Positive pain relief

New compound may help reduce chronic opioid use and facilitate dose tapering

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CAMBRIDGE, Mass.—Drug development company Ethismos Research reported that a study of its lead compound amitifadine, a triple uptake inhibitor, showed that the compound demonstrated independent pain-relieving effects while significantly reducing the self-administration of the opioid remifentanil without reducing its analgesic effects in rats being treated with both in acute and chronic settings. The research was published in Psychopharmacology in March. The results suggest that amitifadine may be a useful complementary treatment to opioids in treating pain, aiding with tapering off of opioids and offering a promising counter to opioid dependency brought on by prolonged use.
Amitifadine is a triple reuptake inhibitor of serotonin, norepinephrine and dopamine. It has been developed to date as an antidepressant for major depressive disorder and treatment-resistant depression.
“Amitifadine is a single molecule that can be imagined as similar to a serotonin–norepinephrine reuptake inhibitor (like duloxetine), with the difference that amitifadine also inhibits dopamine reuptake, and thus modulates the dopamine pain circuit and treats the emotional aspects of pain,” explained Anthony McKinney, founder and CEO of Ethismos Research.
“In the U.S., the primary method to treat chronic pain—especially since the late 1990s—has involved opioids,” says McKinney. “Currently, 2 million Americans suffer from opioid addiction. Government data shows that 80 percent of those taking heroin initiated their use of opioids with recreational oral opioids. In addition, it is known that a portion of oral opioids are diverted to non-medical use. If amitifadine can reduce chronic opioid exposure, there is potential to reduce the number of new opioid addictions.”
If successfully developed, amitifadine would be used as an adjunct to chronic opioids for opioid-sparing and facilitation of taper in patients with chronic pain. It would be given orally as a separate prescription alongside an opioid treatment and would serve as a non-opioid analgesic to facilitate gradual opioid dose reduction over six months, with the goal of eliminating the opioid by the end of that period. This time horizon is consistent with a recent FDA Advisory Committee notice pertaining to opioid tapering and reducing chronic opioid use.
“The FDA Advisory notice to prescribers is relevant because many chronic opioid patients have been forced to rapidly taper their pain medications by their physicians or their medical plans,” McKinney comments. “This has led to rapid-taper patients having poor outcomes.”
Amitifadine would simultaneously address the psychiatric symptoms that occur during opioid treatments and during dose reduction, such as negative affect, anxiety, anhedonia and weight gain. Once a patient is weaned all the way off opioids, amitifadine could continue to serve as the long-term pain medication.
Ethismos is targeting the approximately 10 million patients in the United States who take opioids for pain for three months or longer, which is defined as chronic use.
According to McKinney, “With three months of opioid exposure, the risk of still being on opioids nearly four years later is 80 percent; the longer one is on opioids, the higher the risk of overdose and addiction. After three months, the risk of opioid-induced mental sequelae—the risk of depression— increases by 25 percent, and after six months the risk rises to 50 percent.”
The company is undergoing a fundraising campaign in anticipation of a Phase 2 chronic pain trial.
“Our plans are to complete the fundraising this spring, make clinical supplies, prepare and file the opioid-sparing/taper IND, and then initiate a Phase 2 POC chronic pain trial,” McKinney tells DDNews. “This would confirm the amitifadine pain profile. Once this is complete, Ethismos would be in a position to initiate the six-month Phase 2b opioid-sparing/facilitation of taper trial.”
The company currently has a three-year trial and five-year grant under consideration by the National Institute for Drug Abuse (NIDA). McKinney says the grant was turned down in early 2020, but NIDA has requested for Ethismos to re-submit the grant unchanged since the publication of its most recent results. This offers the possibility of a federal grant to support the program.
“We are engaging in discussions with institutional investors interested in a preventative approach to the opioid crisis as well as a thoughtful approach to why people relapse in substance use disorders,” he remarks. “This offers a Phase 2 program with several potential multibillion indications for investors looking for a strategic exit in the 2023 time period.”
Although focusing on chronic opioid exposure and opioid taper as an initial indication, Ethismos is exploring amitifadine in multiple indications, including maintenance of chronic remission after ketamine treatment, prevention of methamphetamine relapse and nicotine cessation.
“Amitifadine has already gone through 10 human safety and Phase 2 dosing trials (in major depressive disorder and treatment-resistant depression) with no major safety signals, and is ready to move into Phase 2 trials in multiple indications,” McKinney states.

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