Kratom: Clinical Implications for Nurse Practitioners

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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.
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  1. Kratom’s status as an opioid is disputed. Computer models are not a stand-in for scientific research. Ibogaine and Salivnorin A are not classified as opiates and their primary psychoactive molecules bind to opioid receptors. Also debatable are the reports of respiratory depression. The FDA is using it’s influence here to paint a different picture than what we see in the research. Without more research on the effects it would be irresponsible to schedule it alongside the likes of heroin. Don’t let politics blend with medical science.

  2. Kratom isn’t “extracted”. Kratom is a whole leaf from a tree in the coffee family that hits some opioid receptors. Yes it can be addictive if misused just like many other substances, but it does much more good than harm. I see both sides of this story but the vast majority of people that drink kratom tea are not using it to get high. They are using it for pain management (without the risk of respiratory depression or the other side effects that come with pharmaceutical opioids), depression, anxiety, restless legs syndrome, chronic regional pain syndrome, IBS, etc. Plain kratom leaf used alone is not dangerous, it has given millions of people their lives back. I agree there needs to be more research, but in the mean time, the FDA is trying to ban it. When has banning something ever been successful? We are just at the point of legalizing marijuana. Let’s not take two steps back and ban a plant that helps millions of Americans in a myriad of ways. I urge you to talk to some of the people responsibly using kratom, because I guarantee you that there is another, much less sinister side to this story.

  3. Kratom is not classified as an Opiod. Even your first sentence makes it clear that research on Kratom is lacking. Absolutely not surprised that everything in your article that smells of BS is referenced to articles from the FDA. The FDA has not conducted any research on Kratom. Please try instead to only cite actual scientific papers that have been published in reputable journals, I am pretty sure your article would look completely different. The FDA has been asked before how do they know that Kratom is so bad and they didn’t have a straight answer, the sources that you cite from the FDA like 2 and 11 point to what can only be described as fiction blog entry from a college freshman, they don’t show any simulation results or any actual experiments, instead we are supposed to believe that their computer model accurately describes a substance that they themselves say has not been researched, not to mention that their supposed computer simulation experiment was apparently conducted by nameless people, does not contain a single reference and doesn’t show any numerical or graphical results. Also if you are citing a reference, you should write “according to…”, not just copy and paste from the source, as this gives the impression that you conducted your own research or writing your own conclusion.

  4. I find this article to be extremely biased. I’ve never seen people have horrible side effects from kratom and it’s definitely not an opioid. It’s a plant in the coffee family. Some of the alkaloids do effect opioid receptors, but not in the same was as standard opioids. Mitragynine has a high affinity to the mu opioid receptors but with very low activity. Because of this, it doesn’t cause individuals to get high like they do on painkillers or heroin, but still helps treat pain similar to Suboxone. Kratom has a complex number of alkaloids, some even being mu opioid antagonists. This is why it’s considered very difficult to overdose on unadultered plain leaf kratom. It’s also not an extract. It’s just the plant. Kratom is to mitragynine & 7-hydroxymitragynine as the coffee tree is to caffeine. You can even grow a kratom tree in your own backyard!

    Kratom personally changed my life forever. I had struggled with many health issues that medications were ineffective at treating. Before I found kratom, I was in constant pain, suicidal and wasn’t able to work or live my life. Since finding it, I now work full time and have never been happier and healthier.

    As you can imagine, this whole media campaign against kratom is devastating to my morale. I found something that finally helps and now the government and media outlets want to demonize it and make it sound like some bathsalts like synthetic drug out addicting people and ruining lives. That’s simply not true.

    Because it makes you feel better, yes it can be addictive. But so is coffee, fatty, sugary foods and sex. No one is trying to ban those, yet sugar and fat causes more deaths than kratom ever could. Acetaminophen poisoning kills more people in a week than kratom has in years. Even if the FDA’s bogus 44 deaths were true, there’s millions of users and only 44 deaths. Sounds pretty safe to me. We can’t just keep banning every single thing that can cause harm for a certain minority of people. Not everyone becomes addicted to coffee, but should we ban it because some do? There’s lots of deaths a year from caffeine poisoning, should we ban it then? I don’t think so.

    Articles like this, are extremely damaging to not only Kratom’s reputation but have severe consequences because they mislead people who may benefit from it and could even help a future ban. What will I do if it’s banned? Go back to the horrible life I once had? What if I keep using it? Do I deserve to be locked in jail like some thief or rapist? It’s not fair and shame on you for not writing an article that shows both side of the story. Anyone can focus on negatives, it doesn’t make it the full picture.

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