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Kratom, an Emerging Drug of Abuse: A Case Report of Overdose and Management of Withdrawal

Diep, Jack MD*; Chin, David Tian BS; Gupta, Somdatta MD; Syed, Faraz DO§; Xiong, Ming MD, PhD; Cheng, Jianguo MD, PhD*

doi: 10.1213/XAA.0000000000000658
Case Reports
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Kratom is an herb indigenous to Southeast Asia with psychoactive opioid compounds, often used as a treatment for chronic pain or opiate withdrawal symptoms. It is legally and readily available via Internet sales and has been identified as an emerging drug of abuse in the United States. Kratom use has been associated with psychosis, seizures, and even death. At lower doses, kratom acts as a stimulant, while at higher doses, it produces analgesia and euphoria. Here, we describe the successful management of kratom overdose and withdrawal in a young man with negative toxicology screens.

From the *Department of Pain Management, Cleveland Clinic, Cleveland, Ohio; Rutgers New Jersey Medical School, Newark, New Jersey; Department of Anesthesiology and Perioperative Medicine, Rutgers New Jersey Medical School, Newark, New Jersey; and §Department of Critical Care Medicine, Englewood Hospital and Medical Center, Englewood, New Jersey.

Accepted for publication September 12, 2017.

Funding: None.

The authors declare no conflicts of interest.

Address correspondence to Jack Diep, MD, Department of Pain Management, Cleveland Clinic, 9500 Euclid Ave, C-25, Cleveland, OH 44195. Address e-mail to diepj@ccf.org.

Mitragyna speciosa, more commonly known as kratom, is a tropical tree from the coffee tree family (Rubiaceae) indigenous to Southeast Asia and parts of Africa.1,2 For centuries, kratom leaves have been chewed, brewed in teas, and ingested due to its stimulant, euphoric, and analgesic effects.2 Farmers and laborers in Southeast Asia have used low doses (1–5 g) to combat fatigue, while higher doses (5–15 g) have been used by natives as a substitute for opium due to powerful opioid-like effects.2,3 The effects of kratom occur within 5–10 minutes after ingestion and may last for 2–5 hours.

Over 25 alkaloids have been identified in kratom extract with mitragynine identified as the primary active alkaloid. It acts as a partial opioid receptor agonist that is 13 times more potent than morphine.1,4 7-hydroxymitragynine is a minor active alkaloid also found in kratom but is 4 times more potent than mitragynine.1,4 Both alkaloids are thought to act on supraspinal µ- and δ-opioid receptors, explaining the analgesic and euphoric effects of kratom.3 For the same reason, naloxone has been suggested as a possible reversal agent.1,3

While kratom has been well known in Southeast Asia, it is relatively new in the United States. However, kratom use and abuse have exponentially increased in the United States in recent years.5 The number of calls received by US poison centers increased from 26 in 2010 to 263 in 2015, with a total of 660 calls between 2010 and 2015.5 There have been estimates of 3–5 million users within the United States.2,6 An online cross-sectional study was able to obtain over 10,000 unique responses primarily from within the United States in under a month from an announcement on the American Kratom Association’s homepage, demonstrating kratom’s increasing prevalence and popularity.7

The rise of kratom use is attributable to several factors. Numerous websites market kratom as a legal, affordable, and easily obtainable alternative treatment for opioid withdrawal, or tout alleged medicinal uses for reducing appetite, stomach cramps, and diarrhea.2,4 As a result, chronic opiate users have turned to kratom as an alternative treatment for their narcotic abuse.4 A survey of over 8000 current kratom users showed that it was primarily used to treat acute or chronic pain (68%) or emotional/mental conditions such as anxiety, depression, or posttraumatic stress disorder (67%).7

There have been increasing reports of emergency room (ER) visits and hospitalizations due to kratom overdose and withdrawal.3 While there have been reports of fatalities associated with kratom use accompanied with other substances, currently, there is no evidence of kratom being the sole contributor to an individual’s death.4 Here, we present the successful management of a 24-year-old man who overdosed on kratom without concomitant substance use.

Written informed consent was obtained from the patient.

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CASE

A 24-year-old man with Asperger syndrome, depression, and long-term substance dependence was found down and minimally responsive. He was hypothermic (94.8°F) and had a seizure witnessed by emergency medical service personnel for which he received lorazepam and was taken to the ER. His initial vital signs were stable, and there were no focal deficits. His mother provided insight on a history of recreational drug use including both alcohol and kratom. On presentation, a urine drug screen was negative for alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates, and oxycodone. His blood glucose level was 103 mg/dL. An arterial blood gas showed acute respiratory acidosis requiring the institution of invasive mechanical ventilation. He was administered lorazepam and loaded with levetiracetam due to concerns for status epilepticus. Additionally, he received empiric antibiotic coverage for bacterial meningitis and deep venous thrombosis prophylaxis. His electrocardiogram revealed a prolonged QT interval (corrected QT interval 492 milliseconds) and sinus bradycardia (58 bpm); he had a white blood cell count of 19,000 and an elevated total creatine kinase (1342 U/L) indicating acute rhabdomyolysis. Computerized tomography of the head revealed no abnormalities.

He was transferred to the intensive care unit (ICU) and started on propofol, fentanyl, and dexmedetomidine infusions. Continuous video electroencephalography was initiated, and he was aggressively hydrated for his rhabdomyolysis. His ICU course was complicated by an episode of self-extubation secondary to agitation and delirium. After the initial period immediately after the extubation, the patient was doing well but subsequently developed worsening delirium requiring multiple ICU personnel to control the patient. Medications including lorazepam, haloperidol, and hydromorphone were given without significant resolution of his symptoms. It was then determined that the reinstitution of invasive mechanical ventilation and sedation were necessary to help treat delirium and maintain safety for both the patient as well as the staff. Overnight, the patient remained stable and his total creative kinase peaked at 8099 U/L. Video electroencephalography revealed no seizure activity. He was extubated the morning after and remained stable without issues. With resolution of his rhabdomyolysis, he was transferred to the psychiatric unit given his history of recent suicidal ideation and hospitalization. Medications started during the admission include sertraline, gabapentin, trazodone, zolpidem as needed for sleep, and lorazepam as needed for anxiety.

On day 13, he was started on buprenorphine 2 mg and hydroxyzine 50 mg daily with a plan for long-term maintenance therapy to control his kratom cravings. The patient reported that he was taking up to 600 mg of kratom daily. On day 25, buprenorphine was increased to a dose of 4 mg twice a day due to persistent signs and symptoms of withdrawal.

On day 28, he was discharged to an inpatient rehabilitation center where he underwent intense behavioral therapy. His discharge medications included buprenorphine 4 mg twice a day, hydroxyzine 50 mg daily, gabapentin 300 mg three times a day, sertraline 150 mg daily, trazodone 75 mg daily, and lorazepam 0.5 mg once daily as needed for anxiety. Initially, the patient was taken off buprenorphine on admission; however, due to persistent withdrawal and the patient’s desire to be on buprenorphine to control his cravings, the patient was started on buprenorphine/naloxone 2 mg/0.5 mg three times a day. He remained on buprenorphine/naloxone and eventually tapered off after 45 days. He was subsequently discharged home a week later.

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DISCUSSION

Adverse effects of kratom include hypertension, cognitive and behavioral impairment, and dependence potential.8 Side effects in regular heavy users include nausea, weight loss, fatigue, constipation, insomnia, dry mouth, polyuria, and hyperpigmentation of the cheeks.2,4,7,8 Serious deleterious effects include cardiotoxicity, nephrotoxicity, and hepatotoxicity. Kratom has been shown to potentiate Torsades de Pointes in human cardiomyocytes.9 Chronic recreational use of kratom has also been associated with rare instances of acute liver injury with onset within 2–8 weeks of use.10 Hepatic injury is typically cholestatic with elevated bilirubin levels and may be complicated by concomitant renal failure and bone marrow toxicity.11

Patients in withdrawal present with nausea, diaphoresis, blurred vision, severe abdominal cramps, diarrhea, mydriasis, insomnia, irritability, hostility, aggression, restlessness, emotional lability, rhinorrhea, myalgia, and arthralgia.1–3,7 Kratom overdose is associated with seizures, psychosis, coma, hallucination, paranoia, severe emesis, respiratory depression, and possibly death.2,3 In a case series from the Virginia Poison Center, seizures were more frequently reported.12 Generalized seizure and development of mild rhabdomyolysis were seen in 1 person ingesting kratom as an athletic performance enhancement, which is similar in presentation to our case.

Research of kratom toxicity in humans has thus far been limited, and further studies are needed to understand kratom’s full effects on the body. There have been animal studies in canines and rodents, which have demonstrated toxic and lethal effects at different concentrations in the different species, suggesting that there may be an unexplained species-specific response.2,4 Death has been reported when kratom is used in conjunction with other substances such as modafinil, carisoprodol, fentanyl, diphenhydramine, caffeine, morphine, tramadol, and propylhexedrine.1,4,8

Kratom withdrawal and overdose management are not well described in the literature. However, due to the rise of kratom use and ER visits for withdrawal or overdose, it is essential to describe current attempts to treat patients on kratom. Detection requires liquid chromatography or ion mass spectrometry.4,8

Since the active alkaloids of kratom exhibit effects on μ-opioid receptors, it is not surprising that withdrawal symptoms are like that of opioid withdrawal. Therefore, prior attempts to treat kratom withdrawal have mimicked treatment of opioid withdrawal. Galbis-Reig et al13 described the use of a combination of high-dose clonidine and hydroxyzine for physical and mental symptomatic relief, followed by naltrexone therapy on discharge to prevent additional symptoms. Dihydrocodeine, an opioid agonist, and lofexidine, an α-adrenergic antagonist, have also been reported to successfully manage kratom withdrawal in an addicted individual.8

There are currently no guidelines or studies regarding the best method to treat kratom toxicity, withdrawal, or maintenance of long-term sobriety. In a case series, benzodiazepines were the most frequently used treatment (33%).12 Naloxone, an opioid receptor antagonist, has been suggested as a reversal agent in acute toxicity, although there are currently no reports of its use in a clinical setting.3 Buprenorphine and methadone therapy have been suggested for long-term maintenance of sobriety, and naltrexone was used in a prior case report.13 Buprenorphine and hydroxyzine were successfully used in our patient during his prolonged hospitalization to reduce his symptoms of withdrawal and maintain his long-term sobriety.

Because of the emerging popularity of kratom and the oft-confounding clinical presentation, providers need to have a high index of suspicion to diagnose this relatively rare condition. Physicians need to familiarize themselves with the pharmacology and adverse effects of kratom and understand the tenets of management both of the acutely ill patient as well as the chronic pain patient. The use of buprenorphine or buprenorphine/naloxone should be considered in management of patients who present with kratom withdrawal. It is important to use a multidisciplinary approach, including family, to develop a plan for long-term care to prevent relapse and harm to the patient. Finally, our patient’s lengthy admission allowed us to observe and document the natural progression of kratom overdose and recovery, which can help guide management of future cases.

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DISCLOSURES

Name: Jack Diep, MD.

Contribution: This author helped prepare the manuscript.

Name: David Tian Chin, BS.

Contribution: This author helped prepare the manuscript.

Name: Somdatta Gupta, MD.

Contribution: This author helped prepare the manuscript.

Name: Faraz Syed, DO.

Contribution: This author helped prepare the manuscript.

Name: Ming Xiong, MD, PhD.

Contribution: This author helped prepare the manuscript.

Name: Jianguo Cheng, MD, PhD.

Contribution: This author helped prepare the manuscript.

This manuscript was handled by: Raymond C. Roy, MD.

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REFERENCES

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