Toxcard: Kratom

Authors: Neha Ray, MD (Emergency Medicine Resident, Atrium Health’s Carolinas Medical Center), Ann-Jeannette Geib, MD (Emergency Medicine Attending, Medical Toxicologist, Atrium Health’s Carolinas Medical Center) // Reviewed by: Cynthia Santos, MD (@Cynthia Santos, MD); Alex Koyfman, MD (@EMHighAK); and Brit Long, MD (@long_brit)

 

Case:

A 26-year-old female with a history of opioid-use disorder presents to the emergency room with nausea, anxiety, and myalgias. She is adamant that she has not taken narcotic pills, IV drugs, or other illicit substances for over a year. She does report however that she has been purchasing kratom on the internet for the last year, but she has not had access to it for the last two days.


Questions:

What is kratom and is it safe?

What considerations should the emergency physician have for patients who use kratom?


Background:

  • Kratom (Mitragyna speciosa) is a plant native to Southeast Asia. It has been used for centuries as an herbal remedy for a variety of ailments.
  • In recent years, Kratom has been increasingly popular in the United States. While it has not been approved by the FDA for therapeutic use, there are an estimated 3-5 million Kratom users in the US. 1
  • Kratom has been shown to produce both stimulant and opioid-like analgesic effects and has been used for the treatment of opioid use disorder (OUD), pain, and anxiety.

Clinical Effects

  • Kratom has mitragynine-type indole alkaloids that can interact with opioid receptors and produce some opioid-like effect. The active substance in kratom is mitragynine, an indole alkaloid. It also has an active metabolite, 7-hydroxy mitragynine, that appears to have greater affinity for mu opioid receptors than mitragynine.2,3 Kratom is thought to act at the mu opioid receptor without activating the β-arrestin-2 signaling pathway that produces some of the side effects of classical opioids.2,4
  • At low to moderate doses, kratom has mild stimulating effects, likely due to multiple alkaloids in the herbal mix.5,6 With typical dosing, there are opioid-like effects, including analgesia and euphoria, though the euphoric effects of kratom tend to be less intense than classical opioids.5
  • Kratom is overall thought to be less likely to cause significant respiratory depression compared to classical opioids. In a review of poison center calls, only one death was noted which was in the setting of co-ingestants.7 A study of UK, western European, and US deaths related to kratom found polysubstance use in nearly 83% of decedents, with the most common co-intoxicants being opioids, benzodiazepines, antidepressants, and/or other psychopharmaceuticals.8
  • The most common adverse effects are agitation, tachycardia, and nausea and are usually mild overall.9
  • More serious effects including cardiotoxicity [bradycardia, asystole], acute liver injury, and seizures have been reported.9 Alkaloid extracts from Kratom work on multiple receptors including calcium channel blockade, and intravenous lipid emulsion has been attempted for treatment in one overdose case.10,11  Acute liver injury typically occurs within the first 8 weeks of use and can involve severe hyperbilirubinemia or prolonged cholestasis, and typically resolves with discontinuation of kratom.12  Multiple case reports indicate that kratom may be a pro-convulsant.13  In one case, changes on brain MRI were noted for a patient with recurrent seizures associated with Kratom use.14 Traditional anticonvulsants have been used with some success, as has detoxification.13, 14
  • There have been several deaths reported in the setting of Kratom use, but causality is unclear or associated with coingestants in most of these cases.7,9

Pearls

  • While kratom itself is much less likely to cause respiratory depression compared with classical opioids, lack of regulation makes contaminated samples more likely.6 Consider intentional or unintentional co-ingestions in patients who report Kratom use.
  • There have not been any multi-center, controlled clinical trials regarding the therapeutic effects of Kratom, but there is significant anecdotal evidence suggesting a possible role in managing OUD and chronic pain.5 Kratom has been shown to lead to tolerance and dependence, however, this is typically milder than with classical opioids.1 There are multiple case reports of buprenorphine use to treat kratom dependence.15,16
  • There is evidence, though limited, that kratom has attenuated euphoria and abuse potential when compared to classical opioids, indicating a possible therapeutic role for kratom.5
  • While kratom itself appears relatively safe at therapeutic doses, be wary of potential drug-drug interactions. There is evidence that mitragynine inhibits cytochrome P450 2C9, 2D6 and 3A4.17 Potential interactions in humans have specifically been reported with amlodipine and quetiapine.1 Providers should also be wary of interactions with any CNS-active substances.1
  • When treating patients with suspected or known OUD, clinicians should ask patients what they are using to prevent or treat withdrawal, including herbal substances.
  • Kratom is considered a Drug of Concern by the United States DEA.10

Case Conclusion

The ED physician identifies that the patient’s presentation is due to kratom withdrawal. They discuss both symptomatic treatment as well as initiation of buprenorphine. The patient is agreeable to buprenorphine administration and has improvement in her symptoms. She is discharged with a warm hand-off to substance use disorder treatment.


References:

  1. Veltri C, Grundmann O. Current perspectives on the impact of Kratom use. Subst Abuse Rehabil. 2019;10:23-31. Published 2019 Jul 1.
  2. Váradi, András, et al. “Mitragynine/corynantheidine pseudoindoxyls as opioid analgesics with mu agonism and delta antagonism, which do not recruit β-arrestin-2.” Journal of medicinal chemistry 59.18 (2016): 8381-8397.
  3. Eastlack SC, Cornett EM, Kaye AD. Kratom-Pharmacology, Clinical Implications, and Outlook: A Comprehensive Review. Pain Ther. 2020 Jun;9(1):55-69. doi: 10.1007/s40122-020-00151-x. Epub 2020 Jan 28. PMID: 31994019; PMCID: PMC7203303.
  4. Raehal KM, Walker JK, Bohn LM. Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther. 2005 Sep;314(3):1195-201. doi: 10.1124/jpet.105.087254. Epub 2005 May 25. PMID: 15917400
  5. Prozialeck WC, Jivan JK, Andurkar SV. Pharmacology of kratom: an emerging botanical agent with stimulant, analgesic and opioid-like effects. J Am Osteopath Assoc. 2012;112(12):792-799.
  6. Eggleston W, Stoppacher R, Suen K, Marraffa JM, Nelson LS. Kratom Use and Toxicities in the United States. Pharmacotherapy. 2019 Jul;39(7):775-777. doi: 10.1002/phar.2280. Epub 2019 Jun 13. PMID: 31099038.
  7. Anwar M, Law R, Schier J. Notes from the Field. Kratom (Mitragyna speciosa) Exposures Reported to Poison Centers — United States, 2010–2015. MMWR Morb Mortal Wkly Rep 2016;65:748–749.
  8. Corkery JM, Streete P, Claridge H, Goodair C, Papanti D, Orsolini L, Schifano F, Sikka K, Körber S, Hendricks A. Characteristics of deaths associated with kratom use. J Psychopharmacol. 2019 Sep;33(9):1102-1123. doi: 10.1177/0269881119862530. Epub 2019 Aug 20. PMID: 31429622.
  9. Post S, Spiller HA, Chounthirath T, Smith GA. Kratom exposures reported to United States poison control centers: 2011-2017. Clin Toxicol (Phila). 2019 Oct;57(10):847-854. doi: 10.1080/15563650.2019.1569236. Epub 2019 Feb 20. PMID: 30786220. Prozialeck WC, Avery BA, Boyer EW, et al. Kratom policy: The challenge of balancing therapeutic potential with public safety. Int J Drug Policy. 2019;70:70-77.
  10. Hassan Z, Muzaimi M, Navaratnam V, Yusoff NH, Suhaimi FW, Vadivelu R, Vicknasingam BK, Amato D, von Hörsten S, Ismail NI, Jayabalan N, Hazim AI, Mansor SM, Müller CP. From Kratom to mitragynine and its derivatives: physiological and behavioural effects related to use, abuse, and addiction. Neurosci Biobehav Rev. 2013 Feb;37(2):138-51. doi: 10.1016/j.neubiorev.2012.11.012. Epub 2012 Dec 1. PMID: 23206666.
  11. Aggarwal G, Robertson E, McKinlay J, Walter E. Death from Kratom toxicity and the possible role of intralipid. J Intensive Care Soc. 2018;19(1):61-63. doi:10.1177/1751143717712652
  12. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Kratom. [Updated 2020 Apr 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548231/
  13. Alsarraf, E., Myers, J., Culbreth, S. et al.Kratom from Head to Toe—Case Reviews of Adverse Events and Toxicities. Curr Emerg Hosp Med Rep 7, 141–168 (2019). https://doi.org/10.1007/s40138-019-00194-1
  14. Tatum WO, Hasan TF, Coonan EE, Smelick CP. Recurrent seizures from chronic kratom use, an atypical herbal opioid. Epilepsy Behav Case Rep. 2018;10:18-20. Published 2018 Apr 17. doi:10.1016/j.ebcr.2018.04.002
  15. Buresh M. Treatment of Kratom Dependence With Buprenorphine-Naloxone Maintenance. J Addict Med. 2018 Nov/Dec;12(6):481-483. doi: 10.1097/ADM.0000000000000428. PMID: 29944481.
  16. Khazaeli A, Jerry JM, Vazirian M. Treatment of Kratom Withdrawal and Addiction With Buprenorphine. J Addict Med. 2018 Nov/Dec;12(6):493-495. doi: 10.1097/ADM.0000000000000435. PMID: 30383616.
  17. Hanapi NA, Ismail S, Mansor SM. Inhibitory effect of mitragynine on human cytochrome P450 enzyme activities. Pharmacognosy Res. 2013 Oct;5(4):241-6. doi: 10.4103/0974-8490.118806. PMID: 24174816; PMCID: PMC3807987.

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