Continuing Education Activity

Kratom (Mitragyna speciosa) is a plant indigenous to Southeast Asia, typically consumed by tea or powder, with physiologic effects similar to opioids, as well as stimulants. There is an increasing prevalence of kratom use, raising concern for possible dependence, addiction, and toxicity. Given the increasing popularity and the potential harm this substance could cause, it is essential to understand how it works, its physiologic side effects, and any possible treatment options for symptoms related to a toxic overdose. This activity reviews the etiology, presentation, evaluation, and management/prevention of kratom toxicity and also reviews the role of the interprofessional team with management.

Objectives:

• Summarize the pathophysiology/toxicokinetics of kratom toxicity.
• Outline the signs, symptoms, and examination findings for patients with kratom toxicity.
• Describe management strategies for kratom toxicity.
• Review the interprofessional team approach to identifying and improving care for managing patients suffering from kratom toxicity.

Indications

With the rise in patients taking naturalistic approaches to healthcare, it is crucial to be aware of kratom and the risks associated with its ingestion.[1] Kratom (Mitragyna speciosa) is a plant indigenous to southeastern Asia, typically consumed as tea or powder, with physiologic effects similar to opioids and stimulants. The use of kratom in southeastern Asia has been common for the past few centuries, but it is gaining popularity in the West.[2] As there is an increasing prevalence of kratom use, there is also increasing concern for possible dependence, addiction, and toxicity.[3] Given the increasing popularity and the potential harm this substance could cause, it is essential to understand how it works, its physiologic side effects, and any possible treatment options for symptoms related to a toxic overdose.

Traditional use of kratom consisted of remedies for treating symptoms of opiate addiction and withdrawal. Also, it is popular among laborers in rural southeastern Asia for pain relief and fighting off fatigue.[3] Given the potential for addiction and dependence, it has since been banned in Malaysia and Thailand.[4] However, the prevalence of kratom use has increased in the United States, where it is typically used as a recreational drug. From 2011 to 2017, there were over 1800 calls to poison control centers for kratom ingestions, with the majority of those calls occurring in the last two years, indicating a rapid increase in use.[5] 

The primary motivation for kratom use varies, but some patients with opioid dependence resort to other methods of self-medication, with kratom being an inexpensive alternative. The Drug Enforcement Administration does not recognize kratom as a controlled substance. Thus, it is not subject to the United States Controlled Substances Act, so there is little regulatory oversight regarding the substance's purity, potency, and safety.[3][6] As kratom is an unregulated substance, it is difficult to ascertain the actual concentration of mitragynine, the most prevalent substance in kratom, which can put patients at risk for the potential dangers of the substance.

Mechanism of Action

Kratom has only four known pharmacologically active compounds.[7] Of these active compounds, mitragynine is the most prevalent, but 7-OH-mitragynine is more pharmacologically active.[8] Also, 7-OH-mitragynine is an oxidized metabolite of mitragynine.[9] Mitragynine is hepatically metabolized to 7-OH-mitragynine.[3] Compared to morphine, 7-OH-mitragynine has about 13 times the affinity for opioid receptors. 7-OH-mitragynine has about 46 times the affinity for opioid receptors compared to mitragynine.[10][11] Some studies suggest mitragynine is an agonist at the mu and delta receptors, while 7-OH-mitragynine targets the mu and kappa receptors, although some studies argue that both act as partial agonists at the mu and delta receptors.[11][12][13] 

The half-life of mitragynine has an estimated half-life of 3 hours.[14] When ingested orally, there appears to be linear pharmacokinetics with biphasic elimination.[15] It remains unclear as to the specific mechanism these metabolites have at certain receptors; also, the wide variety of kratom alkaloids and their potential pharmacologic properties make assessing its net physiologic effects challenging.[16][17] 

One of the important differences between opioids and the alkaloids in kratom is that they are pharmacologically and structurally different. Like opioids, the alkaloids from kratom initiate G-protein-coupled receptors (GPCR) signaling; however, the major difference is that the kratom alkaloids don't initiate the beta-arrestin pathway.[18] This is important because the beta-arrestin pathway is responsible for some of the adverse symptomatology seen in opioid use, including respiratory depression, sedation, and constipation.[18][19] Given the selective nature of kratom alkaloids and the inactivation of the beta-arrestin pathway, kratom makes a promising substance for pain management. 

Administration

Given the current opioid epidemic, physicians are encouraged to avoid overprescribing opioids for pain management. However, patients who develop an opioid dependence may resort to alternatives, like kratom, as their opioid prescriptions become more difficult to obtain. Kratom has been used by some patients wishing to self-medicate for health conditions associated with chronic pain, where it has been seen as an inexpensive, legal option.[20] As the Food and Drug Administration does not regulate kratom, it is ingested in many ways by patients, although it is typically ingested after the leaves are crushed and then either smoked, brewed in tea, or placed in capsules for ingestion. As kratom has a wide variety of alkaloids, and their potential pharmacologic properties vary, it is difficult to assess the drug's net physiologic effect.[16][17] 

When ingested orally, there appears to be linear pharmacokinetics with biphasic elimination.[15] The half-life of mitragynine, one of the more prevalent active compounds in kratom, has an estimated half-life of 3 hours.[14] An important factor regarding its metabolism is that mitragynine is converted via hepatic metabolism into 7-OH-mitragynine.[21] This is important as 7-OH-mitragynine is thought to be a more metabolically active metabolite, leading to most of the effects that kratom produces.[21] Given the variety of ways kratom is ingested, more research needs to be done to determine if the way this substance is ingested plays a role in determining overall physiologic side effects. 

Adverse Effects

Kratom and its metabolites can cause a variety of symptoms, including neurologic, metabolic, and psychological symptoms. A study by the National Poison Data system in 2019 found that the most common presenting symptoms after kratom ingestion included agitation, tachycardia, drowsiness, and confusion.[22] As many patients with chronic pain, or a history of opioid dependence, turn to alternatives for managing their symptoms, kratom has become a popular choice; however, given this substance is unregulated, it has the potential for patients to develop dependence, addiction, and toxicity.[13] 

Multiple organ systems are at risk for potential injury due to kratom ingestion. Multiple case studies have found a range of toxicities and adverse events associated with kratom use, including hepatotoxicity, seizure and coma, lung injury, kidney injury, and cardiotoxicity.[23] Pregnant patients who use kratom have an additional risk of their newborns developing neonatal abstinence syndrome.[24][25][26] Long-term cognitive impairment has also been seen in those with chronic kratom use.[27] In some cases, kratom toxicity has also been linked to death.[28] It is also important to remember that kratom is an unregulated substance, so the potential for tampering makes it potentially dangerous. Also, patients with a history of polysubstance abuse are predisposed to kratom toxicity and death.[29]

Contraindications

There is little information regarding absolute contraindications for kratom use; however, there is a risk of possible pharmacologic interactions for patients who ingest it. Mitragynine, a substrate of kratom, appears to inhibit glucuronidation by UDP-glucuronosyltransferases (UGT).[30] This interaction is important as possible co-ingestions with other drugs with known UGT substrates, like buprenorphine or ketamine, can contribute to toxicities and lead to fatal supratherapeutic levels of drugs and their substrates.[31][32] Therefore, it is likely best for patients who take medications metabolized by UGT to avoid kratom use or consult their clinician before using kratom. 

Also, patients with liver, neurologic, pulmonary, renal, or cardiac disease should avoid this substance as there have been multiple case studies showing that kratom can potentially cause injury to these organ systems.[23] It is also best for pregnant patients to avoid kratom use due to the potential for newborns to develop neonatal abstinence syndrome.[25][26] The unregulated status of this substance makes it difficult to ascertain the actual concentration of its active metabolites, making kratom ingestion potentially harmful. Patients with a history of polysubstance abuse should also attempt to avoid this substance, as polysubstance abuse is a risk factor linked to kratom-related deaths.[29]

Monitoring

As most patients who present after kratom ingestion will be first seen in the emergency department, it is best for healthcare providers to focus on the patient's airway, breathing, circulation, neurologic status, and initial resuscitation. As these patients can present with various symptoms, it is best to keep a broad differential. Labwork and imaging can vary based on the patient's presentation. If kratom toxicity is suspected or known, it is also important, and likely beneficial, for providers to consult their local poison control center early in managing patients to help guide monitoring, treatment, and patient disposition. 

Monitoring and screening patients for suspected kratom ingestion can be complex, as it does not typically appear on routine drug screens. Presentation for kratom toxicity can differ as symptoms can vary based on the dose administered and whether the ingested kratom had been altered. The physiologic effects of kratom ingestion vary based on a dose-dependent manner, where stimulant-like effects are seen at lower doses, and opioid-like effects are seen at higher doses.[16][17] Toxicities typically occur when the ingested dose exceeds 8 grams.[22] There are no specific guidelines on the length of time patients need to be monitored, but mitragynine, one of the major substrates of kratom, has a reported half-life of 3 hours.[14]

After kratom ingestion, a patient's presenting symptoms can help guide evaluation, work-up, and management. Multiple organ systems are at risk for potential injury after kratom ingestion. Multiple case studies have found a range of toxicities and issues due to kratom, including hepatotoxicity, seizure and coma, lung injury, kidney injury, and cardiotoxicity.[23] Pregnant patients who use kratom have an additional risk of newborns developing neonatal abstinence syndrome.[24][25][26] Long-term cognitive impairment has also been seen in those with chronic kratom use.[27] In some cases, kratom toxicity has been linked to death.[28] It is also important to remember that kratom is an unregulated substance, so the potential for tampering makes it potentially dangerous. Also, given its unregulated status, patients with polysubstance abuse predispose patients to toxicity and death.[29]

Toxicity

As many patients with kratom toxicity will primarily be seen in the emergency department, performing a primary survey and assessing the patient's airway, breathing, and circulation is crucial. Developing a broad differential in these patients is imperative as initial presenting symptoms may vary based on the dose of kratom ingested. Also, screening for kratom misuse is primarily based on patient disclosure, as kratom is not detected on regular drug screens.

There are no formal, evidence-based guidelines for the treatment of kratom toxicity. Presentations for kratom toxicity can differ as symptoms vary based on the dose ingested and whether the substance has been altered. The physiologic effects of kratom ingestion vary dose-dependently, where stimulant-like effects are seen at lower doses, and opioid-like effects are seen at higher doses.[16][17] Toxicities typically occur when the ingested dose exceeds 8 grams.[22] Multiple organ systems are at risk for injuries related to kratom use, with hepatotoxicity, seizure and coma, lung injury, kidney injury, and cardiotoxicity being reported. For pregnant patients who use kratom, there is also the risk of neonates developing neonatal abstinence syndrome.[33][25][26] Evaluation should be tailored toward the patient's presenting symptoms. Also, it is likely beneficial for providers to contact their local poison control center to help for guidance and assistance if kratom ingestion is suspected or known. 

At higher doses, kratom toxicity can mimic an opioid toxidrome. While there are reversal agents, like naloxone, for opioid overdoses, the efficacy of reversal agents has not been well established with kratom toxicity. However, there are cases that have reported potential benefits, and some studies have recommended their use.[34][35] There have also been cases of kratom toxicity causing acute drug-induced hepatitis, in which treatment with N-acetylcysteine has been used, as in other cases of drug-induced hepatitis.[36] Standard seizure management with anti-epileptics is warranted for patients who develop seizures after kratom ingestion.[33]

Enhancing Healthcare Team Outcomes

Kratom ingestion and toxicity require an interprofessional approach. Depending on the severity of presenting symptoms, critical care, nursing, pharmacy, social work, and addiction services may be required. Nursing and pharmacy are essential for the initial resuscitation and delivery of medications. Pharmacists, in particular, need to be knowledgeable about the effects of this substance so they can inform patients and other interprofessional healthcare team members regarding kratom use. Critical care teams and psychiatry involvement is crucial for critically ill patients with possible co-ingestions and those with suicidal intent. Social work and addiction services are necessary for those motivated to control their drug addiction. Overall, kratom use, toxicity, and withdrawal require further research to develop definitive management practices.