As the opioid epidemic continues to ravage the United States, patients and physicians are looking for less-addictive alternatives for pain control.

For a growing number of U.S. patients, top among the contenders is kratom, a plant-based product that shows a dose-dependent opioidlike effect. For physicians, toxicologists – and federal regulators, however – the absence of evidence-based studies on the herb’s effectiveness and safety is raising concerns.

There is very little toxicity data regarding kratom – although there have been deaths in the United States, including Florida, attributable to its ingestion,” said Bruce A. Goldberger, PhD , chief of health forensic medicine at the University of Florida in Gainesville. “As far as I know, there have been no clinical trials evaluating the efficacy of kratom to treat pain and mood disorders. All that is known is based on self-report.”

Petros Levounis, MD , an addiction psychiatrist who has treated kratom users, said an inherent challenge is countering patients’ perceptions about the substance.

“Somehow, in the popular culture, kratom has a reputation as being a mild opioid. And we’re not sure about that,” said Dr. Levounis, a member of the American Society of Addiction Medicine. “But the fact that people think it’s more natural and therefore it must be safer is very problematic.”

The uncertainty around kratom raises the stakes when it comes to treating patients. “From a medical perspective, one of the trickiest issues is we’re not sure that naloxone reverses the opioid effects,” said Dr. Levounis, also chair of psychiatry at Robert Wood Johnson Medical School, New Brunswick. “We do use naloxone, but it is not clear that it works as an antidote. This is probably the most problematic area about kratom.”

Origins, demographics

A member of the coffee family, kratom (Mitragyna speciosa) grows in Thailand, Malaysia, Indonesia, and Papua New Guinea, and has been used throughout southeast Asia for many years to manage pain and bolster energy, according to the National Center for Complementary and Integrative Health.

The pharmacologic makeup of the botanical product includes alkaloids similar to other opioid-antagonists, including mitragynine, mitraphylline, and 7-Hydroxymitragynine, according to the U.N. Office on Drugs and Crime. In small doses, kratom has been known to boost energy; in larger doses, it has a sedative, pain-relieving effect. Some people chew fresh kratom leaves for stimulant and analgesic effects, said Oliver Grundmann, PhD , clinical associate professor at the University of Florida, in a presentation about kratom posted on YouTube. Dried kratom leaves can be ground up into powder preparations, he said. Still others consume kratom in the form of a pill, incense, or as a liquid extract, all of which are available online and at some smoke shops.

Dr. Grundmann conducted an anonymous survey last year about kratom and found that most users are white, married or partnered, and employed for wages. Dr. Grundmann’s survey of 8,049 kratom users also found that a majority of users reported having some college. However, the survey found an inverse relationship between years of education and the tendency to use kratom ( Drug Alcohol Depend. 2017 Jul 1;176:63-70 ).

“The more education somebody has, the less likely they are to use kratom for prescription medicine dependency or for an emotional or mental condition,” Dr. Grundmann said.

Anecdotal evidence

One study conducted by David Galbis-Reig, MD , president-elect of the Wisconsin Society of Addiction Medicine, followed a 37-year-old woman who experienced kratom addiction.

Diagnosed with depression, the patient was introduced to kratom by a colleague who told her about kratom’s nonaddictive qualities and who had been using it to treat pain. Over 2 years, the patient became addicted to a liquid extract version of kratom and, during her rehabilitation experienced severe withdrawal symptoms, said Dr. Galbis-Reig, who was not surprised by the patient’s reaction.

“The mitragynine and 7-Hydroxymitragynine very clearly have partial opioid agonist activity with kappa antagonist activity, which is very similar to buprenorphine,” Dr. Galbis-Reig, who is also with American Society of Addiction Medicine, said.

A major concern that Dr. Galbis-Reig’s case brings up is the use of liquid kratom extract.

“My biggest concern is we just don’t know what the stimulant properties of the drug are,” Dr. Galbis-Reig said. “If it turns out the properties are more in line with an amphetamine, I’m not sure that’s a great drug to use in a clinical setting for many conditions.”

But Murray A. Holcomb, MD , an acute care surgeon at Seton Healthcare Family Center, Round Rock, Tex, offered a different take. He said he and his family were first highly skeptical when they first heard about kratom. But after years of trying to help his son overcome his depression and substance abuse, Dr. Holcomb said he was ready to try anything.

After researching and consulting with his colleagues, Dr. Holcomb helped his son acquire the plant. What was expected to be another substance that overpromised and underdelivered turned out to be the real thing.

“Out of desperation, [my son] tried kratom, and within a few short days, he began to experience remission of his symptoms – which was immediately noticeable to all of us who knew him,” said Dr. Holcomb. “It is important to note that kratom does not make him high, loopy, or anything but normal. He lives independently, works full time, maintains healthy relationships, is pleasant and responsible, reestablished contact with his sister and brother, and is largely a happy normal person.”

Not only was his son able to return to his normal life, but the costs for his dose of kratom were within his budget while making minimum wage, similar to a majority of users – who make $35,000-$50,000 per year, Dr. Grundmann’s survey results suggest.

For people with substance use disorder, the issue of addiction always is present, Dr. Holcomb believes, and if that is the case, it’s better to be using kratom than another drug,

“If people steer themselves to kratom rather than something else, that’s probably a good thing, because if someone wants to abuse something, you can’t stop them; you can’t regulate intent,“ Dr. Holcomb said. “Kratom is a partial agonist. It doesn’t make you euphorically high, it doesn’t make you quit breathing, and you don’t really have any withdrawal symptoms, and no one is going to overdose on a natural plant – because it will make them sick to their stomach.”

In a systematic review of studies related to kratom use, investigators found that the product “may be useful for analgesia, mood elevation, anxiety reduction, and may aid opioid withdrawal management. Negative themes also emerged, including unfavorable side effects, especially stomach upset and vomiting,” wrote Marc T. Swogger, PhD , and his colleagues ( J Psychoactive Drugs. 2015 Nov-Dec;47[5]:360-7 ).

“As an opioid substitute, it seems to be used in good effect to decrease opioid withdrawal symptoms, including cravings for more opioids,” said Dr. Swogger, clinical psychologist at the University of Rochester (N.Y.). “People are able to use kratom as a way to get through systemic hoops to get the medicine they need.”

The regulatory fight

In 2016, the Drug Enforcement Administration announced its intentions to classify mitragynine and 7-Hydroxymitragynine, the active ingredients in kratom, as a schedule I drug in order to “avoid an imminent hazard to public safety” after two cases of kratom exposure were reported to the American Association for Poison Control Centers, according to a statement released by the DEA .

In November 2017, Scott Gottlieb, MD , commissioner of the Food and Drug Administration, issued a public health advisory reporting that kratom-related calls to U.S. poison control centers soared 10-fold during 2010-2015. It also said that 36 people have died after using products containing kratom. In light of those developments and with the absence of evidence showing that the substance is safe, the agency is taking action, he wrote.

“To fulfill our public health obligations, we have identified kratom products on two import alerts and we are working to actively prevent shipments of kratom from entering the U.S.,” Dr. Gottlieb wrote. “Kratom is already a controlled substance in 16 countries, including 2 of its native countries of origin, Thailand and Malaysia, as well as Australia, Sweden, and Germany. Kratom is also banned in several states, specifically Alabama, Arkansas, Indiana, Tennessee, and Wisconsin, and several others have pending legislation to ban it.”

In December 2017, a group comprising 17 members of Congress responded wrote a letter to Dr. Gottlieb imploring the Trump administration to recognize the merits of the substance and to drop its intention to make it more difficult to procure.

“Given that numerous stakeholders, former opioid addicts, and scientific researchers vouch for kratom’s safety and support its use, and responsible manufacturers of kratom products ensure that their products are properly labeled for adult-only consumption, we respectfully request that the FDA reconsider its stance and take a closer look at the facts and recent science regarding this plant,” the members wrote in the letter. After the letter was received by the FDA, the DEA decided to hold off on its scheduling.

But controversy surrounding the botanical product continues. Earlier this year, the FDA ordered the recall and destruction of kratom-containing dietary supplements made by a company in Grain Valley, Mo., the agency said in a statement . The FDA also is investigating a possible association between kratom intake and an outbreak of salmonella in North Dakota and Utah, in which 17 of 24 patients reported taking products thought to contain kratom before becoming sick, the agency wrote .

Meanwhile, Dr. Gottlieb issued a statement in February 2018 saying that the agency was able to confirm that kratom contains opioids. “The extensive scientific data we’ve evaluated about kratom provides conclusive evidence that compounds contained in kratom are opioids and are expected to have similar addictive effects as well as risks of abuse, overdose and, in some cases, death. At the same time, there’s no evidence to indicate that kratom is safe or effective for any medical use,” Dr. Gottlieb wrote. “To protect the public health, we’ll continue to affirm the risks associated with kratom, warn consumers against its use, and take aggressive enforcement action against kratom-containing products.”

For physicians like Dr. Levounis, who treat kratom users in emergency departments, patients should heed those warnings. “People erroneously feel that herbal products are milder than other products,” he said. “Nature can manufacture incredibly strong stuff – for good and for bad.”

Dr. Goldberger, Dr. Levounis, Dr. Grundmann, and Dr. Holcomb had no disclosures. Dr. Galbis-Reig disclosed in his study that he is the owner of stock in GW Pharmaceuticals and Cortex Pharmaceuticals, Pfizer bonds, and has spousal ownership of stock in AbbVie, Abbott Pharma, and Hospira. Dr. Swogger and other authors of the systematic review reported serving as consultants for the American Kratom Association, as well as sponsors of other kratom products.

ezimmerman@mdedge.com

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