Learning Objectives/Outcomes: After participating in this CME/CNE activity, the provider should be better able to:
1. Explain the legal, medical, and social aspects of kratom use.
2. Describe how kratom came to be advocated as management of chronic pain.
3. Identify the adverse effects of kratom use.
Kratom is one of the common names for a drug derived from the leaves of Mitragyna speciosa, the tropical evergreen coffee tree. M. speciosa is native to Southeast Asia, and kratom is used more widely there than in the United States. However, this herbal drug has grown in popularity and use here and in the United Kingdom in recent years. Other common and street names include thang, krypton, kakuam, thom, ketum, and biak-biak, the latter being a common name in Thailand.
Much confusion comes from the fact that kratom can have paradoxical effects and actions-stimulation in low doses and sedation or sensory depression in higher doses. More confusion lies in the gray area that kratom occupies in the legal and regulatory arena. And to further muddy the waters, kratom is still not detectable by most drug screening tests that pain practitioners ask their patients to take.
Because pain relief and opioid replacement are 2 of the reasons people use or abuse kratom, pain practitioners must take the initiative to be informed about this drug before they encounter it in patients, whether their patients are already using it, suspected of doing so, or seeking information. Some evidence indicates it could play a role in pain management, but what that role is remains to be seen.
M. speciosa is indigenous to Thailand, Indonesia, Malaysia, Myanmar, and Papua New Guinea.1 The tree itself can grow to a height of more than 80 ft. Kratom has been used in traditional medicines since at least the 19th century for pain control and for its stimulant properties.2 First formally described by Dutch colonial botanist Pieter Korthals in 1839, who named it kratom, it was renamed and reclassified several times before George Darby Haviland provided the final name and classification in 1859.3
Pharmacology
Much of the pharmacology of kratom was not well understood until recently, in part because it appeared that what was known was also contradictory. Nearly all the available literature is from the last 10 years. The herb has stimulant effects at low doses, an opioid-like effect at higher doses, and sedative and sensory-suppressive effects.4
Kratom contains some 25 alkaloids, of which 2 are 13 and 52 times more potent than morphine. The main action of kratom is via the alkaloid, mitragynine. Mitragynine is a stimulant at low doses due to [alpha]-adrenergic properties and an opioid receptor agonist at high doses.5 It is structurally similar to yohimbine.
Mitragynine also stimulates [alpha]2-adrenergic receptors. Similar compounds in this class include dexmedetomidine (a sedative), and clonidine, used to manage anxiety and symptoms of opioid withdrawal. These actions may explain why kratom can be dangerous when used in combination with other sedatives.
Mitragynine is metabolized in humans via phase I and phase II mechanisms. Metabolites are renally excreted.4 Experimentally, kratom extracts have been shown to inhibit CYP3A4, CYP2D6, and CYP1A2 enzymes, presenting the potential for serious drug interactions.4
There are an estimated 3 million to 5 million people in the United States who use kratom. Although the US Drug Enforcement Administration (DEA) proposed a ban in 2016, 142,000 signatures on a petition caused the DEA to reverse its decision.
Kratom is not yet detected by routine drug screening. A public health advisory was issued in 2017, although kratom is not scheduled as a controlled substance. In the United States, as of 2019, kratom is readily available in head shops, gas stations, and over the internet.
Uses
Kratom has been used in the following ways:
* As traditional medicine;
* To assist in opioid withdrawal; and
* For recreational purposes.
The onset of action, depending on the dose, may include agitation, hypertension, delirium, and/or rhabdomyolysis. This onset can occur within 5 to 10 minutes and lasts for about 3 to 5 hours.
The leaves of kratom are consumed by chewing; by drying and smoking; by putting into capsules, tablets, or extract; or by boiling into a tea.
In countries where the tree is native, kratom has wide uses as a traditional remedy. The leaves may be chewed to relieve musculoskeletal pain and increase energy, appetite, and sexual desire, rather as khat is used in Yemen and coca in Peru.4 The leaves or their extracts (often powdered) may be applied for wound healing or as a local anesthetic. Other uses include in the treatment of coughs, diarrhea, and intestinal infections.3 In Thailand, extracts are used for deworming purposes.
Workers in laborious or monotonous professions may chew kratom to decrease exhaustion, to elevate their moods, or as a painkiller.3 In Thailand, kratom was "used as a snack to receive guests and was part of the ritual worship of ancestors and gods."6 Because of its bitterness, sugar or other sweeteners are often added.
As early as 1836, kratom was reported as an opium substitute in Malaysia. Kratom was also used as an opium substitute in Thailand in the 19th century.2 Due to its opioid-like action, kratom has been used as assistance in opioid withdrawal. Animal studies suggest that the primary mitragynine pharmacologic action occurs at the [micro]- and [delta]-opioid receptors, and serotonergic and noradrenergic pathways in the spinal cord. Stimulation at postsynaptic [alpha]-2 adrenergic receptors, and receptor blocking at 5-hydroxytryptamine 2A, may also occur. The 7-hydroxymitragynine may have a higher affinity for the opioid receptors. Partial agonist activity may be involved.
Animal studies indicate that these opioid receptor effects are reversible with the opioid antagonist naloxone.
Spurred on by recent concerns and the exploding opioid crisis, proponents tout kratom as a safer and less addictive alternative to opioids for management of pain and opioid addiction. An online survey of kratom users (2867 current users and 157 former users) indicated that kratom was used primarily to relieve pain (48% of respondents), and for anxiety, posttraumatic stress disorder, or depression (22%), to increase energy or focus (10%), and to help cut down on opioid use and/or relieve withdrawal (10%). Bad adverse reactions, overwhelmingly mild and self-managed, were about 13%.7
Little data exist to reveal how often kratom is used worldwide for opioid withdrawal and substitution. Kratom is not detected by typical drug screening tests, requiring more sophisticated measures that are not often available.8 However, kratom use seems to be increasing among those self-managing chronic pain with opioids purchased without a prescription and are cycling (but not quitting) their use.8 To date, kratom has not been approved in the United States for opioid withdrawal, despite protests from the American Kratom Association and others.
As of 2018, there have been no formal trials to study the efficacy or safety of kratom to treat opioid addiction according to FDA commissioner Scott Gottlieb, MD. There is no reliable evidence to support the use of kratom as a treatment for opioid use disorder," according to a statement Gottlieb issued in 2018.9
The antikratom faction argues that kratom, itself, is a dangerous and addictive drug that should be banned.
Kratom is also a popular recreational drug, especially in Thailand, where a commonly served tea-based cocktail known as "4 x 100" is made up of a mix of kratom leaves, cough syrup, Coca-Cola, and ice. As of 2012, use of the cocktail was a severe problem among youth in 3 provinces along the border of Malaysia and Southern Thailand.10
Adverse Effects
The American Association of Poison Control Centers reported 1807 calls of exposure to kratom and a 52-fold increase between 2011 and 2017. Thereafter, the US Centers for Disease Control and Prevention (CDC) analyzed data from the State Unintentional Drug Overdose Reporting System.11
Kratom was detected on postmortem toxicology testing in 11 states from July 2016 to June 2017 and in 27 states during July through December 2017. Data on 27,338 overdose deaths confirmed 152 tested positive for kratom (7/16-12/17).12 Kratom was identified as the cause of deaths in 91 cases. In 80% of these deaths, there was a history of substance abuse.
The incidents reported were described as predominantly intentional use by males at home. Approximately a third of these incidents necessitated hospital admission and were considered serious. Postmortem toxicology testing detected multiple substances for almost all those who died, with fentanyl and fentanyl analogs being the most frequently identified comixed substances.5 Even more recently, 90 deaths associated with kratom overdose were reported in JAMA and in the press.13,14
Similar findings were identified in a study conducted in the United Kingdom, where kratom use is also common. Analyses of 156 cases revealed the vast majority of people seeking medical attention after adverse effects related to kratom were male (80%), with a mean age of 32.3 years, white (100%), and with a history of drug abuse (95%).15
In that UK study, reasons for use included self-medication, recreation, relaxation, bodybuilding, and avoiding positive drug tests.
Mitragynine alone was identified/implicated in 23% of cases. Polysubstance use was common (87%), usually consisting of controlled or recreational drugs, therapeutic drugs, and alcohol.
Causes of death included toxic effects of kratom with or without other substances such as benzodiazepines, modafinil, O-desmethyltramadol, alcohol, paroxetine, lamotrigine, antidepressants, dextromethorphan, diphenhydramine, morphine, acetaminophen, and propylhexedrine, and underlying health issues.16 Such polypharmacy does confound the issue as to what role kratom played in fatalities.
A recent study from researchers looking at New York data and also that of the National Poison Center indicated an alarming increase in morbidity and mortality associated with kratom use.17 A total of 2312 kratom exposures were reviewed with 935 cases involving kratom as the only substance. Most common symptoms were agitation (18.6%), tachycardia (16.9%), drowsiness (13.6%), vomiting (11.2%), and confusion (8.1%). Serious effects were also reported, consisting of seizure (6.1%), withdrawal (6.1%), hallucinations (4.8%), respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%).
Kratom was listed as a cause or contributing factor in the death of 4 decedents identified by the county medical examiner's office. The authors concluded that "kratom use is increasing and is associated with significant toxicities. It is not reasonably expected to be safe and poses a public health threat due to its availability as an herbal supplement."
Recurrent seizures have been reported in at least 1 case. A 19-year-old man developed recurrent seizures after daily kratom abuse as a self-treatment for anxiety. Following recurrent focal impaired awareness seizures in addition to generalized tonic-clonic seizures, he was begun on antiseizure drugs and the seizures subsided. However, brain MRI at 29 months showed bilaterally symmetric T1-hyperintensity in globus pallidus, subthalamic nuclei, and cerebral peduncles, suggesting kratom abuse may be associated with structural brain lesions on MRI and symptomatic focal epilepsy.18
Yet another recent report has linked kratom use with liver disease in several case reports. In one instance a 40-year-old woman presented with symptoms of mixed cholestatic and hepatocellular liver injury without clear etiology. Studies suggested autoimmune hepatitis, autoimmune hepatitis-primary biliary cholangitis (PBC) overlap syndrome, or drug-induced liver injury. However, autoantibodies-including anti-mitochondrial antibody (AMA)-were negative. A liver biopsy in this patient showed granulomatous hepatitis with prominent duct injury, suggestive of AMA-negative PBC.19 Finally, the patient's history of kratom use was revealed. When kratom was discontinued, this patient's symptoms improved.
The authors concluded that kratom-induced hepatic toxicity may manifest with variable biochemical and clinical abnormalities histologically and may mimic AMA-negative PBC.
Of further concern was the finding of 199 cases of salmonellosis in 41 states, linked with kratom consumption; 38% of the illnesses were serious enough to lead to hospitalization.20 In April 2018, the FDA issued a mandatory recall over concerns of salmonella contamination of several kratom-containing products. Samples of the products, manufactured by Triangle Pharmanaturals and marketed under the brand name Raw Form Organics, tested positive for salmonella contamination. The manufacturer did not comply with federal requests for voluntary recall. However, the FDA publicly announced this contamination concern and advised consumers to immediately discard any such products to prevent serious health risks. FDA Commissioner Gottlieb stated that the recall was "... based on the imminent health risk posed by the contamination of this product with salmonella" and not related to other regulatory concerns. The FDA and the CDC conducted a study, concluded a few months later. No known deaths were linked with the outbreak.
Use During Pregnancy as Opioid Replacement
Kratom has been used during pregnancy. Indeed, it may be an emerging treatment for self-management of opioid use disorder in the obstetric population.21 Awareness of kratom use is important for obstetrical care providers who should consider opioid replacement for pregnant women with kratom dependence. As a result of maternal dependence, neonates may also become dependent.
A case of neonatal abstinence syndrome (NAS) secondary to maternal drug presented in a term infant whose mother was self-medicating with kratom tea.22 The baby required oral morphine for NAS. After 12 days in neonatal intensive care unit, the baby was discharged on oral morphine, which was discontinued after 2 months.
Addiction Risk
Addiction to kratom, as with any opioid, is not uncommon and may prove difficult to treat. A recent study emphasized how chronic use can lead to dependence, tolerance, and withdrawal upon cessation, and clinicians are seeing an increasing number of presentations involving the latter.23
The authors note that health care workers need to be aware of the withdrawal symptomatology and implement a similar approach for opioid withdrawal with long-term maintenance to prevent relapse. Buprenorphine-naloxone has been shown to be successful.24
It would appear that kratom offers advantages, but at the same time may exert fatal effects. A recent review attempted to rationalize these conflicting situations.25 The authors, all of whom are involved in kratom research, concluded that:
(a) User reports and results of preclinical studies in animals strongly suggest that kratom and its main constituent alkaloid, mitragynine, may have useful activity in alleviating pain and managing symptoms of opioid withdrawal, even though well-controlled clinical trials have yet to be done.
(b) Even though kratom lacks many of the toxicities of classic opioids, there are legitimate concerns about the safety and lack of quality control of purported "kratom" products that are being sold in the United States.
(c) The issues regarding the safety and efficacy of kratom and its mitragynine constituent can only be resolved by additional research. Classification of the Mitragyna alkaloids as Schedule I controlled substances would substantially impede this important research on kratom.
Government Regulation
On August 30, 2016, the DEA announced its intention to place the active materials in the kratom plant into Schedule 1 of the Controlled Substances Act as a warning about an imminent hazard to public safety.26 Strong protests resulted, and 51 members of the US House of Representatives and 9 Senators sent letters to acting DEA administrator Chuck Rosenberg protesting the listing. And, as noted earlier in this article, 142,000 people signed an online White House Petition protesting the action. The DEA withdrew its notice of intent in October 2016, while inviting public comments. Commissioner Scott Gottlieb responded in 2017:
Patients addicted to opioids are using kratom without dependable instructions for use and, more importantly, without consultation with a licensed health care provider about the product's dangers, potential side effects or interactions with other drugs. There's clear data on the increasing harms associated with kratom. Calls to US poison control centers regarding kratom have increased 10-fold from 2010 to 2015, with hundreds of calls made each year. The FDA is aware of reports of 36 deaths associated with the use of kratom-containing products. There have been reports of kratom being laced with other opioids like hydrocodone. The use of kratom is also associated with serious side effects like seizures, liver damage and withdrawal symptoms.
Several states and the US Army have made kratom illegal. In 2018, the FDA supervised the voluntary destruction of kratom dietary supplements by a nationwide distributor in Missouri, and encouraged all companies involved in kratom commerce to remove their products from the market.
On February 26, the FDA warned a California manufacturer of a kratom product called "Mitrasafe" that the supplement was not confirmed as safe, was not approved as a dietary supplement or drug, and was illegal for interstate commerce with the following statement:
"The FDA recommends that consumers not use these or any kratom products and dispose of any products currently in their possession."
Furthermore, the FDA noted in April 201927:
"There is no reliable evidence to support the use of kratom as a treatment for opioid use disorder; there are currently no FDA-approved therapeutic uses of kratom ... and the FDA has evidence to show that there are significant safety issues associated with its use. ...[K]ratom is not approved for any medical use, is potentially unsafe in commercial products available in the United States, and remains on an import alert where imported supplies would be confiscated."
Advocacy
The American Kratom Association is a lobbying and advocacy group in support of kratom use. In addition to its mission of educating the public about kratom, the association provides legislative updates from around the nation and maintains an approval program of vendors that practice good manufacturing standards to promote safety of kratom products.
Conclusion
Kratom, a relatively new product in the United States, may have beneficial effects as a substitute for opioids or for management of opioid withdrawal. However, serious side effects and even deaths have been reported. Although it is not presently listed as a Schedule 1 substance, further research is indicated to define what place it has in the management of pain and other conditions.
References