Abstract
Background: Opioid agonist therapy with buprenorphine is an effective, evidence-based treatment for opioid use disorder. However, there has been increasing use of alternative substances which can still produce opioid-like effects. One of these substances is the herbal supplement kratom. The chemical composition of kratom, specifically mitragynine and 7-hydroxymitragynine, has partial mu-opioid receptor agonist and antagonist effects at the kappa- and delta-opioid receptors. Due to its addictive potential, accessibility, and legal status, there have been increasing cases of kratom use disorder (KUD). Thus, it is important to consider effective treatment options for this nontraditional substance. Methods: Twenty-eight patients self-identified kratom as their primary substance of use. Length of kratom use ranged between 1 month and 25 years, with an average daily kratom dose of 92 g/d. Nine patients were inducted on a buprenorphine/naloxone dose between 1 and 6 mg, 18 patients between 8 and 16 mg, and 1 patient at 20 mg. Three patients were stabilized on a dose at 4 mg, 23 patients between 8 and 16 mg, 1 patient at 18 mg, and 1 patient at 20 mg. Results: There was no correlation between stabilizing dose of buprenorphine/naloxone and past daily dose of kratom. As of March 2020, 20 of the 28 patients were still receiving outpatient buprenorphine/naloxone treatment. Six patients were lost to follow-up due to missed appointments, 1 tapered down to 0.25 mg of buprenorphine/naloxone and self-discharged, and 1 moved out of town. The rest have remained in treatment from 5 to 22 months, with an average duration of 11 months. Of the 28 patients, 68%, 82%, and 82% had negative test results for mitragynine at 4, 8, and 12 weeks of treatment, respectively. Conclusions: To our knowledge, this is the largest case series exploring long-term buprenorphine/naloxone treatment for KUD. Our findings suggest buprenorphine/naloxone can be used as an effective treatment option for KUD.
Introduction
Opioid overdose mortality rates have increased within the past several years, accounting for 47,600 American deaths in 2017 alone. 1 However, opioid prescribing rates have been decreasing during this time due, in part, to implementation of prescribing guidelines and drug monitoring programs, contributing to increased use of nonprescription opioids. 2 One herbal supplement with increasing reports of exposure and use in the United States is kratom (Mitragyna speciosa). 3 From 2011 to 2017, the United States poison control centers reported a 52.5-fold increase in the annual number of reported kratom exposures. 4 Kratom is available in numerous forms (e.g., leaves, powder, pills) and is easily accessible online and in various shops. 5 The annual prevalence of kratom use disorder (KUD) in the United States is estimated to be 0.8%, with an estimated 1.3% lifetime use. 6 While the lifetime prevalence of KUD is relatively low, past-year usage for kratom in 2018 was higher than that of heroin, methamphetamine, and lysergic acid diethylamide (LSD). 6 While there has been debate regarding classifying kratom as a Schedule I substance, kratom currently remains unscheduled, due in part to debates from both sides. 7
Kratom is composed of a number of different compounds, but the ones of major significance are mitragynine and 7-hydroxymitragynine. Mitragynine has been shown to be a partial agonist at the mu-opioid receptors and a competitive antagonist at the kappa- and delta-opioid receptors. 7 , 8 Similarly, 7-hydroxymitragynine acts as an opioid receptor agonist and antagonist at the mu- and kappa-opioid receptors, respectively. 8 Other compounds in kratom have been identified to contribute to anti-inflammatory and anti-depressant effects, in addition to treating musculoskeletal pain. 9 The estimated half-life of kratom is approximately 23 hours. 10 However, there are conflicting reports of the half-life of mitragynine being as short as 3 hours. 11 It has been suggested that due to kratom's lipophilic nature, it could be stored in fatty tissue, thereby increasing the duration that kratom is present in the body. 12 It should be mentioned that most of these findings are based on animal models, as human pharmacokinetics of kratom have not yet been fully explored. 12
The effects of kratom are dose-dependent. When kratom is taken at doses below 5 g, there is a stimulatory effect (similar to coffee), thereby reducing fatigue. 10 Taking doses between 5 g and 15 g typically contributes to euphoria, reduced opioid-withdrawal symptoms, and effects similar to other opioids. 10 At doses higher than 15 g, kratom causes a sedative effect. 10 Those who use kratom regularly can become dependent and/or experience withdrawals, 13 as well as developing craving, tolerance, and cross-tolerance to morphine. 14 Individuals with regular kratom use may experience opioid-like withdrawals after discontinuation, including psychological and physical symptoms such as mood changes, irritability, restlessness, loss of appetite, yawning, itching, insomnia, runny nose, vomiting, diarrhea, muscle pain, and tremors. 13 , 14 Thus, treatment options for KUD may be similar to opioid use order treatment based on these shared features. 15
Both kratom and buprenorphine bind to mu-opioid receptors. As mentioned above, kratom is known to have opioid effects, which leads to dependence. There is ample evidence that buprenorphine is effective for opioid dependence. 12 , 15 – 17 If a patient is dependent on kratom, buprenorphine may reduce kratom withdrawals and cravings, similarly to how buprenorphine would reduce withdrawals and cravings for opioids.
There have been emerging case series regarding long-term treatment with buprenorphine, a partial opioid agonist, for KUD. While the use of buprenorphine for KUD is not novel, prior case series presented only a handful patients (sample sizes 1–8). 12 , 15 – 17 A case series of 3 patients explored how contingency management for buprenorphine treatment of KUD can provide better retention rates and outcomes, showcasing that various treatment forms for KUD are being explored. 18 A recent case series and systematic literature review article found that buprenorphine treatment dose seems to be correlated with dose of prior kratom use. 16 However, a limitation of this study included a sample size of 8 patients and the potential for confounding variables. 16 The most recent case study identified 1 patient who was successfully treated with buprenorphine-naloxone for kratom dependence, with significant improvement in withdrawal symptoms and pain relief, as well as anxiety and depression symptoms. 17 However, a significant limitation to the study was that they had no available lab test to determine whether the patient was using kratom during treatment. 17 Despite the limitations with sample sizes and lab technology in these case studies, it is evident that buprenorphine is a promising treatment for individuals experiencing kratom dependence.
In this largest case series to date, we present 28 patients who have received medication-assisted treatment with buprenorphine/naloxone (referred to as “buprenorphine” for the remainder of the case series) for KUD in an office-based setting. Since mitragynine is not detected on presumptive urine drug testing (UDT), urine samples were collected and analyzed via definitive testing, which utilizes liquid chromatography-mass spectrometry 5 to quantitatively detect mitragynine. The frequency of definitive UDT decreased as patients stabilized. UDT has been suggested to provide more objective data and potentially have the ability to impact clinical decisions. 19
Deidentified archival patient data in the electronic medical records (eClinicalWorks) were filtered to only include patients who identified kratom as their primary substance of use and were subsequently treated with buprenorphine. The target variables analyzed for each patient included past duration of use and average daily dose of kratom, buprenorphine induction dose, stabilizing buprenorphine dose, current buprenorphine dose, current outpatient appointment frequency, definitive UDT results, duration of ongoing treatment, and current treatment status.
This study underwent institutional review board evaluation by Washington State University. The Washington State University Human Research Protection Program determined that this case series was not engaged in human subject research as per federal definitions. The archival data used for analysis were all de-identified. As a result, written consent forms were not obtained from participants.
Review
There were 28 patients with diagnosed KUD (11 females and 17 males) who were included in the case series, with ages ranging from 24 to 53 years (average = 36 years). Patients were seen in various clinic locations: Alaska (Anchorage: 1); Washington (Arlington: 1, Bellingham: 1, Everett: 2, Kennewick: 1, Oak Harbor: 1, Olympia: 1, Portland/Vancouver: 12, Spokane: 1); Montana (Great Falls: 1, Helena: 1, Missoula: 3); and North Dakota (Bismarck: 1, Williston: 1). Patients reported past average daily dose of kratom between 0.06 g/d to more than 850 g/d, with an average daily dose of 92 g. The duration of kratom use ranged from 1 month to 25 years.
Buprenorphine, kratom, opioids, and various other substances were tested for in the definitive UDT. All patients performed a home induction with buprenorphine after their first appointment. Providers instructed the patients to wait 24 hours from their last kratom use before starting buprenorphine to prevent precipitated withdrawals. Patients were also advised to refrain from all benzodiazepines, alcohol, and sedatives while taking buprenorphine. All patients were given clear instructions on proper dosing method, so that they could get the most effective results (i.e., let the buprenorphine dissolve for at least 20 minutes under the tongue before swallowing or spitting saliva, and no eating, drinking, or smoking for another 20-30 minutes to allow the medication to fully absorb). Buprenorphine was to be taken daily in the morning.
Most of the patients were inducted on daily doses between 4 and 8 mg after their first appointment, with the majority of patients stabilizing on daily doses between 12 and 16 mg. Twenty-one patients had a second appointment 1 to 4 days after their first appointment, while the rest were seen 5 to 6 days after their first appointment. Fifteen patients reported significant relief from withdrawal symptoms and cravings at their second appointment. Seven patients continued to have moderate withdrawal symptoms and cravings at their second appointment and reported significant improvement once their dose was increased. Six patients reported mild, manageable withdrawal symptoms and cravings at their second appointment that went away after the kratom metabolized out of the system and suboxone built up in the system. It took 2 to 3 weeks for most patients to stabilize on a buprenorphine dose, as some continued to have mild to moderate withdrawal symptoms and cravings, requiring a higher stabilizing dose than their initial induction dose. Some patients stabilized sooner than others and either continued to take the same dose or reduced their dose. See Table 1 for detailed dosing. The Pearson correlation coefficient between stabilizing buprenorphine dose and past average daily dose of kratom was found to be 0.124; Table 2 briefly summarizes these findings. None of the patients self-reported precipitated withdrawal symptoms following the initiation of buprenorphine treatment.
Daily Buprenorphine Doses Throughout Treatment.
Buprenorphine induction dose = the very first dose the patient took at home after their first appointment.
Stabilizing buprenorphine dose = the daily dose on which the patient was stabilized (i.e., experienced no kratom withdrawal symptoms or cravings).
Last/current buprenorphine dose = the most recent daily dose prescribed to the patient.
Previous Daily Kratom Use and Daily Stabilizing Buprenorphine Dose Comparisons.
As of March 2020, 20 out of the 28 patients were still receiving outpatient buprenorphine treatment. Six patients were lost to follow-up due to missed appointments, 1 patient tapered down to 0.25 mg of buprenorphine and self-discharged, and 1 patient moved out of town. The patients who are still receiving buprenorphine treatment have remained in treatment from 5 to 22 months, with an average duration of 11 months.
UDT results demonstrated that 69% of the patients had negative results for opioids throughout the entire duration of treatment. Out of the 69% of the patients with negative findings for opioids, 78% are still in treatment. The definitive UDT results for mitragynine are summarized in Table 3. At the time of the first appointment, 93% of patients had positive test results for mitragynine. At 4 weeks, 8 weeks, and 12 weeks of treatment, 68%, 82%, and 82% of patients had negative results for mitragynine, respectively. Nine patients admitted to restarting kratom use during treatment (4 restarted kratom only within the first 6 weeks of treatment, while 5 restarted kratom occasionally throughout treatment). There was 1 patient who had positive test results for mitragynine during the first 6 weeks but denied any kratom use.
Mitragynine Urine Drug Test (UDT) Results.
Self-reported relapse only within the first 6 weeks of treatment.
Self-reported relapse occasionally throughout treatment.
Denial of any relapses despite positive UDT results for mitragynine in the first 6 weeks of treatment.
Conclusions
This case series suggests an advantageous clinical response in patients with KUD who were treated with buprenorphine. There was no significant correlation between past average daily dose of kratom use and stabilizing buprenorphine dose as supported by the Pearson correlation coefficient of 0.124. There were no cases of precipitated withdrawal symptoms when patients were started on partial agonist treatment with buprenorphine.
Given the conflicting reports on the half-life of kratom and its chemical compounds, we analyzed definitive UDT results after patients were in treatment for 4 weeks, despite having UDT results from earlier visits. At 4 weeks, 68% of patients had negative test results for mitragynine, which increased to 82% by 8 weeks of treatment.
There was a significant overall decrease in kratom use as treatment progressed, as evidenced by the decreasing percentage of positive UDT for mitragynine. Patients who restarted kratom use during treatment also self-reported using less kratom than they initially used before starting treatment. The higher percentage of positive definitive UDT results for mitragynine early in treatment could reflect residual detection of mitragynine in the urine, possibly due to the lipophilic nature of kratom. However, human pharmacokinetics of kratom needs to be further explored.
This case series suggests an advantageous clinical response in patients with KUD who are treated with buprenorphine. Treatment should be tailored to each individual to determine the appropriate buprenorphine dose. Similar to the case with treatment for other opioids, providers should proceed with caution as the potential for relapse and use of other substances is still a factor in the treatment of KUD with buprenorphine. Although this case series suggests that buprenorphine can be used as an effective treatment for kratom use disorder, further research with larger sample sizes is needed to build upon the dearth of literature available for determining the effectiveness of buprenorphine for the treatment of KUD.
Footnotes
Acknowledgements
No additional funds were granted to authors for their work on this manuscript.
Disclosure statement
Two of the authors (Viktoriya Broyan and Jeffrey Allgaier) are paid employees of Ideal Option, PLLC, which is the parent company of the outpatient clinics where patients in this case series were treated. No additional funds above base salaries were paid to these employees. One of the authors (Jessica Brar) received a summer research internship stipend from Ideal Option, PLLC. No potential conflict of interest was reported by the author(s).
Author contributions
Substance Abuse journal authorship criteria has been reviewed. All 4 authors meet authorship criteria. This case series is an original submission and has not been previously published. All of the authors listed have participated and contributed in the data analysis and writing of this manuscript.