Kratom: Clinical Implications for Nurse Practitioners

The United States (US) is seeing an increase in issues arising with the use of the herbal supplement kratom.

Research regarding kratom, the safety profile, efficacy, and best practice is significantly lacking.¹ Kratom is not legally marketed in the US as a medication or dietary/herbal supplement.² Kratom is classified as an opioid. It is addictive and users may experience severe health consequences including death. Kratom’s popularity continues to grow due to unsubstantiated claims about its health benefits and perceived decreased drug withdrawal effects during rehabilitation.² Despite growing usage, kratom is not well known to medical practitioners.

What is Kratom?

Kratom (also known as Thang, Biak, Ketom, Thom, and/or Kauam on the street) is a chemical substance extracted from the tropical evergreen tree, Mitragyna speciosa (M. speciosa) from the family Rubiaceae (coffee), native to southeast Asia.^1,3,4 The leaves and extracts from the tree have a long history of use and misuse in southeast Asia.⁴⁵ Kratom leaves can be chewed, smoked, or consumed as a tea/drink.^1,4 It is used in cuisine, for increased energy (primarily in day laborers), for medicinal purposes, and in religious ceremonies.⁶ In the mid 20th century, kratom was used to manage opioid withdrawal due to the low risk of respiratory depression and abuse potential in comparison to other pharmacotherapies. In the 1990s, kratom use became prevalent in the US.⁴ This was likely due to internet marketing and the migration of those that use kratom from southeast Asia and Europe. In the US, kratom has been used for relief of chronic pain, symptoms of opioid withdrawal, and maintenance of opioid abstinence.^4,6 Kratom is cheaper and easier to purchase than heroin and methamphetamine.⁶ By 2016, the kratom market was exceeding 207 million dollars with over 10,000 retail outlets and millions of consumers.⁴

Kratom is comprised of many compound alkaloids that have different functional properties.^3,4,6 Two have calcium channel blocking action, and at least two (7-hydroxymitragynine and mitragynine) act specifically as opioid agonists acting on the supraspinal mu- and delta- receptors. The alkaloid 7-hydroxymitragynine is four times more potent than mitragynine, which is thirteen times more potent than morphine.⁴ At lower doses, kratom produces stimulant effects, while at higher doses it produces opioid like effects.^4,6 The onset of action for kratom is approximately five to ten minutes, lasting about two to five hours.^4,6

Mitragynine produces a stimulant effect due to the alpha-2 adrenergic receptor agonist properties blocking the stimulation of 5-HT2A receptors and post-synaptic alpha-2 adrenergic receptors.^3,4 It produces a skeletal muscle relaxant effect due to interference at the neuromuscular junction. Mitragynine is lipophilic with a terminal half-life of over 23 hours with a high volume of distribution.^3,4,6

Research has been lacking and limited in regards to the pharmacology of kratom.⁴ The difference between the extracts and powders sold in the United States and the leaves and powders used in southeast Asia vary. With little to no regulation, products sold in the United States can be cut with other substances such as hydrocodone.³

Kratom Clinical Considerations

While the use of kratom by itself holds major health risks, the combination of kratom with bacterial salmonella increases the severity of problem. Many kratom users are interested in the product for recreational use and/or opioid-like effects (euphoria and pain relief), in spite of side effects including respiratory depression, vomiting, nervousness, weight loss and constipation.⁷ A mentioned previously, kratom has both stimulant and opioid-like effects. Hostility, aggression, excessive tearing, aching of muscles and bones, and jerky limb movements have been noted in those who have used kratom as adjuvant therapy for withdrawal from opioids.⁴ More serious side effects include: seizures, kidney failure, liver damage, and death.⁸ Recreational long-term use of kratom is associated with acute liver injury. This injury occurs within two to eight weeks of initiation of the consistent use of kratom powder or tablets. This use creates symptoms of fatigue, nausea, pruritus, and dark urine followed which is then followed by jaundice. The liver insult is cholestatic in nature with the potential of serum bilirubin levels rising above 20 mg/dL. Acute renal failure and bone marrow toxicity may accompany the severe cholestasis. Fever may be seen with or without an accompanying rash. Corticosteroids have been used in cases of suspected kratom hepatotoxicity; however, the efficacy has not been proven.⁸

Clinical Testing for Kratom

After review of the literature, it appears that blood and urine laboratory testing for kratom in hospitals and clinics has not been standardized. Developing an accurate, reliable and sensitive identification method for new drug compounds often takes some time due to the analytical chemistry that must be completed.⁹ Mitragynine can be detected in urine and plasma through liquid chromatography-tandem mass spectrometry and ion mobility spectrometry.^9,10 When unsure of what substance a patient may be under the influence of, it would be prudent, if the presentation is appropriate, to add mitragynine detection to laboratory tests ordered. Immunoassays are being developed for rapid detection, however, to date, none have been approved by the Food and Drug Administration (FDA).¹⁰

FDA Recognition of Kratom as an Opioid

The FDA has been concerned with the safety risks of kratom since 2010.¹¹ Telephone calls regarding kratom to poison control centers have spiked tenfold from 2010-2015. As of February 6, 2018, 44 deaths have been associated with the use of kratom. The FDA has been investigating kratom for scientific data, and adverse event reports have clearly revealed that kratom should be classified as an opioid.¹¹

To establish kratom as an opioid, the FDA analyzed the chemical structure of kratom compounds to determine biologic targets.¹¹ The analysis predicted that 22 of the 25 compounds in kratom bind to mu-opioid receptors. This analysis, with previous available experimental data, confirmed that two of the top five most prevalent compounds (including mitragynine) are known to activate opioid receptors (“opioid agonists”). The FDA has concluded that there is no reliable evidence to support the use of kratom as a treatment for opioid dependency disorder and warns that significant safety issues exist. The FDA is eager to evaluate evidence that could demonstrate a medicinal purpose for kratom, however there have been no requests or evidence submitted to begin this process. The FDA has stated, “Kratom should not be used to treat medical conditions, nor should it be used as an alternative to prescription opioids. There is no evidence to indicate that kratom is safe or effective for any medical use.”¹¹

FDA Recall of Kratom due to Salmonella Risks

A mandatory recall for kratom products made by the Las Vegas company, Triangle Pharmanaturals, due to salmonella contamination has been issued by the FDA.¹² The company has ignored the FDA requests to return the products in the voluntary recall. “This action is based on the imminent health risk posed by the contamination of this product with salmonella,” said FDA Commissioner Dr. Scott Gottlieb, “and the refusal of this company to voluntarily act to protect its customers and issue a recall, despite our repeated requests and actions.” The FDA recalled products from Triangle Pharmanaturals include: Raw Form Organics Maeng Da Kratom Emerald Green, Raw Form Organics Maeng Da Kratom Ivory White, and Raw Form Organics Maeng Da Kratom Ruby Red. The FDA also warned that any other kratom products made or sold from by Triangle Pharmanaturals should be discarded.¹²

Salmonella Contaminated Kratom

As of April 5, 2018, The CDC has reported a 38 state outbreak of salmonella related to kratom with 132 people infected with outbreak strains of Salmonella I 4, Salmonella Javiana, Salmonella Okatie, or Salmonella Thompson.⁵ The normal duration of illness is approximately four to seven days, with most patients recovering without treatment. Unfortunately, in the current salmonellosis outbreak associated with kratom products, of the 132 people infected, 38% have been hospitalized, Seventy-six (76%) of 103 people fell ill after reportedly consuming kratom in various forms (tea, pills, or powder).⁵

Most people report consuming the powder form of kratom.⁵ Diagnosis-laboratory scientists have identified Salmonella infection by culturing patient samples. If Salmonella bacteria grow, then the diagnosis is culture confirmed. The public health laboratories notify the CDC of atypical serotypes which are sent to National Salmonella Reference Laboratory for more characterization or confirmation. As of May 2018, 199 cases of salmonellosis in 41 states have been tied to kratom ingestion. Molecular fingerprinting identified the majority of salmonella cases with Salmonella I 4,[5],12:b:-. Other serotypes of salmonella have caused illness including: Salmonella Heidelberg, Salmonella Javiana, Salmonella Okatie, Salmonella Thompson and Salmonella Weltevreden.⁵ The FDA calls for voluntary testing of kraton products yielded 81 samples which were collected and tested.² Forty-two samples were found to be contaminated with salmonella. This finding suggests that a user of kratom from these samples had a 52% chance of exposed to this bacteria.² This alarming rate of contamination of salmonella in combination with the opioid effect may produce extreme health risks especially in the immunosuppressed patient population.

Salmonella Illness

Clinical features of Salmonella infection begin approximately 12-72 hours after being exposed to the bacteria, and include: diarrhea, fever, and abdominal cramps.¹³ Populations at higher risk for severe illness include: children younger than 5 years, adults older than 65, and people with weakened immune systems14. The typical duration of illness is approximately 4 to 7 days, with most people recovering without treatment.¹⁴ In uncomplicated cases, symptoms resolve without treatment. Patients should be encouraged to increase oral fluid intake. In cases of severe dehydration, intravenous fluids should be considered.¹⁴ Patients exhibiting bloody diarrhea should be viewed as high risk for sepsis. In rare cases, Salmonella infection can cause death unless the person is treated promptly with antibiotics. Invasive Salmonella may present as sepsis, meningitis, osteomyelitis, or septic arthritis.¹³

Conclusion of Salmonella Tainted Kratom CDC Investigation

On May 24, 2018, the CDC ended the investigation of salmonella tainted kratom.⁵ The investigated noted a total of 199 people were infected from strains of salmonella associated with kratom contamination; noting that 38% of ill people were hospitalized.⁵ There were no deaths noted in the investigation. The CDC advises that kratom contaminated products may still be available for purchase and have the ability to make people sick.⁵

Recommendations for Reporting Illness associated with Kratom use

The FDA is warning consumers not to use any products labeled as containing kratom. Health care professionals and consumers should report any adverse events related to products containing kratom to the FDA’s MedWatch program by:

• Completing and submitting the report online at www.fda.gov/medwatch/report.htm; or
• Downloading the form, or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178

References

1. Swogger MT, Walsh Z. Kratom use and mental health: A systematic review. Drug and Alcohol Dependence. 2018;183,134-140. Aggarwal G, Robertson E, Walter E. Death from kratom toxicity and the possible role of intralipid. Journal of the Intensive Care Society. 2018;19(1),61-63.
2. Statement from FDA Commissioner Scott Gottlieb, M.D. and FDA Deputy Commissioner for Foods and Veterinary Medicine Stephen Ostroff, M.D., on the ongoing risk of salmonella in kratom products https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm612420.htm Published July 2, 2018. Accessed July 22, 2018.
3. Aggarwal, G., Robertson, E., McKinlay, J. & Walter, E. (2018). Death from kratom toxicity and the possible role of intralipid. Journal of the Intensive Care Society, 19(1), 61-63. doi: 10.1177/1751143717712652
4. Henningfield JE, Fant RV, Wang DW. The abuse potential of kratom according to the 8 factors of the Controlled Substances Act: Implications for regulation and research. Psychopharmacology. 2017;235(2),573-589.
5. Centers for Disease Control.Multistate Outbreak of Salmonella Infections Linked to Kratom (Final Update) https://www.cdc.gov/salmonella/kratom-02-18/index.html CDC multistate outbreak Published May 24, 2018. Accessed June 18, 2018.
6. Pizarro-Osilla C. Introducing…kratom. Journal of Emergency Nursing. 2017;43(4),373-374.
7. FDA News Release US Marshals seize dietary supplements containing kratom https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm480344.htm
8. National Institutes of Health LiverTox Clinical and Research Information on Drug Induced Liver Injury. https://livertox.nih.gov/Kratom.htm seize kratom- toxicity and kratom Published April 10, 2018. Accessed June 25, 2018
9. Fuenffinger N, Ritchie M, Ruth A, Gryniewicz-Ruzicka C. Evaluation of ion mobility spectrometry for the detection of mitragynine in kratom products. Journal of Pharmaceutical and Biomedical Analysis. 2017;134(5),282-286.
10. Liu L, Wheeler SE, Venkataramanan R, Rymer JA, Pizon AF, Lynch MJ, Tamama K. Newly emerging drugs of abuse and their detection methods: An ACLPS critical review. American Journal of Clinical Pathology. 2018;149(2),105-116.
11. Statement from FDA Commissioner Scott Gottlieb, M.D., on the agency’s scientific evidence on the presence of opioid compounds in kratom, underscoring its potential for abuse www.fda.gov/newsevents/newsroom/pressannouncements/ucm595622.htm Published February 6, 2018. Accessed July 18, 2018.
12. FDA News Release FDA orders mandatory recall for kratom products due to risk of salmonella https://www.fda.gov/Safety/Recalls/ucm603536.htm
    Published April 3, 2018. Accessed June 18, 2018.
13. Centers for Disease Control. Information for Healthcare Professionals and Laboratories https://www.cdc.gov/salmonella/general/technical.html salmonella treatment Published March 9, 2018. Accessed June 18, 2018.
14. Centers for Disease Control. Salmonella Infections Linked to Kratom https://www.cdc.gov/salmonella/kratom-02-18/signs-symptoms.html CDC s/s of salmonella and treatment Published March 9, 2015. Accessed June 18, 2018.