Kratom and Interventional Orthobiologics Procedures
As you know, I often write about what I experience seeing patients. While Kratom has been on the periphery of my consciousness like it probably has been for many physicians, this past week, it was thrust to the forefront. This “drug” sold in gas stations and online turns out to be a potent opioid receptor agonist, or said another way, it’s a legal and potentially dangerous narcotic drug being sold without any controls and is likely wreaking havoc with procedural anesthesia here in the US. It also may be impacting orthobiologics like PRP or bone marrow concentrate. Let’s dig in.
What Is Kratom?
Kratom is derived from a tropical evergreen tree that’s native to Southeast Asia. It’s sold extensively online, and in some gas stations, and despite confirmed reports of more than 90 overdose deaths in 2016-17, it has not yet been scheduled by the DEA or regulated by the FDA (1). In low doses, it’s a stimulant, and in higher doses, it acts like an opioid. That narcotic-like effect is because it acts at opioid receptors.
Because it can control pain like an opioid, pain patients often get exposed to this drug on Facebook or other social media platforms where it’s sold extensively. Because of its abuse potential and the fact that it depresses respiratory drive like a narcotic, the DEA in 2016 stated that it had the intent to regulate Kratom as a Schedule 1 drug (2). However, an outcry from advocates caused the DEA to cancel their intention to schedule. The FDA has recommended to the WHO that Kratom be banned internationally. As of this writing, no actions curbing the availability of the drug have been successful.
Overdosing on an Herbal Supplement?
In 2022, an AP news story discussed that Atlanta parents had found their son dead after overdosing on Kratom (3). The Georgia Bureau of Investigation determined that their son had no other substances in his body other than Kratom and that he overdosed from its active ingredient called mitragynine. Dozens of wrongful death lawsuits have been filed, with a Washington jury recently awarding 2.5 million USD in a Kratom death case (6). In addition, a Florida woman was awarded 4.6 million USD after a medical examiner said she died of acute Kratom intoxication. She had ordered Kratom from an online ad.
The American Kratom Association claims this is a billion-dollar industry, with vendors importing 2,000 tons a month into the U.S. How can a patient overdose on a herbal supplement sold in truckstops and on Facebook? One of its ingredients is an alkaloid opioid analog, mitragynine. This drug operates at the same receptors (mu, delta, and kappa opioid receptors) as morphine which leads to a depressed respiratory drive. However, while clinical cases of Kratom overdose causing respiratory depression have been reported, animal studies refute that claim (7-9).
Despite 1.7 million Americans aged 12 and older using Kratom in 2021, reliable information on the annual death rate due to overdose is hard to find (4). A dozen states regulate Kratom, and five have banned it altogether. The FDA claims that any product containing Kratom is not a dietary supplement but an adulterated and unapproved drug product (5).
Recently the Kratom advocacy groups have stated that they want the FDA to regulate the substance but that the agency has refused to regulate it and instead has focused on a ban. They blame the lack of FDA regulation for the cause of the recent deaths and lawsuits. However, what these groups don’t really seem to understand is that FDA has stated it wants to regulate Kratom, just not as a supplement. They want to regulate it as a prescription drug, requiring 5-10 years of clinical trials and hundreds of millions of dollars per new Kratom drug application. This means that if these groups get what they ask for, no Kratom will be sold in the US for the next decade.
Is This Stuff Addictive?
A 2014 study out of Malaysia, where bars serving Kratom-laced tea and other drinks are common, reported on 293 regular users (11). More than half of the regular users (> six months of use) developed severe Kratom dependence problems, while 45% showed moderate Kratom dependence. These users had withdrawal effects when they stopped consuming, not unlike withdrawal from narcotics.
The Effects of Kratom on Anesthesia
There is a single case report of a heavy Kratom user undergoing a long facial surgery who required 5,400 mg of propofol, 5.5 mg of remifentanil, 3,200 mg of esmolol, 19 mg of nicardipine, 52 mcg of dexmedetomidine in divided boluses, 400 mcg of fentanyl, 2 mg of morphine, 800 mg IV acetaminophen, and bupivacaine infiltration of the surgical sites by the surgeons (10). The patient exited anesthesia in agitated delirium and struggled with post-op pain relief.
My experience is similar. We have recently struggled with anesthesia on patients who are Kratom users. These patients require much higher doses of anesthesia, much like a patient addicted to narcotics or who regularly uses THC or Low Dose naltrexone. For example, it’s not uncommon in my experience for Kratom users to take ordinarily lethal doses of IV versed/fentanyl and still be conversant and alert.
In many ways, the Kratom anesthesia literature is in the same place as the THC research 5-years ago. The latter is now mature enough that it’s begun appearing as a routine lecture and warning to CRNAs and anesthesiologists at conferences. I suspect that five years from now, the same warnings will occur about Kratom.
Kratom and Orthobiologics
The active ingredient of Kratom, Mitragynine, is toxic to cardiomyocytes and, by extension, induced pluripotent stem cell-derived cardiomyocytes (12). This substance also blocks nerve action potentials and interferes with the neuromuscular junction (13). Mitragynine also may disrupt critical cell-cell barriers leading to problematic absorption of other drugs (14).
Little is known about the direct effects of Mitragynine on mesenchymal stem cells (MSC) or orthobiologic targets like chondrocytes or tenocytes. However, one concern is that it may interfere with platelet function like COX-2-specific NSAIDs. For example, one study has shown COX-2 inhibition (15). This is a concern, as COX-2 inhibition can lead to problems with bone-to-tendon integration and fracture healing (16,17).
There is also a body of literature on how COX-2 inhibition could directly impact MSC function (18). Basically, COX-2/PGE2 plays an important role in maintaining the essential life functions of MSCs, such as the ability to proliferate, migrate and differentiate.
Hence, Kartom should be discontinued before any orthobiologic procedure, much like NSAIDs are restricted during these procedures.
Kratom Conclusions
Kratom is a drug, NOT an herbal supplement. It works at narcotic receptors and may have less activity than opioids at those receptors, but it is still addictive and potentially fatal if taken in large quantities. Based on what I have observed and what others have published, it increases patient anesthesia risk, much like a patient taking narcotics. It also inhibits COX-2, so it should be discontinued in any patient undergoing orthobiologic care, just like an NSAID.
The upshot? In the age of Facebook and social media sales of poorly regulated and potent drugs, it’s tough to keep up. Kratom is something I had associated with truck stop, hillbilly heroin, but we’re seeing more orthobiologic patients tell us they’re taking it, or we find out later after we struggle with patient anesthesia. Either way, it’s now something that we all should ask patients about and understand that it could impact orthobiologic outcomes.
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References:
(1) Kuehn B. Kratom-Related Deaths. JAMA. 2019;321(20):1966. doi:10.1001/jama.2019.6339
(2) DEA. DEA Announces Intent To Schedule Kratom. https://www.dea.gov/press-releases/2016/08/30/dea-announces-intent-schedule-kratom. Accessed 8/4/23.
(3) Associated Press. Parents sue over son’s death after he took kratom supplement. https://apnews.com/article/health-business-lawsuits-georgia-us-food-and-drug-administration-46027961c11d27c3cee56c547a4a1664 Accessed 8/5/23
(4) Substance Abuse and Mental Health Services Administration. National Survey on Drug Use and Health. https://www.samhsa.gov/data/sites/default/files/reports/rpt39443/2021NSDUHFFRRev010323.pdf Accessed 8/5/23
(5) USFDA. FDA and Kratom. https://www.fda.gov/news-events/public-health-focus/fda-and-kratom Accessed 8/5/23
(6) NPR. Herbal supplement kratom targeted by lawsuits after a string of deaths. https://www.npr.org/2023/07/08/1186514144/kratom-herbal-supplement-lawsuits-deaths-fda Accessed 8/5/23
(7) Henningfield, J.E., Rodricks, J.V., Magnuson, A.M. et al. Respiratory effects of oral mitragynine and oxycodone in a rodent model. Psychopharmacology 239, 3793–3804 (2022). https://doi.org/10.1007/s00213-022-06244-z
(8) Chinnappan J, Navari Y, Casini D, Palanisamy N, Parikh N, Seedahmed E. Kratom-Induced Acute Respiratory Distress Syndrome (ARDS). Eur J Case Rep Intern Med. 2023 Mar 29;10(4):003835. doi: 10.12890/2023_003835. PMID: 37051477; PMCID: PMC10084802.
(9) Hill R, Kruegel AC, Javitch JA, Lane JR, Canals M. The respiratory depressant effects of mitragynine are limited by its conversion to 7-OH mitragynine. Br J Pharmacol. 2022 Jul;179(14):3875-3885. doi: 10.1111/bph.15832. Epub 2022 Mar 30. PMID: 35297034; PMCID: PMC9314834.
(10) Lund E, Low AB, Allan JD, Puentes JA, Flynn DN. Anesthetic Challenges Posed by Heavy Kratom Users. Cureus. 2022 Mar 5;14(3):e22864. doi: 10.7759/cureus.22864. PMID: 35399423; PMCID: PMC8982483.
(11) Singh D, Müller CP, Vicknasingam BK. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms and craving in regular users. Drug Alcohol Depend. 2014 Jun 1;139:132-7. doi: 10.1016/j.drugalcdep.2014.03.017. Epub 2014 Mar 22. PMID: 24698080.
(12) Lu J, Wei H, Wu J, Jamil MF, Tan ML, Adenan MI, Wong P, Shim W. Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes. PLoS One. 2014 Dec 23;9(12):e115648. doi: 10.1371/journal.pone.0115648. PMID: 25535742; PMCID: PMC4275233.
(13) Chittrakarn, Somsmorn & Keawpradub, Niwat & Sawangjaroen, Kitja & Kansenalak, Supaporn & Janchawee, Benjamas. (2009). Mitragynine and Methanol Extract of Kratom Leaf (Mitragyna speciosa Korth.) Inhibited Compound Nerve Action Potential.
(14) Hanapi NA, Chear NJ, Azizi J, Yusof SR. Kratom Alkaloids: Interactions With Enzymes, Receptors, and Cellular Barriers. Front Pharmacol. 2021 Nov 17;12:751656. doi: 10.3389/fphar.2021.751656. PMID: 34867362; PMCID: PMC8637859.
(15) Utar Z, Majid MI, Adenan MI, Jamil MF, Lan TM. Mitragynine inhibits the COX-2 mRNA expression and prostaglandin E₂ production induced by lipopolysaccharide in RAW264.7 macrophage cells. J Ethnopharmacol. 2011 Jun 14;136(1):75-82. doi: 10.1016/j.jep.2011.04.011. Epub 2011 Apr 12. PMID: 21513785.
(16) Sauerschnig, M., Stolberg-Stolberg, J., Schmidt, C. et al. Effect of COX-2 inhibition on tendon-to-bone healing and PGE2 concentration after anterior cruciate ligament reconstruction. Eur J Med Res 23, 1 (2018). https://doi.org/10.1186/s40001-017-0297-2
(17) Simon AM, Manigrasso MB, O’Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res. 2002 Jun;17(6):963-76. doi: 10.1359/jbmr.2002.17.6.963. PMID: 12054171.
(18) Kulesza A, Paczek L, Burdzinska A. The Role of COX-2 and PGE2 in the Regulation of Immunomodulation and Other Functions of Mesenchymal Stromal Cells. Biomedicines. 2023; 11(2):445. https://doi.org/10.3390/biomedicines11020445
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