• HutherDoyle

Kratom?

By Tim Wiegand, MD, FACMT, FAACT, DFASAM



A Case…

A 27 year-old male with history of anxiety, depression and opioid use disorder, most recently using intranasal heroin, has been in treatment now for 2 months after “tapering off Suboxone®,” at a local detoxification facility. He has been coming to group and individual counseling sessions regularly with good attendance and participation. His urine toxicology testing has been negative for opiates and fentanyl, and no other drugs except low levels of THC (he intermittently uses cannabis). During a counseling session at the outpatient program, he reports starting “Kratom” a few days after he left the detox. He’s now spending over $ 50.00 daily on it and states that he can’t afford this and that he’s also having withdrawal if he doesn’t use the Kratom at least a few times daily. He wants to know what he should do to stop.


What is Kratom?

Kratom is the common name for a tropical tree/plant native to parts of Southeast Asia and Africa. More formally, Kratom is known as Mitragyna speciosa and it is indigenous to Thailand, Indonesia, Malaysia, Myanmar and Papua New Guinea, where it has been used in both traditional remedies and recreationally since early in the 19th century. Kratom users chew the leaves to relieve musculoskeletal pain, increase energy, stimulate appetite and as an aphrodisiac. Some Kratom users chew leaves while working to enhance energy and alertness. In these ways, Kratom leaves are used similarly to the way khat and coca leaves are used by cultures that have access to coca leaf or khat plants. Kratom leaves are also used topically on wounds/cuts to promote healing and numb pain.


The active constituent of Kratom is a chemical called mitragynine. At low doses, mitragynine has stimulant effects and at higher doses it has opioid effects and stimulant effects are more pronounced. It is active at the mu opiate receptor, the same receptor that common opioids including oxycodone, heroin, fentanyl or even buprenorphine act at, which causes their primary effect. Mitragynine also activates the delta opioid receptor and it has effects on serotonin receptors among other actions. Mitragynine also activates the alpha-2 receptor, similar to clonidine or the anesthetic dexmedetomidine, although it seems to also counteract this receptor, like yohimbine, so that a mixture of excitation and sedation occur depending on the dose and other actions (Prozialeck WC, et al).


Kratom can be chewed as in the leaves are chewed and saliva swallowed. The leaves can also be crushed and turned into a powder which is then encapsulated. Kratom is also consumed as a tea, often with a sweetener added. While Kratom is not scheduled in the United States it has been under review by the DEA and other regulatory agencies. In fact it was nearly emergently listed as a schedule I drug in 2016 but at the last hour the decision was stayed pending further review. In some of the countries where Kratom is used indigenously it is scheduled (e.g. Thailand and Malaysia among others).


Kratom has become increasingly popular in the United States and is sold as a natural stimulant and opioid to help treat pain or even help detoxify oneself from other opioids, including buprenorphine or heroin. While generally available since around 2010, it's general popularity in the United States has increased and, as popularity has increased, so have reports of toxic effects from exposures to Kratom. The United States Poison Control Center National Poison Data System (NPDS) serves as a catalogue of calls to Poison Centers in the United States. In a review by Post S, et al detailing NPDS exposures from 2011 to 2017 toxic exposures were described (Post S, et al). These included 1807 exposures with numbers increasing year on year. In fact, over 65% of the exposures during this 8 year period were from 2016-17 and overall during the study period, use increased 52-fold from 2011 to 2017. Most Kratom calls to Poison centers involved adults > 20 years of age (89%) and the majority were for males (71%). There were 11 deaths associated with Kratom exposure, however, most of these also involved other substances. In 2 of the individuals that died, Kratom leaves or products were the only drug reported. Common symptoms from Kratom intoxication include, agitation and irritability (21%) and tachycardia (20%). When combined with other sedating drugs, Kratom caused CNS depression, and in some cases, even respiratory depression. Kratom does not show up on standard drug screens as an opiate or other substance, but it can be detected using specific assays typically only available through reference labs as ‘send outs’. In this case, the tests are looking for the active chemical mitragynine and/or a metabolite of mitragynine.

The patient reports that he has been using about 7 grams of Kratom in pill/capsule form since coming out of detox. He reports withdrawal similar to opioids…

The effects from Kratom typically start quickly after ingestion (e.g. 10-15 minutes) and they are fairly short-lived with most effects dissipating within 1-2 hours. While potency varies and some products sold commercially are advertised as, “concentrates” or “extracts" low doses, where a user has more stimulant effects, are in the 1 to 5 gram range and opioid effects occur more so when higher doses are taken typically in the 5 to 15 grams range. At higher doses, some of the stimulant effects, such as tachycardia and tremor, also occur with greater frequency.


Continuous use of Kratom over several days to weeks can cause tolerance to occur and ultimately an individual can become dependent on Kratom, so that with cessation, withdrawal occurs. When someone who is dependent upon Kratom abruptly stops taking it, they can experience withdrawal symptoms. Kratom withdrawal occurs typically within 12 to 18 hours after last use. The signs and symptoms of withdrawal from Kratom include things such as: mydriasis, nausea, sweats/chills, muscle and bone aches, tremors and twitches, diarrhea, rhinorrhea, congestion, insomnia, irritability and anxiety–typical opioid withdrawal symptoms.


The patients states that every time he tries to cut down on using Kratom he has terrible insomnia and anxiety and can’t keep anything in his stomach –much less feel like eating.


Kratom withdrawal includes typical opioid-like withdrawal symptoms, although it is not perfect –remember there are other opioid and non-opioid receptors involved. Management of withdrawal is typically done using supportive medications such as Clonidine and the antihistamine Hydroxyzine or Diphenhydramine. Kratom dependence can also be treated with an opioid agonist. Buprenorphine has been used for Kratom withdrawal. I’ve treated several patients both acutely in the ED and hospital setting and in the outpatient clinic with Buprenorphine, with good effect. I typically add Clonidine and Hydroxyzine, as needed, for the first 1-2 weeks after starting Buprenorphine, with most frequent and higher doses of Hydroxyzine and clonidine during the induction phase in between the last Kratom use and initiation of Buprenorphine. Clonidine is particular effective, as Mitragynine has effects similar to other drugs which are classified as Imidazolines, a class which Clonidine falls under. Essentially, some of the withdrawal symptoms can be also taken away with Clonidine. While there are reports of Buprenorphine being used to treat Kratom dependence and withdrawal, there are also reports of the opposite, the use of Kratom to ‘detox’ from Buprenorphine or other opioids. I’ve spoken to individuals who’ve struggled with their use of Kratom and were looking to stop using it, very frustrated with the cost, the dependence and withdrawal. I’ve also spoken to individuals that use Kratom to treat chronic pain or opioid dependence and withdrawal and feel less restricted taking it as a tea several times a day compared to taking a prescribed medication like Buprenorphine. Some Kratom users also appreciate the ability to use it outside of a prescription, without need for insurance and at their own discretion.


One of the problems associated with Kratom use is the lack of standardization in products and the lack of any consistent way to ensure that Kratom products are free from contamination or other drug and chemical adulteration. This has led to several recent outbreaks of illness in Kratom users. From October, 2017 to February, 2018 in the United States there was a multi-state outbreak of 28 people in 20 different states who were infected with Salmonella after consuming Kratom pills, powder or tea and other unidentified sources of Kratom (CDC). The FDA has also reported adulteration of some products with heavy metals, and Kratom has been associated with liver injury in some cases. The most common type of injury is called Cholestatic Jaundice although it is not clear if this occurs with Kratom, from an adulterant, or from some other reason (Patano F, et al). There have also been fatal overdoses and other types of toxicity from Kratom that had been adulterated with other drugs and chemicals. In Sweden in 2010-2011, there were several fatal overdoses associated with the use of a particular brand of Kratom sold as “Krypton Kratom.” This product contained a synthetic opioid called O-Desmethyltramadol, which had been added to the Kratom in order to make it stronger. The users that died simply overdosed, similar to a heroin or Fentanyl overdose, and they died from respiratory failure (Rosenbaum CD, et al). While this was a limited outbreak occurring in 2010-11 in Sweden it illustrates some of the problems associated with Kratom use and availability including adulteration by other substances.


The patient met with the addiction provider, who assessed him to have mild opioid withdrawal. He was seen about 28 hours after last use of a tea he’d made with his last bunch of Kratom capsules. The patient was given a prescription for Clonidine and for 2/0.5 mg films of Buprenorphine/Naloxone and an observed induction was completed. The 2/0.5 mg dose of Buprenorphine/Naloxone completely took away all of the withdrawal symptoms and he was continued on 2/0.5 mg films of Buprenorphine/Naloxone 2 x daily and Clonidine 0.1 mg PO QID with instructions to taper over 2-3 weeks by 0.1 mg every 5-7 days. The patient was maintained on Buprenorphine/Naloxone for 6 months and then moved out of state and was linked to another treatment provider. He was very happy having switched to Buprenorphine stating he didn’t have to spend the money and in general he felt better, “no ups and downs the ‘Subs’ last much longer…”


Medical Director’s Kratom PEARLS:

Kratom contains chemicals that activate opioid receptors. It is used to treat pain, as an opioid substitute recreationally for the ‘high’, to treat opioid withdrawal, and to occasionally substitute for Buprenorphine or methadone. Mitragynine is the active chemical in Kratom at low doses it has stimulant effects and at higher doses it has opioid effects (although some stimulant effects are also observed –tachycardia and tremor).Kratom is not detected as an opioid on drug tests although there are send out tests from reference labs that can be used to detect Kratom (Ask your Toxicologist if you have a drug testing question!)Persistent Kratom use can cause dependence and withdrawal when users abruptly stop after prolonged use.Kratom products have been adulterated with other drugs –Kratom users run the risk of exposure to other substances, chemicals, drugs and there have been outbreaks of Salmonella associated with Kratom use. Kratom has been associated with a certain type of liver injury (although this is not common). Kratom withdrawal can be treated with Buprenorphine (often Clonidine is also added) if you have a patient dependent on Kratom consider referral to your MAT clinic or at least review the case with your Medical Director or other providers.


Dr. Wiegand is the Medical Director at Huther Doyle and is the Director of Toxicology at Strong Memorial Hospital.


If questions about Kratom or other toxicology/addiction products Timothy J. Wiegand, MD, FACMT, FAACT, DFASAM can be reached at either of the following email address: timothy_wiegand@urmc.rochester.edu or Twtoxmd@gmail.com and follow him on Twitter at: TWtoxMD


References:

1.) Post, Sara; Spiller, Henry A.; Chounthirath, Thitphalak; Smith, Gary A. (20 February 2019). "Kratom exposures reported to United States poison control centers: 2011–2017". Clinical Toxicology: 1–8. PMID: 30786220.

2.) Rosenbaum CD, Carreiro SP, Babu KM (2012). "Here today, gone tomorrow…and back again? A review of herbal marijuana alternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines". Journal of Medical Toxicology. 8 (1): 15–32. PMID: 22271566.

3.) Pantano, F; Tittarelli, R; Mannocchi, G; Zaami, S; Ricci, S; Giorgetti, R; Terranova, D; Busardò, FP; Marinelli, E (16 April 2016). "Hepatotoxicity Induced by "the 3Ks": Kava, Kratom and Khat". International Journal of Molecular Sciences. 17 (4): 580. PMID: 27092496.

4.) https://www.cdc.gov/salmonella/kratom-02-18/index.html

5.) Buresh M. Treatment of Kratom Dependence With Buprenorphine-Naloxone Maintenance. Journal of Addiction Medicine. 2018 Nov/Dec; 12(6): 481-483. PMID: 29944481.


Upcoming….

Next month blog will focus on the use of buprenorphine in the Emergency Department and Hospital setting!

See this commentary https://link.springer.com/article/10.1007%2Fs13181-019-00718-x

co-authored by Dr. Wiegand and published in this month’s Journal of Medical Toxicology: A New Way Forward in the Emergency Department (Schwarz E, Laes JR, Wiegand TJ. A New Way Forward in the Emergency Department. Journal of Medical Toxicology published online 5, July 2019).

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