Kratom and Future Treatment for the Opioid Addiction and Chronic Pain: Periculo Beneficium?

Abstract

Kratom (Mitragynaspeciosa), a natural existing plant found in South-East Asia, is tradi-tionally used as an herb to help to elevate a person's energy and also to treat numerous medical ailments. Other than the analgesic property, kratom has been used as an agent to overcome opioid withdrawal as it contains natural alkaloids, i.e. mitragynine, 7-hydroxymitragynine, and MGM-9, which has agonist affinity on the opioid receptors, including mu (μ) and kappa (κ). The role of neural reward pathway linked to μ-opioid receptors and both dopaminergic and GABA-ergic interneurons that express μ-opioid receptors were deliberated. However, kratom has been reported to be abused together with other illicit substances with high risk of potential addiction. There are also anecdotes of an adverse effect and toxicity of kratom, i.e. tremor, fatigue, seizure, and death. Different countries have distinctive regulation and policy on the plantation and use of this plant when most of the countries banned the use of it because of its addiction problems and side effects. The aim of this review is to highlight on the potential use of kratom, a unique 'herbs" as a substitution therapy for chronic pain and opioid addiction, based on the neurobiological perspective of pain and the underlying mechanism of actions of drug addiction.

Acute mitragynine administration suppresses cortical oscillatory power and systems theta coherence in rats

“…However, negative effects of kratom have also been documented including a druginduced 'high' (Kruegel and Grundmann, 2018), adverse effects on cognition (Apryani et al, 2010;Senik et al, 2012;Yusoff et al, 2016) and addiction risk (Negus and Freeman, 2018;Yusoff et al, 2016Yusoff et al, , 2017. The diverse effects of the plant are potentially derived, at least in part, from the pharmacological properties of two of the active alkaloids, mitragynine and 7-HMG, that have been shown to exhibit agonism at the MOR and delta opioid receptors (Ismail et al, 2019;Prozialeck et al, 2012), alpha2adrenergic receptors (Matsumoto et al, 1997;Prozialeck et al, 2012), as well as antagonism at serotonin 5HT2A receptors (Matsumoto et al, 1997;Prozialeck et al, 2012).…”

“…This activity is commonly attributed to the major alkaloid present in kratom, mitragynine, as well as its derivative 7-hydroxymitragynine (7-HMG) (Idayu et al, 2011; Kruegel et al, 2019). Although both alkaloids have been shown to act via the opioid receptors, with the greatest binding affinity for the mu opioid receptor (MOR) subtype, they are considered to be ‘atypical opioids’ due to the fact that their agonism of the MOR is β-arrestin sparing (Ismail et al, 2019; Kruegel et al, 2016; Takayama et al, 2002). G-protein coupled receptor activation of β-arrestin has been linked to morphine tolerance and respiratory depression (Bohn et al, 2000; Varadi et al, 2016), making mitragynine a promising alternative as it may induce analgesia and antinociception without bringing forth the accompanying adverse and potentially life-threatening effects that result with classical opioid use (Varadi et al, 2016).…”

Case Report: Treatment of Kratom Use Disorder With a Classical Tricyclic Antidepressant

“…Kratom may be used according to users' taste and adjusted according to the desired effects, with low doses producing stimulant and activating effects and high doses sedative and tranquilizing effects (65)(66)(67), although these dose-related effects were not confirmed in a recent study and was unrelated to the amount and duration of kratom use (68). Many people, especially in South-East Asia, get to use kratom after being addicted to opioids and in the attempt to quit; others are prompted to use kratom due to its anxiolytic and mood enhancing effects (69)(70)(71). It is expected that upon discontinuing, rebound mood and anxiety symptoms emerge.…”

The Antidepressant-Like and Analgesic Effects of Kratom Alkaloids are accompanied by Changes in Low Frequency Oscillations but not ΔFosB Accumulation

“…Mitragyna speciosa , commonly referred to as kratom, is a tree species that is native to Southeast Asia and it has been used by individuals for centuries both recreationally and medicinally to improve mood and manage acute and chronic pain ( Singh et al, 2016 ; Ismail et al, 2019 ). However, the increase of kratom sales across Europe and North America have resulted in growing concerns over its safety, with several European countries and states within the United States banning the plant or instituting age restrictions in its use ( Cinosi et al, 2015 ).…”

“…The alkaloid profile observed within kratom is dominated by the class of compounds known as the monoterpenoid indole alkaloids, of which mitragynine and 7-HMG are the most studied examples. Both alkaloids have been found to activate the mu-opioid receptor (MOR), however unlike many other MOR agonists, they are ß-arrestin sparing ( Kruegel et al, 2016 ; Ismail et al, 2019 ). For this reason these alkaloids have been termed “atypical opioids” ( Adkins et al, 2011 ; Kruegel et al, 2019 ), and as ß-arrestin signaling has been shown to mediate opioid-induced tolerance and side effects such as respiratory depression, it is believed that kratom may offer an analgesic alternative ( Takayama et al, 2002 ; Kruegel et al, 2016 ; Ismail et al, 2019 ).…”