on steroids. In some of the Southern California suburbs, on plots laid out with three-bedroom houses in the 1950s, seven-thousand-square-foot mansions barely squeezed between the lot lines, leaving no place for yards in which to enjoy the California sun.

In Northern California’s Humbolt and Mendocino Counties, 1960s hippies became the last great American pioneers by escaping their parents’ artificial world. They lived in tepees without electricity and funded the venture by growing pot. Now their children and grandchildren, like mad scientists, were using chemicals and thousand-watt bulbs, in railroad cars buried to avoid detection, to forge hyperpotent strains of pot. Their weed rippled like the muscles of bodybuilders, and growing this stuff helped destroy the natural world that their parents once sought. Today, great new numbers of these same kids – most of them well-off and white – began consuming huge quantities of the morphine molecule, doping up and tuning out.

What gave the morphine molecule its immense power was that it evolved somehow to fit, key-in-lock, into the receptors that all mammals, especially humans, have in their brains and spines. The so-called mu-opioid receptors – designed to create pleasure sensations when they receive endorphins the body naturally produces – were especially welcoming to the morphine molecule. The receptor combines with endorphins to give us those glowing feelings at, say, the sight of an infant or the feel of a furry puppy. The morphine molecule overwhelms the receptor, creating a far more intense euphoria than anything we come by internally. It also produces drowsiness, constipation, and an end to physical pain. Aspirin had a limit to the amount of pain it could calm. But the more morphine you took, Coop said, the more pain was dulled.

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For this reason, no plant has been more studied for its medicinal properties than the opium poppy. As the mature poppy’s petals fall away, a golf-ball-sized bulb emerges atop the stem. The bulb houses a goo that contains opium. From opium, humans have derived laudanum, codeine, thebaine, hydrocodone, oxymorphone, and heroin, as well as almost two hundred other drugs – all containing the morphine molecule, or variations of it. Etorphine, derived from thebaine, is used in dart guns to tranquilize rhinoceroses and elephants. [Amazingly, Etorphine has hit the streets of America as an opiate which teens and young adults are taking to get high, only to be dropping dead due to its potency.]

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Tobacco, coca leaves, and other plants had evolved to be pleasurable and addictive to humans out of the gate. But the morphine molecule surpassed them in euphoric intensity. Then it exacted a mighty vengeance when a human dared to stop using it. In withdrawal from the drug, an addict left narcotized numbness and returned to life and to feeling. Numbed addicts were notoriously impotent; in withdrawal they had frequent orgasms as they began to feel again. Humans with the temerity to attempt to withdraw from the morphine molecule were tormented first with excruciating pain that lasted for days. If an addict was always constipated and nodding off, his withdrawals brought ferocious diarrhea and a week of sleeplessness.

The morphine molecule resembled a spoiled lover, throwing a tantrum as it left. Junkies say they often have an almost constipated tingling when trying to urinate during the end of withdrawal, as if the last of the molecule, now holed up in the kidneys, was fighting like hell to keep from being expelled. Like a lover, no other molecule in nature provided such merciful pain relief, then hooked humans so completely, and punished them so mercilessly for wanting their freedom from it.

Certain parasites in nature exert the kind of control that makes a host act contrary to its own interests. One protozoan, Toxoplasma gondii, reproduces inside the belly of a cat, and is then excreted by the feline. One way it begins the cycle again is to infect a rat passing near the excrement. Toxoplasma gondii reprograms the infected rat to love cat urine, which to healthy rats is a predator warning. An infected rat wallows in cat urine, offering itself up as an easy meal to a nearby cat. This way, the parasite again enters the cat’s stomach, reproduces, and is expelled in the cat’s excrement – and the cycle continues.

The morphine molecule exerts an analogous brainwashing on humans, pushing them to act contrary to their self-interest in pursuit of the molecule. Addicts betray loved ones, steal, live under freeways in harsh weather, and run similarly horrific risks to use the molecule.

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It became the poster molecule for an age of excess. No amount of it was ever enough. The molecule created ever-higher tolerance. Plus, it had a way of railing on when the body gathered the courage to throw it out. This wasn’t only during withdrawals. Most drugs are easily reduced to water-soluble glucose in the human body, which then expels them. Alone in nature, the morphine molecule rebelled. It resisted being turned into glucose and it stayed in the body.

“We still can’t explain why this happens. It just doesn’t follow the rules. Every other drug in the world – thousands of them – follows this rule. Morphine doesn’t,” Coop said. “It really is almost like someone designed it that way – diabolically so.”

The above is taken from Sam Quinones’ best-selling nonfiction book “Dreamland: The True Tale of America’s Opiate Epidemic.” ©2015, New York, NY: Bloomsbury Publishing.

America’s Fentanyl Crisis

Every day 91 Americans fatally overdose on an opioid drug. It may be a prescription analgesic or heroin–4 to 8 percent of people who misuse painkillers transition to heroin–but increasingly it is likely to be heroin’s much more potent synthetic cousin fentanyl. In the space of only two years, fentanyl has tragically escalated the opioid crisis. This drug is 50 to 100 times more potent than morphine and able to enter the brain especially quickly because of its high fat solubility; just 2 milligrams can kill a person, and emergency personnel who touch or breathe it may even be put in danger. Unfortunately, many people addicted to opioids as well as other drugs like cocaine are accidentally being poisoned by fentanyl-laced products.

Although fentanyl is a medicine prescribed for post-surgical pain and palliative care, most of the fentanyl responsible for this surge of deaths is made illicitly in China and imported to the United States via the mail or Mexican drug cartels. Its high potency and ease of manufacture make it enormously profitable to produce and sell. According to the Drug Enforcement Agency (DEA), one kilogram of fentanyl can be purchased in China for $3,000 to $5,000 and then generate over $1.5 million in revenue through illicit sales in America. Thus, distributors of illicit drugs are eager to adulterate heroin or cocaine powder with fentanyl or put it in counterfeit prescription drugs, such as pills made to look like prescription pain relievers or sedatives. Last month, for example, a wave of deaths in Florida was linked to fake Xanax pills containing fentanyl.

Deaths from fentanyl and a handful of other synthetic opioids tripled from 3,105 in 2013 to 9,580 in 2015, and those numbers are likely underestimates; some medical examiners do not test for fentanyl and many overdose death certificates do not list specific drugs involved. Thus far, New Hampshire has recorded the most fentanyl overdoses per capita; an NIDA-funded study found that in 2015, almost two-thirds of the 439 drug deaths in that state involved fentanyl. Although most who fatally overdose on fentanyl are unaware of what they have taken, news of such fatalities has unbelievably driven some people with severe opioid addictions to seek it out. Part of the cycle of an opioid use disorder is increased tolerance, causing diminished response to the drug, which leads users to seek products with higher potency so they can experience the euphoria they initially felt. Roughly one-third of opioid users interviewed as part of the study in New Hampshire knowingly sought fentanyl.

The fentanyl problem is already a high priority for policymakers. Last month, NIDA’s Deputy Director Wilson Compton testified before Congress on the science of fentanyl, accompanied by representatives from the DEA, the Office of National Drug Control Policy (ONDCP), the CDC, and other agencies. Diplomatic and law enforcement efforts to cut off the supply of illicit fentanyl and the chemicals needed to manufacture it will be important, but the emergence of very high potency opioids–which can be transported in smaller volumes–will make addressing supply increasingly difficult. Thus, a public health strategy to address the opioid crisis and overdose epidemic is more important than ever.

First, we must improve pain management and minimize our reliance on existing opioid pain medications. Second, treatment centers and healthcare systems must make much wider use of available, effective medications for opioid addiction (Buprenorphine, Methadone, and extended-release Vivitrol). Third, the opioid-overdose reversing drug naloxone needs to be made as widely available as possible, both to emergency first responders as well as to opioid users and other laypeople who may find themselves in a position to save a life. In cases of fentanyl overdose, multiple doses of naloxone may be needed to reverse an overdose, and additional hospital care may be needed. All individuals who overdose on opioids need to be linked to a treatment program to prevent it from happening again.

From the blog of Dr. Nora Volkow, Dir., National Institute on Drug Abuse
April 6, 2017