The New York City Police Department reported a startling statistic last week: a 38% increase in fatal opioid overdoses in the city last year. Approximately 1,300 fatalities – more than homicide (335) and traffic collision (220) deaths combined – were recorded, mainly as a result of heroin and painkiller overdoses.
How did we get here? Why the unexpected surge? What happens now?
Both recreational use and addiction resulting from pain management are to blame for the uptick in overdoses. And poor policy may be making matters worse. Josh Bloom of the American Council on Science and Health believes a nationwide crackdown on narcotics intended to prevent addiction and save lives seems to have had the opposite effect.
He cites OxyContin, a favorite of addicts that was reformulated, making it harder to abuse. While illicit use of the drug did decline, many abusers switched to using heroin, which is far more dangerous. Bloom believes, “Nothing illustrates the folly of government policy better than the rising number of pain sufferers who turn to street heroin because they can no longer get legal medication.”
The arrival of synthetic opioids, specifically fentanyl, has also played a central role in the spike of fatal overdoses. Fentanyl is 50 to 100 times more potent than heroin and is legally used as a component of anesthesia to prevent pain during surgeries and medical procedures. In the illegal drug market, fentanyl is mixed with heroin in unknown quantities, making it impossible for even veteran heroin users to predict their tolerance accurately. The severity of this problem can be seen in the statistics – for example, in Massachusetts last year, 75% of accidental overdose fatalities had fentanyl in their systems.”
It is all about the dopamine
Dopamine is an organic neurotransmitter that is essential to human life. It stimulates the brain’s pleasure and reward centers in response to actions like eating, drinking, and sex – fundamental drivers of human existence. Dopamine in higher levels can create a sense of euphoria and eliminate even the most unbearable pain.
The Slippery Slope of Addiction. Opiates are powerful and quickly addictive.
Opiates are both fast-acting and highly addictive. They prompt the brain to release dopamine in full force – a feeling that one addict described as a “four-hour orgasm.” But the brain cannot continue to operate at such an extreme. It adjusts so that users will need some level of opiate just to feel normal again.
And this adjustment happens quickly. Withdrawal becomes difficult and painful, and for some, impossible to overcome. This short statnews.com video illustrates what happens when heroin users try to pull back.
A big problem getting bigger
According to the Surgeon General’s 2016 Report, 23 million people in the United States needed treatment for substance abuse last year. 11% of those received treatment, which costed around $33 billion. 4% of those funds were spent on pharmacotherapy.
New Drugs to fight the battle against addiction
With just 4% of expenditure on pharmacotherapy it would seem like there should be room for growth in new drug treatments. As a comparison, 28% of expense for treating mental health is for pharmacotherapy.
We have identified a few new technologies and upstarts that hold some promise for a drug to battle addiction by addressing the dopamine surge.
It is Dopamine surge that leads to relapse
Dopamine surges are part of the brain’s reward circuity. They are common to all substance and behavioral addictions. Addiction hijacks the reward circuits and creates pathophysiologic surges.
A primary approach to fighting drug dependency is simply avoiding all triggers and impulses, typically the people and places connected to the pleasures that stimulate dopamine surges.
Surges trigger craving. No Surge, No craving. Amygdala Neurosciences.
Reducing the pathophysiologic dopamine surge is the idea behind a company formed just weeks ago by a group of executives that spun out a drug from Gilead Sciences. The company, Palo Alto based Amygdala Neurosciences, made their first public presentation at the BioCentury conference in New York April 6th.
The company’s drug, ANS-66637, prevents pathophysiologic dopamine surges and associated craving without changes to basal dopamine (steady consistent base level).
The Kudzu plant?
First researched at Harvard and tested as a means to reduce binge drinking (link) this novel, First-In-Class, compound based on the Kudzu plant. Also called Japanese arrowroot, it is a group of plants climbing, coiling, and trailing perennial vines native to much of eastern Asia, and Southeast Asia, (wikipedia).
It was first developed CV Therapeutics and then at Gilead Sciences (GILD) where nearly $75 million has been invested in its development. Since that time the project has:
- Published their Mechanism of Action, MOA: ANS-6637 prevents pathophysiologic dopamine surges and associated craving without changes to basal dopamine. Nature Medicine. September 2010
- Published preclinical studies show: anti-craving for alcohol, cocaine, heroin, nicotine, methamphetamine and binge eating; and an anxiolytic effect. New England Journal of Medicine. January 28th 2016.
- Phase-1 safety data in 97 subjects well tolerated with no side effects. Initial indications for alcohol, cocaine and opioid use disorders.
The company is now raising capital now for a Phase-2 studies starting in 2017 and believe they will be Phase-3 ready in 2019, Gilead is a 20% shareholder in the new company.
Savant HWP and the pain pleasure pathway
Another promising drug in development is from small company in Northern California, Savant HWP that has developed a novel approach to addiction treatment targets the dopamine “reward” pathway in the brain that drives pleasure-seeking behaviors associated with addiction. Targeting the brain’s central reward pathway enables Savant to develop drug candidates potentially effective against all forms of substance abuse,
Savant’s approach is unique in addiction medicine. Current anti-addiction medications are either agonists or antagonists for the addictive substance’s primary receptor site of action (such as methadone for heroin addiction, low doses of nicotine for nicotine addiction and naltrexone for opiate dependence) and are themselves often harmful and addictive. These types of receptor strategies do not directly target the underlying addictive mechanism in the brain (extreme fluctuations of dopamine in the mesolimbic system leading to drug craving) that Savant’s novel approach targets.
In September 2012, Savant received a $6.5 million grant from the National Institute on Drug Abuse (“NIDA”) to support the preclinical development of 18-MC for the treatment of cocaine abuse. Additionally Savant has plans to study the drug’s use against drug withdrawl and craving from morphine, with follow up studies of 18-MC’s effects on long-term craving in morphine, cocaine and methamphetamine drug abusers.
18-MC, is an orally active, synthetic compound that modulates dopamine fluctuations in the mesolimbic system of the brain. Data from animal models demonstrate the efficacy of 18-MC in a broad array of substance addictions, including cocaine, opiate, methamphetamine, nicotine and alcohol, as well as over-eating.
These treatments can be segregated into treatment for withdrawal symptoms and treatment for long-term craving. According to the company there are no treatments for craving for either cocaine or methamphetamine addiction. A recent analysis by the National Institute on Drug Abuse (NIDA) estimates the market size for a first-in-class treatment for cocaine addiction at $1.2 billion in annual revenue.
Savant HWP plans to run clinical trials of 18-MC in 2017, first with smokers in Brazil, followed by tests with opioid and cocaine addicts in the U.S.
Avoiding the deaths. Faster Naloxone delivery at overdose
Recognizing that the difference between an effective and fatal opioid dosage can be small and unpredictable, another company is developing a means to save those that have overdosed.
The most prevalent hazard during an opioid overdose is respiratory depression (ie. you stop breathing). A small public company in Santa Monica, CA, Opiant [NASDAQ: OPNT (est. Market Cap $45 million) has developed an alternative to injection treatments.
Their naloxone nasal spray, a treatment for opioid overdoses and that is now coming to market in In collaboration with Adapt Pharma (link),
Currently, Naloxone, an opioid antagonist can prevent and reverse overdose through binding to opioid receptors in the brain and thus prevent exogenous opioids (such as heroin or opioid painkillers) from activating these opioid receptors. Once injected it can reverse opioid overdose, but is only effective if administered in time.
The company’s NARCAN® (naloxone HCl) Nasal Spray has FDA approval for commercial use in the United States. Designed to be administered by a broad population, it’s advantage that a trained healthcare professional is not required to administer the drug.
An uncertain future
The problem is not going away anytime soon. Increased awareness Hopefully innovative companies and smart policy will address what many now call the most significant health challenge in the United States today.