VOLUME 34, ISSUE 2

Because of efforts to limit opioid prescriptions, many patients have turned to kratom to help with their pain. Kratom is considered legal by the federal government, and although it has been outlawed in several states, in Texas it is readily available via the internet, vape shops, and gas stations. An estimated 2 to 3 million Americans used kratom in 2019 (1). Because some consider it to be an herbal medication, not all patients may be forthcoming about their usage of it.

Kratom originates from leaves of a tree in Southeast Asia where it was used as a traditional remedy to relieve pain or increase energy. Over the last ten years, its popularity has soared in the United States with kratom used for a recreational “legal high” or as remedy for anxiety, depression, chronic pain, or opioid withdrawal. Mitragynine, a kratom alkaloid, has shown promise in the management of opioid addiction in multiple animal studies; however, kratom’s effectiveness in opioid abuse management remains unproven in human clinical trials.

Kratom is most commonly administered as a tea, powder, capsule, or gum. At low doses (1-5 g) it provides stimulating effects and mood elevation while at higher doses (5-15 g) it offers analgesic effects with sedation and stupor occurring at very high doses (15+ g). It is undetectable in a standard drug screen, but liquid chromatography-mass spectroscopy can detect its active metabolites in urine for up to two weeks. Kratom’s physiologic effects begin 10 to 20 minutes after ingestion with full effects occurring at 30 to 60 minutes and a duration of action of 5 to 7 hours (2).

Kratom has a complex pharmacological profile as it contains multiple alkaloids which may vary with plant age and the geographical areas in which the plant is grown. Additionally, there are multiple active metabolites, mechanisms of action, and receptor targets which have not been fully described. In vitro and in vivo studies have been performed but there is a paucity of human studies. Mitragynine is the most abundant (~66%) of kratom’s forty alkaloids while 7-hydroxymitragyine (7-OH) is the most potent but less abundant alkaloid (~2%) (3). Mitragynine was found to share a similar analgesic potency as codeine in dogs and less potency than morphine in mice (4, 5). It was also reversed by naloxone in mice studies (6). Subcutaneous 7-OH administration in mice demonstrated tolerance to 7-OH, cross tolerance to morphine, and reversal by naloxone (7). The 7-OH alkaloid is 13 times more potent than morphine and 46 times more potent than mitragynine (8). Recently, 7-OH has been identified as the product of mitragynine conversion by cytochrome P450 (9).

Mitragynine and 7-OH interact with opioid, adrenergic, serotonergic, and dopaminergic receptors. The compounds act as partial agonists at mu opioid receptors but as competitive antagonists at the delta and kappa opioid receptors which may explain the lack of respiratory depression observed with its use. In addition, these two alkaloid components are agonists at alpha-2 adrenergic receptors which may account for their sedative effects. The stimulant effects of the compounds are thought to be related to their agonist activity at the 5-hydroxytryptophan (5HT) 2a, 2c, and 7 receptors which may also contribute to favorable effects on anxiety and depression. The compounds are also agonists at the dopamine-2 receptors the significance of which is still unclear.

Mitragynine has anti-inflammatory effects. It inhibits the production of prostaglandin-E2 via the inhibition of cyclooxygenase (COX)-2 expression in a dose dependent manner; however, mitragynine may inhibit the COX-1 expression at higher doses(10).

Kratom is metabolized by the cytochrome P450 system and metabolites are renally excreted. Its inhibition of the P450 enzymes may increase the risk of toxicity of other drugs. These drugs include: fentanyl, tramadol, diphenhydramine, benzodiazepines, morphine, and acetaminophen.

Like any medication, kratom also has side effects. Side effects in the order of most to least common include agitation/ irritability, tachycardia, nausea, drowsiness, confusion, and hypertension. Serious adverse effects associated with toxicity include seizures, hallucinations, respiratory depression, coma, hypotension, bradycardia, rhabdomyolysis, hepatoxicity, prolonged QT intervals/ torsades de pointes, and cardiac arrest. Seizures, hepatic toxicity, intracerebral hemorrhage, and hyperkalemia have been proposed in case reports linked to kratom usage after other causes of the disease processes were ruled out and the resolution of the medical issue after discontinuation of kratom. Most cases of reported fatalities have occurred when kratom is ingested with other drugs. According to a CDC report of overdose deaths, 80% of kratom related deaths occurred in those with history of substance abuse (11).

Kratom proponents claim that the medication carries little risk for abuse and addiction in humans based on animal studies. In studies involving rats that self-administered medications, mitragynine did not have a high self-administration rate (12, 13). However, the rats maintained high self-administration rates of 7-OH (12). In a survey of regular kratom users in Malaysia, 32% increased intake over time, 64% experienced withdrawal symptoms after 1 to 3 days and 89% had at least one unsuccessful attempt to abstain suggesting that kratom carries an element of dependence in humans (14).

Anesthesiologists will encounter patients who are regular users of kratom with some of these encounters occurring in kratom overdose or withdrawal situations. Regular users may have a high tolerance to anesthetics, requiring higher doses for induction and maintenance and a resulting higher risk of poorly controlled postoperative pain. Regional and neuraxial anesthetics as part of a multimodal approach to post-operative pain control may be considered to offset the tolerance and to decrease the reliance on opioid medications. If emergence delirium occurs, it may be difficult to distinguish between kratom withdrawal and poorly controlled pain due to opioid tolerance as the etiology.

Kratom withdrawal involves symptoms similar to those of opioid withdrawal and management is comparable, though formal guidelines have not been established. Withdrawal symptoms include irritability, nervousness, restlessness, dysphoria, insomnia, pupillary dilation, lacrimation, rhinorrhea, nausea, vomiting, diarrhea, myalgia, arthralgia, and muscle spasms. Withdrawal begins 12 to 16 hours after the last dose and symptoms typically subside within four days of abstinence (15). Medications that target receptors affected by kratom are helpful for symptomatic treatment during this period: non-steroidal anti-inflammatory drugs for COX receptors, hydroxyzine/ gabapentin for 5-HT receptors, clonidine / lofexidine for alpha-2 receptors, and dihydrocodeine/ buprenorphine for opioid receptors. Similarly, there are no guidelines for maintenance therapy in these patients, but buprenorphine/naloxone, methadone, and naltrexone have all been used successfully.

In instances of kratom overdose, priority is given to airway protection, ventilation, and circulation. Naloxone can be administered for respiratory depression and may be helpful if in scenarios of concomitant opioid use. However, it must be noted that naloxone may also precipitate withdrawal in these scenarios. Benzodiazepines and anticonvulsants are used for seizure prophylaxis and management. Intravenous fluids are essential to lower the risk of liver toxicity and rhabdomyolysis. Steroids and acetylcysteine may also be administered to reduce the risk of liver toxicity. Renal failure from kratom toxicity has also been described, but it is not as prevalent as liver failure. Kratom related electrocardiogram changes, such as prolonged QTc interval and torsade de pointes, have been observed which may require treatment with magnesium or cardiac pacing. If haloperidol is selected to manage agitation, the risks associated with QTc prolongation should be considered.

With the rapid increase in kratom users and the associated complications, the United States Drug Enforcement Agency (DEA) announced its intention to categorize kratom as a schedule I drug in 2016. This announcement was met with widespread protests by kratom advocates, and the decision was reversed six weeks later, with kratom instead being placed on the “Drugs of Concern” list. The DEA asked the Food and Drug Administration to perform an analysis of the abuse potential of the drug and give recommendations based upon this analysis. Since 2016 there have been no further updates to kratom’s scheduling status. Consequently, physicians are facing an increasing number of patients who are using this poorly understood drug that may have some benefits, but also has many associated complications.