What data exists on the use of buprenorphine and buprenorphine-naloxone for the treatment of kratom withdrawal?
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Background
Kratom (Mitragyna speciosa) is a tree indigenous to Southeast Asia and refers to products derived from its leaves.1,2 The products are marketed as herbal supplements and available in various forms, such as powder, capsules, tablets, extract, or teas. Historically, in Southeast Asian cultures, kratom has been used as a natural remedy to relieve pain, manage fatigue, and enhance mood.2,3 In recent years, kratom has gained popularity in the United States (US) as individuals have been using it to self-manage opioid withdrawals and as a recreational drug.2-4
Kratom’s leaves contain several bioactive alkaloids, with the 2 most well-studied being mitragynine and 7-hydroxymitragynine.1,2 Mitragynine acts as a partial agonist at the mu-opioid receptors, producing opioid-like analgesic effects. Additionally, some research suggests that mitragynine also binds to adrenergic, serotonin, and dopamine receptors, which may lead to the reported arousing effects experienced.2 Similarly, 7-hydroxymitragynine acts as an agonist at the mu-opioid receptor.1,2 It is believed that 7-hydroxymitragynine is up to 10 times more potent than morphine. Other compounds in kratom have been identified in animal models for anti-depressant and pain-relieving effects.2 Based on anecdotal evidence, it is theorized that kratom’s effects are dose-dependent, with lower doses (<5 grams) associated with stimulant properties, and higher doses (5 to 15 grams) associated with opioid- or sedative-like effects, although studies have not established dose-dependent effects.1-3
There have been reports of serious adverse events associated with kratom use, including hallucinations, delusions, seizures, high blood pressure, respiratory depression, vomiting, hepatotoxicity, and even death.1-3 Chronic kratom users have also reported severe withdrawal symptoms and cravings upon discontinuation, suggesting the possibility of kratom dependence.1,2,4 To date, kratom is not US Food and Drug Administration (FDA)-approved for any medical use, but is also not a scheduled substance under the Controlled Substances Act.1,2,4 Kratom has been categorized as a ‘drug of concern’ by the US Drug Enforcement Administration and the FDA has issued multiple warnings advising against its use due to significant safety risks and risk of product contamination.1-4
Currently, there is no consensus on appropriate treatment for kratom withdrawal, although buprenorphine, buprenorphine-naloxone, naltrexone, clonidine, and methadone have been described in case reports.5-14 Based on a comprehensive literature search conducted in June 2023, buprenorphine and buprenorphine-naloxone appear to have the most literature and case reports in the treatment of kratom withdrawal. The purpose of this article is to describe the literature available on the use of buprenorphine or buprenorphine-naloxone in the treatment of kratom withdrawal.
Kratom withdrawal
The mechanism of kratom dependence is thought to be similar to opioid dependence and attributed to kratom’s compounds interacting with opioid receptors.2,5 Similarly, kratom intake can lead to euphoric effects and increased energy and concentration, creating positive reinforcement and leading to chronic use, followed by dependence. Attempts to abstain from kratom after chronic use may lead to severe withdrawal symptoms and cravings. Physical symptoms observed with kratom withdrawal may include nausea, chills, gastrointestinal discomfort, rhinorrhea, insomnia, and body aches accompanied by psychological symptoms, such as anxiety, restlessness, depression, and irritability.5 Much of the literature that exists on kratom dependence and withdrawal acknowledge that withdrawal symptoms are generally more prevalent when higher doses in more frequent amounts are consumed.5,6 Consensus of the available data suggests kratom withdrawal severity is generally milder compared to opioid withdrawal, although variability in self-reported symptoms is high. Due to the mechanisms of kratom’s alkaloids, it is thought that kratom withdrawal management may be similar to opioid withdrawal management.
Buprenorphine and buprenorphine-naloxone
Buprenorphine and buprenorphine-naloxone, both of which are FDA-approved for opioid use disorder and dependence, have been used off-label for kratom withdrawal.3,5,6 It is hypothesized that these agents can effectively treat kratom withdrawal and dependence by alleviating withdrawal symptoms and reducing cravings. Buprenorphine, a high-affinity partial mu-opioid receptor agonist, is thought to prevent kratom alkaloids mitragynine and 7-hydroxymitragynine from binding to opioid receptors. Buprenorphine produces opioid-like effects when bound to these receptors, contributing to alleviation of withdrawal symptoms. Buprenorphine can be used alone or in combination with naloxone. The addition of naloxone, an opioid receptor antagonist, to buprenorphine serves as a deterrent against intravenous misuse of opioids or opioid-like substances, such as kratom. Several case reports have described potential efficacy of these agents in kratom withdrawal management, including symptom relief.5-12
Guidelines
Currently, there are no published guidelines for the treatment of kratom withdrawal. However, a US-based scientific expert forum published a commentary with their opinion on treatment of kratom withdrawal based on available data.6 The experts advised caution in using opioids, such as methadone and buprenorphine, as first-line treatment for individuals experiencing kratom withdrawal. These opioids should only be used on a case-by-case basis, especially for individuals with no prior history of opioid use, as their use may lead to opioid tolerance, physical dependence, and an opioid use disorder.
Literature summary
No clinical trials have specifically investigated the use of buprenorphine or buprenorphine-naloxone for the treatment of kratom withdrawal. However, multiple case reports have described successful treatment outcomes with these agents, as summarized in Table 1.7-12 All of the patients described in case reports had comorbid chronic pain or psychiatric conditions and many of them were on additional prescribed and/or illicit substances besides kratom. Based on the reviewed cases, initiating buprenorphine-naloxone as a treatment for kratom withdrawal appears to be a viable option in patients with a past medical history of opioid use disorder or chronic opioid use, regardless of the duration and amount of kratom used. Based on the case series presented by Lei and colleagues, the authors suggested that kratom withdrawal may persist for a longer duration after last kratom use (up to 3 months after discontinuation) compared to typical opioid withdrawal (about 1 week).8 They also suggested that increasing and divided buprenorphine-naloxone dosing may be beneficial in cases of prolonged kratom withdrawal.
In the case series conducted by Weiss and colleagues, authors found a strong correlation between increased kratom dose at presentation and a higher requirement of buprenorphine-naloxone for the initiation dose.9 They proposed that patients using less than 20 g kratom daily could be initiated on buprenorphine-naloxone doses of 4/1 mg to 8/2 mg daily, while those using doses greater than 40 g kratom per day could be initiated with 12/3 mg to 16/4 mg buprenorphine-naloxone per day. This dosing strategy seemed to be consistent with effective doses of buprenorphine-naloxone that were reported in other case reports.
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| Table 1. Case reports of buprenorphine and buprenorphine-naloxone for kratom withdrawal7-12 | ||||
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| Author | Patient description | Kratom use and reported withdrawal symptoms | Buprenorphine or buprenorphine-naloxone dose for kratom withdrawal | Outcomes |
| Hong et al 20237 | 65-year-old male with OUD admitted with chest pain and subsequently diagnosed with stage IV NSCLC | Reported use up to 30 to 40 g kratom daily for unknown duration to alleviate cancer-associated pain 24 to 36 hours after admission: patient experienced myalgias, arthralgia, and restlessness with a COWS score ranging from 7 to 9 | Initially received 5 to 10 mg of oxycodone as needed; however, patient was reluctant to use oxycodone due to his OUD history. Initiated on sublingual buprenorphine–naloxone 2/0.5 mg every 6 hrs; titrated to 4/1 mg every 8 hrs as needed and increased to every 6 hrs for symptom control. | Buprenorphine–naloxone 4/1 mg every 6 hrs managed symptoms of kratom withdrawal and cancer-associated pain for up to 3 months. |
| Lei et al 20218 Patient #1 | 62-year-old male with OUD, cannabis dependence, tobacco use disorder, and chronic pain Desire to quit kratom was due to monthly vomiting episodes lasting 4 to 5 days | Reported use of up to 2.5 to 3 Tbsp (unknown concentration) of kratom daily for unknown duration to manage chronic pain. Abstinence from kratom led to reported diaphoresis and tremors; last kratom use was 7.5 hrs prior to buprenorphine/naloxone induction appointment. Presented with a COWS score of 6 | Initiated on buprenorphine–naloxone 2/0.5 mg; reduced COWS score to 4 within 30 mins; received additional dose of 2/0.5 mg the same day Patient was titrated to increasing doses for withdrawal symptoms until day 67, when patient was stable on 4/1 mg in morning, 4/1 mg in afternoon, and 2/0.5 mg in evening Throughout treatment, patient continued to use cannabis for anxiety, pain, and insomnia | UDS of mitragynine and 7-HMG decreased 24 days after last reported kratom use; undetectable after 66 days |
| Lei et al 20218 Patient #2 | 54-year-old male with OUD and alcohol dependence | Reported total daily dose of 1000 mg kratom capsules for pain management After 5 days off kratom, experienced muscle aches, pain, headaches, nausea, and stomach cramps | Initiated on buprenorphine–naloxone 2/0.5 mg once daily for 5 days via home induction. Throughout treatment, patient reported using kratom, illicit opioids, BZD, zolpidem, and tramadol. Uptitrated regularly until 5 months of treatment, was stabilized on buprenorphine-naloxone 8/2 mg in morning, 4/1 in afternoon, and 4/1 mg at night, and reported not using kratom or any illicit substances. | UDS and BZD tests were negative for illicit substances throughout treatment, despite reports of continuation |
| Lei et al 20218 Patient #3 | 59-year-old female with knee pain, OUD, hypnotic/anxiolytic dependence, cannabis dependence, and tobacco use | Reported use of 16 g kratom daily for an unknown duration to manage opioid withdrawal symptoms, then increased to 30 g daily for withdrawal symptoms and pain Continued withdrawal symptoms included myalgia, paresthesia, and nausea, with intense cravings | Initiated on buprenorphine–naloxone 2/0.5 mg at least 12 hrs after last kratom dose, followed by an additional 2 mg every 2 hrs to control withdrawal symptoms as needed (max 8 mg buprenorphine in the first 24 hrs) Titrated to 8/2 mg, followed by 2/0.5 mg every 2 hrs as needed (max total daily dose of 12/3mg) for 2 weeks Increased to 8/2 mg twice daily (total 16/4 mg daily) and was stable for 1 month before losing supply of buprenorphine-naloxone and subsequently relapsing Buprenorphine-naloxone was re-induced and increased to 8/2 mg 3 times daily, which was stable for 3 months, but patient reported intermittent opioid use | 6 months after last reported use of kratom, UDS was positive for mitragynine and 7-HMG |
| Weiss et al 20219 Case series | 36-year-old male with OCD, alcohol dependence, prior opioid use, anxiety, and depression | Reported initial use of 20 g of kratom daily for 1 year; self-tapered to 4 g of kratom daily Withdrawal symptoms began during self-tapering of kratom | Initiated on buprenorphine–naloxone 4/1 mg daily with the goal to discontinue therapy via slow taper. Stable on 1.25/0.312 mg buprenorphine-naloxone. Withdrawal symptoms reported with 0.5 to 0.75 mg of buprenorphine daily | Authors found a strong correlation between increased kratom dose at presentation and higher buprenorphine-naloxone initiation dose; they proposed that patients using less than 20 g kratom daily could be initiated on buprenorphine-naloxone doses of 4/1 mg to 8/2 mg daily, while those using doses greater than 40 g kratom per day could be initiated with 12/3 mg to 16/4 mg buprenorphine-naloxone per day. |
| Weiss et al 20219 Case series | 37-year-old male with anxiety, depression, and OUD | Reported use of 7 to 14 g of kratom for 6 months to self-treat heroin OUD | Initiated on buprenorphine–naloxone 8/2 mg daily with the goal to discontinue therapy via slow taper. Reports ongoing cravings for heroin and marijuana. |
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| Weiss et al 20219 Case series | 42-year-old female with chronic pain, anxiety, and depression | Reported variable amount of kratom use while simultaneously taking buprenorphine-naloxone 12/3 mg and opioids Unreported withdrawal symptoms | Buprenorphine-naloxone dose was increased to 8/2 mg twice daily; patient was stabilized for at least 4 months with no further kratom use |
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| Weiss et al 20219 Case series | 24-year-old male with autism spectrum disorder and depression with suicidal ideation | Reported 600 mg kratom daily for unknown duration | Initiated buprenorphine 2 mg daily and increased to 4 mg twice daily; switched to buprenorphine-naloxone 2/0.51 mg 3 times daily (total daily dose 6/1.5 mg) and tapered off after 45 days |
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| Weiss et al 20219 Case series | 35-year-old male with anxiety and illicit drug use | Reported 30 g kratom daily for 3 years, then self-tapered to 5 g daily Withdrawal symptoms occurred when attempting to decrease kratom dose below 5 grams | Initiated buprenorphine-naloxone 4/1 mg twice daily, which was titrated to total daily dose of 12/3 mg. Due to patient feeling too sedated, dose was adjusted to 3/0.75 mg twice daily |
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| Weiss et al 20219 Case series | 20-year-old male with ADHD | Reported use of up to 30 g kratom daily for 2 months to manage anxiety and insomnia; self-tapered to 10 to 15 g daily | Initiated buprenorphine-naloxone 4/1 mg once daily; now stable on 3/0.75 mg daily |
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| Bowe et al 202010 | Male age, late 40-years with anxiety, depression, degenerative disc disease, osteomyelitis, chronic back pain, and OUD | Reported initially mixing 2 heaping tsp of powdered kratom (concentration unknown) in water 3 to 4 times per day for 6 months, but escalated to use every 2 hrs, which included waking throughout the night to use Withdrawal symptoms included abdominal cramping, sweating, psychomotor agitation, rhinorrhea, mood disturbances, increased anxiety and depression, and intensifying body pain | Initiated buprenorphine–naloxone 8/2 mg once daily, which provided adequate pain relief, but withdrawal symptoms persisted. Due to persistent withdrawal symptoms, patient was titrated to 8/2 mg twice daily | Within 4 months of initiation of buprenorphine-naloxone, depressive symptoms resolved enough to discontinue duloxetine |
| Buresh 201811 Patient #1 | 60-year-old female with chronic pain managed with opioids and history of alcohol dependence was admitted to ICU due to unintentional overdose of kratom, methadone, oxycodone-acetaminophen, and tramadol | Reported use of 0.25 oz of kratom every 4 hrs for chronic pain in addition to prescribed tramadol Withdrawal symptoms included rhinorrhea, irritability, and increased pain | Initiated on buprenorphine-naloxone 4/1 mg 17 hours after last kratom and tramadol use; dose was titrated and stabilized at 4/1 mg 4 times daily, which decreased pain and withdrawal symptoms | Throughout the 9-month follow-up period, patient was adequately managing pain, achieving functional goals, and able to decrease her pregabalin dose |
| Buresh 201811 Patient #2 | 57-year-old male with chronic pain, anxiety, depression, and OUD | Ongoing and increasing kratom use (concentration or dose unknown) over 1 year Withdrawal symptoms included anxiety, edginess, and leg shaking | Initiated sublingual buprenorphine–naloxone 8/2 mg via home induction 14 hours after last kratom use, which relieved withdrawal symptoms and chronic pain Buprenorphine dose was increased to 6 mg 4 times daily to manage pain. | Patient remained stable on buprenorphine-naloxone for at least 7 months and UDS remained negative for other opiates or kratom metabolites |
| Khazeli et al 201812 | 52-year-old female with depression, chronic pain, and OUD | Up to 1 Tbsp of powdered kratom (concentration unknown) 4 to 6 times per day for 9 months to mitigate chronic pain Withdrawal symptoms included rhinorrhea, diarrhea, upset stomach, anxiety, restless legs, and increased pain | Initiated buprenorphine-naloxone 4/1 mg every 2 hrs (max of 16/4 mg daily) Decreased regimen of 2/0.5 mg 4 times daily eventually became ineffective and was adjusted to 8/2 mg twice daily (max of 16/4 mg daily), where patient reported no additional withdrawal symptoms or cravings for 18 months post-discharge | 48 days after last kratom use, UDS was positive for kratom metabolites, mitragynine and 7-HMG; 2 months later, the UDS was negative. |
| Abbreviations: 7-HMG, 7-hydroxymitragynine; ADHD, attention deficit hyperactivity disorder; BZD, benzodiazepine; COWS, Clinical Opiate Withdrawal Scale; ICU, intensive care unit; NSCLC, non-small cell lung cancer; OCD, obsessive compulsive disorder; OUD, opioid use disorder; UDS, urine drug screen. |
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Conclusion
Due to the increasing popularity of kratom across the US, effective treatment options for kratom dependence and withdrawal are crucial. The mechanism of kratom dependence is thought to be similar to opioid dependence and attributed to kratom’s compounds interacting with opioid receptors. Consensus of the available data suggests kratom withdrawal severity is generally milder compared to opioid withdrawal, although management may be similar. The use of buprenorphine, buprenorphine-naloxone, naltrexone, clonidine, and methadone have been described in case reports for the treatment of kratom withdrawal, with buprenorphine or buprenorphine-naloxone being described for treatment most frequently in identified reports. A US-based scientific expert forum advised caution in using opioids, such as methadone and buprenorphine, as first-line treatment for individuals experiencing kratom withdrawal. They recommend these should only be used on a case-by-case basis, especially for individuals with no prior history of opioid use, as their use may lead to opioid tolerance, physical dependence, and an opioid use disorder. All of the patients described in case reports within this article had comorbid chronic pain or psychiatric conditions and many of them were on additional prescribed and/or illicit substances besides kratom. Based on the reviewed cases, initiating buprenorphine-naloxone as a treatment for kratom withdrawal appears to be a viable option in patients with a past medical history of opioid use disorder or chronic opioid use, regardless of the duration and amount of kratom used. However, clinical trials are needed to confirm any theorized efficacy and safety of treatment options in kratom withdrawal.
References
- NatMed Pro. Therapeutic Research Center. 2023. Accessed June 1, 2023. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=1513
- Kratom. National Institute on Drug Abuse. Published March 25, 2022. Accessed June 10, 2023. https://www.drugabuse.gov/publications/drugfacts/kratom
- Micromedex. Merative. 2023. Accessed June 1, 2023. https://www.micromedexsolutions.com/micromedex2/librarian/
- Kratom (Mitragyna speciosa korth). Drug Enforcement Administration. Published March 2023. Accessed June 10, 2023. https://www.deadiversion.usdoj.gov/drug_chem_info/kratom.pdf
- Bin Abdullah MFIL. Kratom dependence and treatment options: a comprehensive review of the literature.Curr Drug Targets. 2020;21(15):1566-1579. doi: 10.2174/1389450121666200719011653
- Henningfield JE, Chawarski MC, Garcia-Romeu A, et al. Kratom withdrawal: discussions and conclusions of a scientific expert forum. Drug Alcohol Depend Rep. 2023;7:100142. doi: 10.1016/j.dadr.2023.100142
- Hong S, Zimmerman PE, Rao V, Markwalter DW. Buprenorphine–naloxone in the setting of kratom withdrawal, opioid use disorder, and stage IV lung adenocarcinoma. J Palliat Med. 2023;26(5):734-736. doi: 10.1089/jpm.2022.0491
- Lei, J, Butz A, Valentino, N. Management of kratom dependence with buprenorphine/naloxone in a veteran population. Abus. 2021;42(4):e497-e502. doi: 10.1080/08897077.2021.1878086
- Weiss ST, Douglas HE. Treatment of kratom withdrawal and dependence with buprenorphine/naloxone: a case series and systematic literature review.J Addict Med. 2021;15(2):167-172. doi:10.1097/ADM.0000000000000721
- Bowe A, Kerr PL. A complex case of kratom dependence, depression, and chronic pain in opioid use disorder: effects of buprenorphine in clinical management. J Psychoactive Drugs. 2020;52(5):447-452. doi: 10.1080/02791072.2020.1773586
- Buresh M. Treatment of kratom dependence with buprenorphine-naloxone maintenance.J Addict Med. 2018;12(6):481-483. doi:10.1097/ADM.0000000000000428
- Khazaeli A, Jerry JM, Vazirian M. Treatment of kratom withdrawal and addiction with buprenorphine. J Addict Med. 2018;12(6):493-495. doi: 10.1097/ADM.0000000000000435
- Galbis-Reig D. A case report of kratom addiction and withdrawal. 2016;115(1):49-52.
- Jensen AN, Truong QN, Jameson M, Nadal CN. Kratom-induced transaminitis with subsequent precipitated opioid withdrawal following naltrexone. Ment Health Clin. 2021;11(3):220-224. doi:10.9740/mhc.2021.05.220
Prepared by:
Celeste Guzman
PharmD Candidate Class of 2024
University of Illinois at Chicago College of Pharmacy
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
August 2023
The information presented is current as June 1, 2023. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.