Liver Safety Concerns Over Opioid-like Supplement Kratom

Christina Bennett

November 08, 2019

The controversial opioid-like dietary supplement known as kratom might cause liver injury in people who take it, according to a study of prospectively collected cases.

"These are data that we desperately need because, up to this point, there have been only scattered case reports," said Andrew Schreiner, MD, from the Medical University of South Carolina in Charleston, who was not involved in the study but reported the case of a 47-year-old man who experienced kratom-induced liver injury.

Kratom is currently widely available without a prescription and is unregulated, so there is no standardization in the way the product is made or disseminated. "These types of studies are going to be critical if we are ever to approach the regulation of this agent," Schreiner explained.

Currently, nearly 5 million people in the United States use kratom, according to the American Kratom Association.

The leaves of the kratom tree, which grows in Southeast Asia, contain mitragynine and other substances believed to elicit opioid-like or psychotropic effects. People who take kratom typically ingest it as a pill, capsule, or extract, but some smoke, brew, or chew the leaves. Despite efforts to ban the supplement, kratom remains legal in the United States.

Data from a cohort of 404 participants in the Drug-Induced Liver Injury Network Prospective Study will be presented by Victor Navarro, MD, division head of gastroenterology at Albert Einstein Healthcare Network in Philadelphia, at The Liver Meeting 2019 in Boston. All were identified as having liver injury associated with herbal and dietary supplements.

Kratom has become a bit of a go-to.

Eight cases of liver injury in the study cohort were associated with kratom, and the investigators concluded — using an expert-opinion-based causality assessment tool — that seven were caused by kratom.

"One of the challenges in drug-induced liver injury is proving causality," said Schreiner.

The Roussel-Uclaf Causality Assessment Method is commonly used to establish whether a drug of interest triggered an outcome. It looks at a variety of factors, such as time to onset of liver injury, the presence of other risk factors, the use of other agents that could cause a liver injury, and other possible origins of liver injury.

Of the seven patients with liver injury caused by kratom in the study presented, six were men, six were white, five took kratom for its psychotropic effects, and one took it to manage joint pain.

Six of the patients required hospitalization, but all recovered and none required liver transplantation. There was no evidence of rash in any of the patients, but five had jaundice, six had itching, five had abdominal pain, and three had fever.

The median duration of kratom use was 22 days (range, 15 - 49 days) before the onset of liver injury. All patients reported using alcohol.

Table. Results of Liver Function Testing
Measure Median Level Peak Level
Alanine aminotransferase (ALT), U/L 326 362
Aspartate aminotransferase (AST) U/L 154 154
Alkaline phosphatase (Alk P), U/L 292 294
Total bilirubin, mg/dL 9.5 20.1

Navarro and his colleagues calculated a median R factor value of 3.0, which indicates that the cause of injury was mixed hepatocellular–cholestatic injury. Biopsy samples from two patients indicated cholestasis.

The team conducted a chemical analysis of three kratom products and found that all had kratom but no other common hepatotoxins.

Primary care physicians are the ones "on the frontlines" who need to be asking about patient use of herbal or over-the-counter supplements, specifically kratom, said Schreiner.

"Kratom, especially, is a big deal because, as there are wider pressures for physicians to not use opioids for pain relief, more providers are reluctant to prescribe them, which has left patients willing to turn to other agents," he explained. "It sounds as though kratom has become a bit of a go-to in that setting."

Kratom has been linked to multiple deaths, but it is unclear whether the supplement alone can cause death because toxicology tests show that it is rarely the only substance in the blood of patients who die.

For example, of the 91 kratom-caused deaths that occurred from July 2016 to December 2017, most involved other substances, including fentanyl, heroin, benzodiazepines, prescription opioids, cocaine, and alcohol, according to a Centers for Disease Control and Prevention report.

Although it is known that drug-induced liver injury can cause death, whether kratom alone can lead to drug-induced liver injury severe enough to cause death is still unclear, Schreiner said.

The Liver Meeting 2019: American Association for the Study of Liver Diseases (AASLD): Abstract 0212. To be presented November 11, 2019.

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