Kratom:  A Primer on the Controversy Surrounding the Opioid Analogue

By: Mario Ramirez, MD

Reading Time: 7 minutes

Date: 05/12/2020

Filed Under: Clinician Perspective, DEA, kratom, patient safety

Kratom leaves, https://www.usada.org/substance-profile-kratom/We’ve previously written about the challenges clinicians and patients face as they seek non-opioid alternatives for effective pain management.  One such alternative, Mitragyna speciose, or kratom, has been a focus of increased public discussion lately, but is still a topic that many clinicians are unfamiliar with.  AffirmHealth has developed this short primer to help bring you up to speed so that you can have an informed discussion with your patients.

What is Kratom?

Kratom is a tropical evergreen tree of the coffee family that was originally native to Southeast Asia1, and has been used in traditional medicine since at least the 19th century.  Its exact mechanism of action is an area of debate, but there is some evidence that biochemically active compounds and derivatives activate the opioid receptor at sufficient dosages and can be used in mood disorder and pain management.  Historically, it was used in similar fashion as coca or khat leaves in that users would either chew the leaves or brew a tea2, but packaging in the vitamin and supplement industries now includes pills, salves, creams, and other formulations. 

Over the past 20 years, kratom has transitioned from an offbeat herbal supplement into a mainstream topic of the pain management space.  Importantly, kratom sales are not well documented but the numbers of users in the United States is estimated to be between three and five million persons3 with increased attention on its potential use as both a “legal” recreational drug and as a means to mediate opiate addiction.  At moderate doses of 5 to 15 g of raw leaves3,4, the plant’s opioid-related effects become more clinically apparent.  These can include euphoria but may also include adverse opioid related effects such as delayed bowel transit, sedation, and respiratory depression. 

The Controversy

Over the past few years, there has been increasing concern about kratom and a potential threat to public health as the number of kratom linked overdoses and fatalities has increased significantly.  Although many countries around the world have severely restricted kratom sales and distribution, kratom’s legality in the United States is more nuanced.

Beginning in 2013, the plant came under increased scrutiny by the U.S. Drug Enforcement Agency who stated at that time that “there is no legitimate medical use for kratom.5"  In 2016, the U.S. Centers for Disease Control and Prevention presented a report with data showing 660 reports of kratom exposure; of those, 49 or 7.4%, had major side effects that included life threatening signs or symptoms and some residual disability.6    Later, the U.S. Food and Drug Administration published a controversial model, the “Public Health Assessment via Structural Evaluation (PHASE) methodology” which essentially used computer modeling to predict the presence of biochemically active kratom metabolites in the body and how they may behave physiologically.  That study showed that 22 of 25 kratom compounds could bind to the mu-opioid receptor theoretically leading to opioid like effects.3

It is important to note, however, that there is disagreement about whether that computer model accurately predicts physiologic behavior in humans.  In a recent Pain Medicine News article, Andrew Kruegel, PhD, a chemistry research associate at Columbia University, noted that although kratom binds to the mu receptor, it does not do so “in the same way as classic opioids.”  In that same article, Dr. Oliver Grundmann, PhD, of University of Florida College of Pharmacy notes that there is a distinct difference in the binding between opioids and kratom.  As a result, they argue, the downstream biochemical pathways cannot be directly compared and the FDA’s model is fundamentally flawed.3

Kratom Schedule Classification

Between 2011 and February 2018, there have been 44 deaths in the U.S. linked to kratom, though only one of those has featured kratom alone—the remainder included co-ingestions of other medications, drugs, and alcohol.  Depending on the source, this either proves kratom’s significant risk or shows that the substance itself in isolation is actually safe.

In 2016, the DEA considered classifying kratom as a Schedule I drug in part because of kratom related poisoning calls to drug centers. At the time, however, the agency received strong opposition from both the public and a significant number of congressmembers—51 members of the U.S. House of Representatives and 9 Senators sent letters to Acting DEA Administrator Chuck Rosenberg  protesting its listing, and 140,000 persons signed an online White House Petition.7,8  Later that year, the DEA withdrew its notice of intent. 

Similar to the DEA, FDA administrator Scott Gottlieb has pushed to make kratom as federally scheduled substance.  In Feburary 2018, Commissioner Gottlieb released a statement noting that based on scientific evidence, “kratom should not be used to treat medical conditions, [or] as an alternative to prescription opioids.”  He cited the lack of proven efficacy or safety data and noted significant variability in how it is being formulated, manufactured, and sold which creates a public health risk.3

Where We Are Today

Because of increased awareness in recent years by both the public and lawmakers on the opioid epidemic, scrutiny of kratom has become more focused.  The significant costs, both in human lives and financial burden, associated with the epidemic are forcing interested parties to take concrete actions to restrict opioid supplies to the public.  On the state level, several states including Alabama, Arkansas, California, Florida, Illinois, Indiana, New Hampshire, Tennessee, and Wisconsin have all listed kratom as a Schedule I drug within their jurisdictions.  There is some thought that similar action at the federal level will be forthcoming but does not yet exist.  As a result, kratom remains federally legal, but illegal in certain states.  As we have written about previously, these types of policy differences create uncertainty and heighten risk for clinicians managing chronic pain.

It is likely that kratom will be a topic of continuing discussion in the years ahead.  As Dr. Edward Boyer, associate professor emergency medicine at the University of Massachusetts Medical School noted in Pain Management News, “the major problem with kratom is that like supplements generally, and unlike drugs, it's not regulated…that introduces a level of risk which is unacceptable.”3  Given its prevalent use in the U.S., however, it is likely that clinicians across all specialties will encounter its use among their patients.

 

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 1.  https://en.wikipedia.org/wiki/Mitragyna_speciosa

2.  .  Warner ML, Kaufman NC, Grundmann O (2016). "The pharmacology and toxicology of kratom: from traditional herb to drug of abuse". Int. J. Legal Med.(Review). 130 (1): 127–38. doi:10.1007/s00414-015-1279-y. PMID 26511390.

3.  https://www.painmedicinenews.com/Primary-Care/Article/04-18/Kratom-Wars-FDA-Proponents-Square-Off-on-Controversial-Opioid-Like-Plant/48394

4.  Marx, John; Walls, Ron; Hockberger, Robert (2014). "Chapter 156: Hallucinogens". Rosen's emergency medicine : concepts and clinical practice(Eighth ed.). London: Elsevier Health Sciences. pp. 2015–23. ISBN 9781455749874.

5.  "KRATOM (Mitragyna speciosa korth)" (PDF). U.S. Drug Enforcement Administration. January 2013. Archived from the original (PDF) on 11 June 2016.

6.  Anwar, Mehruba; Law, Royal; Schier, Josh (2016-01-01). "Notes from the Field: Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers – United States, 2010–2015". MMWR. Morbidity and Mortality Weekly Report. 65 (29): 748–49. doi:10.15585/mmwr.mm6529a4. ISSN 0149-2195. PMID 27466822.

7.  Ingraham, Christopher (September 30, 2016). "DEA defies senators' appeal to reconsider 'unprecedented' kratom ban". Washington Post.

8.  Stapleton, Christine (September 29, 2016). "Congress members ask DEA not to ban kratom: opioid research needed". Palm Beach Post.

Image: https://www.shutterstock.com/image-photo/kratom-mitragyna-speciosa-mitragynine-drugs-narcotics-498422785

 

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