Researchers Find Alternatives for Acetaminophen Without Liver, Kidney Effects

Acetaminophen, sold over the counter worldwide to control pain and reduce fever, is not the harmless drug it appears for every patient. It is toxic for those with compromised liver function, and long-term use can cause liver or kidney damage.

The coronavirus disease 2019 (COVID-19) pandemic presents a new challenge: patients have severe flu-like symptoms, but the virus can also cause renal failure, so acetaminophen is not the best choice. Doctors and patients need analgesics that go easy on the liver and kidneys but are not addictive, and this week, researchers at LSU Health New Orleans Neuroscience Center of Excellence announced they have discovered a new class of drugs that can do the job.

Hernan A. Bazan, MD, FACS, a professor in the Department of Surgery and Program Director of the Vascular Surgery Fellowship at Ochsner Clinic, and Surjyadipta Bhattacharjee, PhD, a post-doctoral researcher at the LSU Health New Orleans Neuroscience Center of Excellence, led the team that examined how acetaminophen causes damage—and then set out to find alternatives that did not result in oxidation to N-acetyl-p-benzoquinone imine, or NAPQI, the mechanism that most of results in hepatoxicity from acetaminophen.

The team ended up with 2 new chemical entities that reduced pain in modeling studies but without the damage to the liver and renal system, as measured by biomarkers, according to senior author Nicolas Bazan, MD, PhD, Boyd Professor and Director of LSU Health New Orleans Neuroscience Center of Excellence.

"The new chemical entities reduced pain in 2 in models without the liver and kidney toxicity associated with current over-the-counter analgesics that are commonly used to treat pain—acetaminophen and [nonsteroidal anti-inflammatory drugs],” Nicolas Bazan said in a statement. “They also reduced fever in a pyretic model. This is particularly important in the search for an antipyretic with a safer profile in the COVID-19 pandemic and its associated kidney and liver disease in critically ill SARS-CoV-2 patients."

Working with a chemistry group led by Julio Alvarez-Builla, PhD, of the University of Alcala in Madrid, Spain, they tested 21 compounds, seeking acetaminophen analogs. For each compound, the team ran the following tests:

1. A test for liver toxicity, using a human liver cell line,
2. An additional test for liver toxicity using an animal model
3. A test for whether the compound could reduce fever using a mouse model

As potential toxic compounds were set aside, researchers focused on those that could be potential acetaminophen analogs. Two compounds in particular did not produce markers for liver toxicity seen in acetaminophen, and these were tested against acetaminophen for renal function. While acetaminophen caused an increase in serum creatinine, the 2 compounds did not.

Finally, these 2 compounds were tested for their analgesic properties and their ability to reduce fever in male mice; the pain relief and fever-reducing abilities were on par with acetaminophen.

The opioid epidemic has caused CDC to issue guidelines to physicians to limit prescribing of that class of pain medication, and many states have passed laws limiting access to these drugs. However, the LSU Health research team points out that the problem of acute and chronic pain management remains real and costly: CDC data show that an estimated 50 million adults—or 20.4% of the population—had chronic pain in 2016, and 8.0% had high-impact chronic pain.

"Given the widespread use of acetaminophen, the risk of hepatotoxicity with overuse, and the ongoing opioid epidemic, these new chemical entities represent novel, non-narcotic analgesics that exclude hepatotoxicity, for which development may lead to safer treatment of acute and chronic pain and fever," Bazan said.

Reference

Bazan HA, Bhattacharjee S, Burgos C, et al. A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis. Eur J Med Chem. Published online July 6, 2020. doi.org/10.1016/j.ejmech.2020.112600