A Case Report of Kratom Addiction and Withdrawal

A Case Report of Kratom Addiction and Withdrawal

David Galbis-Reig, MD

ABSTRACT

Kratom, a relatively unknown herb among physicians in the western world, is advertised on the Internet as an alternative to opioid analgesics, as a potential treatment for opioid withdrawal and as a “legal high” with minimal addiction potential. This report describes a case of kratom addic- tion in a 37-year-old woman with a severe opioid-like withdrawal syndrome that was managed successfully with symptom-triggered clonidine therapy and scheduled hydroxyzine. A review of other case reports of kratom toxicity, the herb’s addiction potential, and the kratom withdrawal syndrome is discussed. Physicians in the United States should be aware of the growing availabil- ity and abuse of kratom and the herb’s potential adverse health effects, with particular attention to kratom’s toxicity, addictive potential, and associated withdrawal syndrome.

tom, a “nonaddictive, natural option” to “pain killers,” could be a good alternative to treat her pain. She gave the patient some capsules containing dried, crushed kratom leaves. The patient reports that it provided her pain relief and also gave her a “boost of energy.” Given the expense, however, she decided to purchase the concentrated extract off the Internet on the assump- tion that it would last longer because it would require less of the substance. Over the course of the next 2 years, the patient continued to purchase kratom extract

CASE PRESENTATION

A 37-year-old white woman with no previous history of sub- stance abuse treatment was admitted to the inpatient mental health and addiction service after contacting the unit for treat- ment of an “addiction to kratom.” The patient denied any past medical history except for postpartum depression that was par- tially responsive to sertraline, which the patient discontinued on her own. The patient reported that she works as a teacher and was first introduced to kratom 2 years prior to admission by a fellow teacher who was using it to treat her fibromyalgia pain. Because the patient had been in pain from recent carpal tunnel surgery and was concerned about taking opioid analgesics due to their “addictive potential,” her colleague convinced her that kra-

•••

Author Affiliations: Wheaton Franciscan Healthcare–All Saints, Racine, Wis.

Corresponding Author: David Galbis-Reig, MD, Medical Director of Addiction Services, Wheaton Franciscan Healthcare–All Saints, 1320 Wisconsin Ave, Racine, WI 53403; phone 262.687.2365; fax 501.423.1588; e-mail dgalbisreig@aol.com.

from a single Internet site based in Florida for $150 for a 20 ml bottle labeled only with the name of the company and the country of origin (in this case Bali). The patient reported that within 6 months she realized that she was using much more of the kratom than she intended. When she attempted to cut back, she discovered that she would experience cravings as well as sig- nificant withdrawal symptoms consisting of severe abdominal cramps, sweats, blurred vision, nausea, vomiting, and diarrhea. Over the course of the next 1.5 years she attempted to detoxify in the outpatient setting with medication support from 2 outpa- tient providers using low dose clonidine, without success. By this point, the patient had also lost a significant amount of weight, stating that the kratom curbed her appetite. Her husband later told the physician that she was hiding the fact that she had con- tinued to use kratom, was hiding the bottles around the home, and had gone to significant lengths to ensure that he would not discover that she had continued to order kratom online by having the product shipped to local FedEx stores. The patient admitted she was worried that she would lose her family if she did not stop taking the kratom. Despite its effects on her health (weight loss, insomnia, cravings, and decreased overall energy level) and the conflict that her use had been creating in her marriage, she had continued to take the kratom extract. Both her husband and father gave her an ultimatum to stop using the kratom, which led to her contacting the inpatient mental health and addiction unit for assistance.

CME available. See page 53 for more information.

VOLUME 115 • NO. 1 49

On presentation, the patient’s pupils measured approximately 2-3 mm in diameter and she complained only of mild diaphore- sis. She admitted to taking her last dose of kratom at 5 am on the day of admission. She brought her last vial of kratom, which con- tained approximately 2 ml of a clear fluid that she admitted was concentrated kratom extract diluted with water. Unfortunately, there was not enough of the diluted concentrate left in the bottle for laboratory analysis. The initial examination was unremarkable except for mild diaphoresis of the palms and back of the neck and significant cachexia. Electrolytes, renal function, hemogram, and liver studies were within normal limits. Urine toxicology by immunoassay was negative for all drugs of abuse including oxy- codone, opioids, and methadone. A sample of urine was sent for liquid chromatography-mass spectrometry (LC-MS) to detect mitragynine (the active alkaloid in kratom), results of which came back positive at a cutoff value of 10 ng/ml. While an exact toxic concentration has not been clearly established for mitragy-

nine, case reports suggest that side effects of mitragynine, including risk of tors- ade de pointes, appear to be dose depen- dent.1,2 The patient was started on the opioid withdrawal protocol using symp- tom-triggered clonidine at a dose of 0.1- 0.2 mg every 2 hours based on the Clinical Opioid Withdrawal Scale (COWS) Score, a validated scale that scores typical opioid withdrawal symptoms such as pupillary dilatation, diaphoresis, gastrointestinal dis- tress, anxiety, fever, bone and joint pains, increased lacrimation or rhinorrhea, trem- ors, and yawning based on the severity of the symptoms. Scheduled hydroxyzine 50 mg by mouth every 6 hours also was started, along with a 0.1 mg per day cloni- dine patch to assist with withdrawal symp- toms. By 1 pm on the day of admission, the patient’s withdrawal symptoms started to increase rapidly as she developed myal- gias, bone pain, abdominal cramping pain, nausea, and blurred vision due to rapid pupillary dilatation. The patient developed severe withdrawal symptoms by mid-after- noon, which progressed rapidly requiring up to 2 mg of oral clonidine over the next 36 hours as noted by the Clinical Opioid Withdrawal Scale (COWS) Scores (Figure 1) and frequency and dose of clonidine administered (Figure 2). Fortunately, the hyperautonomic symptoms improved rap-

idly over the course of 2 to 3 days. During previous attempts at detoxification, the patient described a prolonged period of severe depression and anxiety. Given the patient’s previous history of postpartum depression only partially treated with sertraline, she also was started on extended release venlafaxine beginning at a dose of 37.5 mg and titrated daily up to 150 mg for her depres- sion. In order to avoid benzodiazepines, the patient was started on pregabalin at a dose of 25 mg by mouth every 8 hours and titrated to 50 mg every 8 hours prior to discharge for her anxi- ety. The patient’s condition stabilized over the course of 3 days in the hospital. After a family meeting with her husband and father, the patient was discharged to home with an appointment to begin participation in a dual partial hospital program. She was provided with a prescription to start naltrexone 50 mg by mouth daily for opioid antagonist therapy to begin no sooner than 7 days after discharge to avoid precipitating any additional withdrawal symptoms.

50 WMJ • FEBRUARY 2016

DISCUSSION

Kratom (Mitragynia speciosa Korth) is an herb indigenous to Thailand and other countries in Southeast Asia that has been used by people in that part of the world for hundreds of years to stave off fatigue and to manage pain, opioid withdrawal, and cough.3 In the past decade, the herb has made its way around the world via Internet sales as an alternative to opioids for pain relief. Unfortunately, kratom is not well known by physicians in the United States. Kratom contains a number of active phyto- chemicals, but the chemical entity mitragynine (the plant’s pri- mary alkaloid) is widely regarded to produce the majority of the plant’s psychoactive effects, with additional contributions from other phytochemicals, including 7-hydroxymitragynine (7-HMG) and mitraphylline.4,5 When ingested orally, the bioavailability of mitragynine is estimated in the laboratory to be approximately 3.03% with an onset of action of approximately 5 to 10 minutes.2 The half-life of mitragynine is not known with certainty, but its effects appear to last several hours consistent with the initiation of withdrawal symptoms within 12 to 24 hours (as occurred in the current case).2 At low doses, mitragynine has stimulant effects, but at high doses, mitragynine behaves like an opioid and has been shown to have agonist activity at the Mu and Kappa-opioid recep- tors.6 Kratom is not currently scheduled by the Drug Enforcement Agency (DEA) but is listed on its “Drugs and Chemicals of Concern” list and is sold on the Internet as a “nonaddictive” herbal alternative for pain control.6,7 It also is used by many as a “legal high” and to assist with withdrawal from opioids. Despite its non- scheduled status with the DEA, in 2013 Wisconsin Act 351 classi- fied kratom as a schedule 1 controlled dangerous substance, mak- ing it illegal to possess or use in Wisconsin.8,9 Mitragynine, the primary active component of kratom, currently is being investi- gated as a potential analgesic with a diminished risk of respiratory depression in overdose compared to traditional opioid analgesics.6

At the present time, however, the clinical properties of mitragy- nine and its potential for development as a therapeutic agent are only in the early stages of investigation.

The Internet is ripe with sites and articles that proclaim the analgesic and stimulant properties of kratom while downplaying its adverse side effects and addictive potential. Numerous case series and reports, however, have described the addictive potential of kratom, both in herbal form and as an extract. The oldest of these published articles dates back to 1975 with an early descrip- tion of kratom addiction in the Thai population.10 In a more recent study carried out to determine the risk of suicide among illicit drug users in Thailand, the investigators report that the pri- mary drug of abuse in their study was kratom (illegal in Thailand since 1943), which was used by 59% of the 537 respondents who admitted to illicit drug use, followed by methamphetamine (24%).11 This epidemiological study, however, did not distinguish between abuse and addiction.

More recently, a number of case series and reports of kratom toxicity have started to surface in the United States and Europe (Table). In one such report, a male patient abusing and addicted to hydromorphone attempted to use kratom to prevent with- drawal and was admitted to the hospital after he mixed the kra- tom with modafanil and suffered a generalized tonic-clonic sei- zure.12 It is unclear if the seizure was a result of the kratom or the combination of the 2 drugs. In a separate case series from Sweden, investigators report on 9 cases of krypton intoxication and death.13 Krypton is an herbal preparation of dried, crushed kratom leaves mixed with another mu-opioid receptor agonist, O-desmethyltramadol.13 The abuse potential, toxicity, and with- drawal symptoms associated with kratom use have been described in at least 3 case series.14-16 Three additional case reports also have demonstrated the potentially fatal effects of kratom without the addition of other mu-opioid agonists.17-19

VOLUME 115 • NO. 1 51

The addictive potential of kratom (specifically mitragynine) has been well described in a discriminative stimulus rat model of addiction with properties similar to morphine and cocaine.20 While the toxicity and addictive potential of kratom and its derivatives has not been well described in human populations, several case series and reports describe a clear addiction poten- tial and a potentially severe, opioid-like withdrawal syndrome in humans.14,16 Toxicity has included reports of palpitations, seizures, and coma.12,16 The most extensive description of kratom with- drawal suggests symptoms of physical withdrawal that include myalgias, pupillary dilatation, insomnia, rhinorrhea, lacrimation, fever, hot flashes, anorexia, and diarrhea as well as psychological withdrawal symptoms that include agitation, anxiety, irritability, and depression.14 Given the mu-opioid agonist effects of the alka- loids mitragynine and 7-hydroxymitragynine found in kratom, the symptom complex of kratom withdrawal is, not surprisingly, similar to the opioid withdrawal syndrome. The investigators of the aforementioned cross-sectional survey study declare that “kra- tom use is associated with drug dependence, drug withdrawal, and craving” consistent with drug addiction.14

Empirical evidence regarding how best to treat the kratom withdrawal syndrome and assist with long-term maintenance of sobriety from kratom is currently lacking, though the current case report suggests that a combination of high dose alpha-2 agonist therapy and hydroxyzine may provide relief from both the physi- cal and mental symptoms of kratom withdrawal. Theoretically, buprenorphine and methadone agonist therapy also might be utilized for long-term maintenance of sobriety in kratom addic- tion, though kratom’s current classification as a distinct chemical entity not related to the opioid class of chemicals creates some medico-legal and regulatory issues that require consideration with respect to opioid agonist therapy. As a result, and because there are no regulatory issues with antagonist therapy, the patient was prescribed oral naltrexone to assist with craving and maintenance of sobriety from kratom.

CONCLUSION

Kratom (Mitragynia speciosa Korth), an herb originating in Southeast Asia, which currently is not scheduled by the DEA, but is classified as a schedule 1 dangerous controlled substance in Wisconsin,21 possesses psychoactive properties that include both stimulant and opioid-like effects. Kratom has grown, and contin- ues to grow, in popularity in the United States and in Wisconsin. Withdrawal symptoms are mediated by the opioid properties of the plant’s primary alkaloid compounds and can successfully be treated using an alpha-2 agonist and hydroxyzine as demonstrated by the current case report in which symptom-triggered clonidine therapy was utilized with COWS in conjunction with scheduled hydroxyzine. Physicians should be aware of the growing availabil- ity of kratom and its potential adverse health effects, especially its toxicity, addictive potential, and withdrawal syndrome.

Funding/Support: None declared.

Financial Disclosures: Dr Galbis-Reig reports ownership of stock in GW Pharmaceuticals and Cortex Pharmaceuticals, Pfizer Inc bonds, and spousal ownership of stock options in Abbvie, Abbott Pharma, and Hospira.

Planners/Reviewers: The planners and reviewers for this journal CME activity have no relevant financial relationships to disclose.

REFERENCES

1. Prozialeck W, Jivan J, Andurkar S. Pharmacology of kratom: an emergening botanical agent with stimulant, analgesic, and opioid-like effects. Am Osteopath Assoc. 2002;112(12):792-799.
2. Manda V, Avula B, Ali Z, Khan I, Walker L, Khan S. Evaluation of the in vitro absorption, distribution, metabolism, and excretion (ADME) properties of mitragynine, 7-hydroxymitragynine, and mitraphylline. Planta Med. 2014;80(7):568-576.
3. Le D, Goggin M, Janis G. Analysis of mitragynine and metabolites in human urine for detecting the use of the psychoactive plant kratom. J Anal Toxicol. 2012;36(9):616-625. 4. Suwanlert S. A study of kratom eaters in Thailand. Bulletin Narcotics. 1975;27(3):21-27. 5. Kittirattanapaiboon P, Suttajit S, Junsirimongkol B, Likhitsathian S, Srisurapanont
M. Suicide risk among Thai illicit drug users with and without mental/alcohol use disorders. Neuropsychiatr Dis Treat. 2014;10:453-458.
6. Nelson J, Lapoint J, Hodgman M, Aldous K. Seizure and coma following kratom (Mitragynina speciosa Korth) exposure. J Med Toxicol. 2010;6:424-426.
7. Kronstrand R, Roman M, Thelander G, Eriksson A. Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend krypton. J Anal Toxicol. 2011;35:242-247.
8. Greenemeier L. Should kratom use be legal? Scientific American. September 30, 2013. http://www.scientificamerican.com/article/should-kratom-be-legal/. Accessed January 14, 2016.
9. Drug Enforcement Administration, Office of Diversion Control. January 1, 2013. http:// www.deadiversion.usdoj.gov/drug_chem_info/kratom.pdf. Accessed January 14, 2016. 10. Singh D, Muller C, Vicknasingam B. Kratom (Mitragyna speciosa) dependence, withdrawal symptoms, and craving in regular users. Drug Alcohol Depend. 2014;139:132-137.
11. Forrester M. Kratom exposures reported to Texas poison centers. J Addict Dis. 2013;32(4):396-400.
12. McIntyre I, Trochta A, Stolberg S, Campman S. Mitragynine ‘Kratom’ related fatality: a case report with postmortem concentrations. J Anal Toxicol. 2015;39(2):152-155.
13. Karinen R, Fosen J, Rogde S, Vindenes V. An accidental poisoning with mitragynine. Forensic Sci Int. 2014;245c:e29-e32.
14. Trakulsrichai S, Tongpo A, Sriapha C, et al. Kratom abuse in Ramathibodi Poison Center, Thailand: a five-year experience. J Psychoactive Drugs. 2013;45(5):404-408. 15. Neerman M, Frost R, Deking J. A drug fatality involving kratom. J Forensic Sci. 2013;58(Suppl 1):S278-S279.
16. Harun N, Hassan Z, Navaratnam V, Mansor S, Shoaib M. Discriminative stimulus properties of mitragynine (kratom) in rats. Psychopharmacology (Berl). 2015;232(13): 2227-2238.
17. Lu J, Wei H, Wu J, et al. Evaluation of the cardiotoxicity of mitragynine and its analogues using human induced pluripotent stem cell-derived cardiomyocytes. PLoS One. 2014;9(12):1-18.
18. Ulbricht C, Costa D, Dao J, et al. An evidence-based systematic review of kratom (Mitragyna speciosa) by the Natural Standard Research Collaboration. J Diet Suppl. 2015;10(2):152-170.
19. Drug Enforcement Administration. Office of Diversion Control. KRATOM (Mitragyna speciosa korth). January 2013. http://www.deadiversion.usdoj.gov/drug_chem_info/ kratom.pdf. Accessed January 14, 2016.
20. Synche Enterprises. Kratom Legal Status. February 9, 2015. http://www.synche. com/tag/kratom-legal-status/. Accessed January 14, 2016.
21. Wisconsin State Legislature. 2013 Wisconsin Act 351. April 24, 2014. https://docs. legis.wisconsin.gov/2013/related/acts/351. Accessed January 14, 2016.

52 WMJ • FEBRUARY 2016

The mission of WMJ is to provide a vehicle for professional communication and continuing education for Midwest physicians and other health professionals.

WMJ (ISSN 1098-1861) is published by the Wisconsin Medical Society and is devoted to the interests of the medical profession and health care in the Midwest. The managing editor is responsible for oversee- ing the production, business operation and contents of the WMJ. The editorial board, chaired by the medical editor, solicits and peer reviews all scientific articles; it does not screen public health, socioeco- nomic, or organizational articles. Although letters to the editor are reviewed by the medical editor, all signed expressions of opinion belong to the author(s) for which neither WMJ nor the Wisconsin Medical Society take responsibility. WMJ is indexed in Index Medicus, Hospital Literature Index, and Cambridge Scientific Abstracts.

For reprints of this article, contact the WMJ at 866.442.3800 or e-mail wmj@wismed.org. © 2016 Wisconsin Medical Society

https://www.wisconsinmedicalsociety.org/_WMS/publications/wmj/pdf/115/1/49.pdf