Kratom (Mitragyna speciosa) Use in a Veteran With Chronic Pain
Kratom (Mitragyna speciosa) is a plant indigenous to Thailand, Myanmar, and Malaysia, with opioid receptor activity traditionally used by Southeast Asian farmers to combat fatigue and to improve work productivity. Amidst a backdrop of increasing opioid misuse and overdose in the United States, kratom has steadily gained popularity among individuals with chronic pain due to its legality, analgesic properties, and ability to mitigate withdrawal symptoms from opioids. Kratom has recently become the focus of Drug Enforcement Agency (DEA) scrutiny. We present the case of a veteran's use of kratom to mitigate symptoms of opioid withdrawal in the context of physical dependence to prescription opioids.
“Mr. B” is a 34-year-old divorced, unemployed, Caucasian male veteran with a history of opioid use disorder, posttraumatic stress disorder (PTSD), and major depressive disorder (MDD), who presented to a Veterans Administration (VA) hospital requesting opioid detoxification.
The veteran had an extensive combat trauma history, serving 18 months in Iraq and Afghanistan as a machine gunner. In addition, he was exposed to improvised explosive device blasts but was never rendered unconscious. He was diagnosed with MDD and PTSD in 2009 after returning from Afghanistan. Prior to being discharged from military service, he was prescribed hydrocodone/acetaminophen and tramadol for back pain related to an injury sustained in Iraq. He denied taking more hydrocodone/acetaminophen than prescribed but acknowledged the possibility that he was taking it for reasons other than treatment of his back pain.
When he returned from deployment in 2010, he began using illicit oxycodone/acetaminophen (300 mg by mouth daily) and denied other routes of administration. He was prescribed buprenorphine/naloxone by a non-VA provider in February 2011 and did not use any illicit opioids for 1 month. He did not follow-up with his non-VA provider and resumed episodic illicit oxycodone/acetaminophen from March 2011 until July 2011. His pattern of use ranged from 30 mg to 150 mg of oxycodone/acetaminophen by mouth daily for 1–2 weeks, followed by abstinence for 1–2 weeks.
In August 2011, the patient entered an intensive outpatient substance use treatment program and discontinued oxycodone/acetaminophen. However, he began brewing kratom tea to mitigate symptoms of withdrawal from oxycodone/acetaminophen. He escalated his use of kratom to 10 grams twice daily to avoid withdrawal symptoms due to development of physiological tolerance to kratom. He denied feelings of euphoria while using kratom, instead experiencing relief from the elimination of withdrawal symptoms. He purchased kratom from online vendors and at specialty stores. When he was unable to procure kratom, he would substitute with illicit buprenorphine/naloxone (4 mg/1 mg). Prior to presenting for detoxification at the VA, he transitioned from kratom to buprenorphine/naloxone under the presumption that medical professionals would be more familiar with detoxification from buprenorphine/naloxone than kratom.
On admission to the VA inpatient detoxification unit, standard admission laboratory results were within normal limits. Urine toxicology was positive for opioids. The veteran was found to have no clinically relevant electrolyte abnormalities. He completed a 3-day uncomplicated detoxification from opioids. Withdrawal symptoms included restlessness, anxiety, sleep disturbance, sweats, chills, and diarrhea. He was discharged to a residential addiction program upon completion of his detoxification.
Native to Southeast Asian countries, kratom is a large tropical tree whose leaves have been traditionally chewed or made into a tea by laborers and farmers for decades to help combat fatigue and improve work productivity (1). As early as the 1800s, it has been used for the treatment of muscle pain, diarrhea, and cough, as well as to enhance productivity (2). Kratom preparations have also been used for centuries to treat morphine dependence in Thailand and to serve as an opium substitute in Malaysia during cultural and religious ceremonies (3). In 1979, kratom was placed under Schedule 5 of the Thai Narcotic Act, making it illegal to buy, sell, import, or possess. In Malaysia, kratom has been placed under the Poisons Act 1952 since 2003, resulting in a penalty or jail sentence for selling it. In recent years, however, kratom has been legally exported to North America and Europe from Indonesia for processing and re-distribution (4).
Kratom has a unique pharmacological (see Table 1) and toxicological (see Table 2) profile and is commonly used for its anxiolytic and antidepressant effects (5). For chronic users, withdrawal symptoms are consistent with that of opioids such as morphine (Table 2) (6). According to the National Institute on Drug Abuse, the number of deaths from heroin has increased 6-fold from 2001 to 2014 (7). While kratom has been associated with several deaths in combination with other substances, there is no solid evidence that it was the sole contributor to an individual's death (Table 2) (6). In 2010, only one case of kratom use was reported in U.S. drug data bases. In 2011, there were 44 reports of kratom use and 81 reports in the first 6 months of 2012. However, as kratom use is not monitored by any national drug use surveys in the United States, it is difficult to quantify the prevalence of its use among the U.S. population (1). Obtaining kratom is a relatively simple undertaking in the United States, as it can be ordered on many websites and shipped directly to an individual's home. It is sold as tablets, capsules, concentrated extracts, or chopped leaves. The fresh or dried leaves of kratom are traditionally brewed into a tea or smoked (5). However, kratom has recently garnered much attention in the media after the DEA announced its intention, on August 31, 2016, to designate it as a Schedule I substance. Following public outcry, the DEA withdrew its notice of intent and instead opened an official public comment period until December 1, 2016. The DEA has also requested that the Food and Drug Administration hasten scientific research, which would be halted if kratom is assigned Schedule I status.
|Primary constituents||Mitragynine (60%) and 7-HMG (2%) (6)|
|Potency||7-HMG > mitragynine; 7-HMG up to 17 times more potent than morphine (10)|
|Receptor activity||Mitragynine and 7-HMG: selective and full agonists of mu-opioid subtype receptors (6); mitragynine: mu, kappa, delta opioid receptor agonist with activity noted at adenosine-2a, postsynaptic alpha-2, dopamine-2s, and various serotonin receptors (2); descending noradrenergic and serotonergic anti-nociceptive activity (9)|
|Dose-dependent effects||Low dose (1–5 g): stimulant-like effects, High dose (5–15 g): opioid-like effects (5)|
|Time to onset of effects||Following ingestion, noticeable in 10–20 minutes; full experience 30–60 minutes (10)|
|Duration of effects||Strongest effects at about 2–4 hours after ingestion, usually lasts 5–7 hours; weak after-effects can be felt as late as the next day (6)|
|Half-life||Mitragynine: 3.4 hours; 7-HMG: 2.5 hours (6)|
|Metabolism||Mitragynine: phase I and II; inhibits CYP450: 3A4, 2D6, 1A2 (11)|
|Elimination||Mitragynine and 7-HMG primarily by urine (11)|
Pharmacological Profile of Kratom
|Withdrawal symptoms||Generally range from non-existent to mild. Physical symptoms: dysphoria, nausea, hypertension, irritability, myalgia, diarrhea, arthralgia, yawning, and insomnia for chronic users (5); psychological symptoms: agitation, anxiety, irritability, and depression for chronic users (14)|
|Short-term side effects||Sleep problems, nausea, constipation, itching, sweating, and temporary erectile dysfunction (6)|
|Long-term side effects||Tremor, hyperpigmentation, and weight loss (6)|
|Infrequent effects||Liver toxicity, seizure (alone or combine with other substances), coma, intrahepatic cholestasis, psychotic symptoms, adult respiratory distress syndrome, and hypothyroidism (5)|
|Fatalities||Reports of death when mixed with tramadol metabolite O-desmethyltramadol, propylhexedrine, and various psychiatric medications (5); no solid evidence exists that kratom was the sole cause of an individual's death (13)|
Toxicological Profile of Kratom
A recent study examining mitragynine pseudoindoxyl, synthesized by an oxidative rearrangement of mitragynine, showed promise for the compound as a potent analgesic. The study found that mice administered mitragynine pseudoindoxyl developed analgesic tolerance more slowly than morphine and showed limited physical dependence, respiratory depression, and constipation and displayed no reward or aversion in conditioned place preference, as well as conditioned place aversion assays (8). Despite the promise of this study, there is a dearth of controlled clinical human studies to better understand the risks and benefits.
The above case highlights the difficulty faced by millions of Americans with opioid use disorder in identifying ways to manage their addiction. It is incumbent upon physicians to educate themselves about the properties of kratom, the limited ability of standard toxicology screens to detect this substance, and the potential to treat patients with addiction and chronic pain. Given the DEA's recent delay in designating kratom as a Schedule I substance, the translation of these findings to clinical practice is of imminent importance as researchers are searching for ways to treat pain and addiction while addressing the opioid epidemic.
Key Points/Clinical Pearls
Kratom (Mitragyna speciosa) is a drug of abuse increasingly utilized in the United States due to its current legality, analgesic properties, and ability to mitigate opioid withdrawal symptoms.
Kratom is now a focus of Drug Enforcement Agency scrutiny amidst the increasing opioid epidemic in the United States.
Kratom is unique in its ability to produce stimulant-like effects at low doses (1–5 grams) and opioid-like effects at higher doses (5–15 grams).
The compound mitragynine pseudoindoxyl, synthesized from the kratom alkaloid mitragynine, shows promise in treating pain and opioid dependence without the adverse effects typical of opioids.
5. : Following the roots of kratom (Mitragyna speciosa): the evolution of an enhancer from a traditional use to increase work and productivity in Southeast Asia to a recreational psychoactive drug in western countries. Biomed Res Int 2015; 2015:1–11 Crossref, Google Scholar
13. : The rush to prohibit kratom. http://www.thestranger.com/seattle/the-rush-to-prohibit-kratom/Content?oid=13321119 Google Scholar
14. : A case report of kratom addiction and withdrawal. WMJ 2016; 115(1):49–52 Google Scholar