Written by Giacomo Sandri
As chronic pain and addiction to painkillers are becoming an ever-growing issue, the exploration of potential alternative routes for managing chronic pain symptoms could be considered a necessity. The therapeutic use of kratom (Mitragyna speciosa) for the management of chronic pain as a substitute to opiates with reference to its pharmacodynamics, pharmacokinetics, dosage and safety will be presented in the following article.
Chronic pain: An overview
Pain is a normal neurological response to a real or impending injury aimed at triggering an appropriate conservational response. Chronic pain is defined as a pain that is perceived beyond the accepted time involved in tissue healing (approximately 3 months) (1). Interestingly, when pain receptors (called nociceptors) which respond to chemical, thermal or mechanical changes get stimulated over a large period of time, the brain neurons responsible for pain processing become over-sensitive, reducing the overall pain threshold of the individual. This process is called central sensitisation and plays a crucial part in the development of chronic pain conditions (2). Moreover, medical literature provides evidence of the complex multidimensionality of chronic pain conditions, meaning that the psychological, emotional, social and behavioural aspects of an individual’s life play a role in the dynamics related to pain perception (3). Chronic inflammation and chronic pain go hand in hand: a prolonged and abnormal inflammatory response mediated by the immune system can lead over time to an increased sensitisation of pain receptors (31). Nutritional deficiencies, excess consumption of pro-inflammatory foods, sedentary lifestyle, exposure to pollutants, gut flora imbalance and inappropriate exercise can all contribute to the process of inflammation and hence chronic pain (32, 33, 34, 35)
Additionally, when the survival mechanism of the body is abnormally activated, stress hormones such as adrenaline, noradrenaline and cortisol change the homeostasis of the tissues, leading to detrimental consequences, such as a decrease in pain tolerance and increase in tissue degeneration. Moreover, the cognitive part of the brain under the influence of stress hormones is less capable to detach the focus from the pain stimulus, meaning that the more stressed the individual is, the more physical pain becomes a burden in his/her life (30).
The burden of chronic pain
In terms of epidemiological data, The Global Burden of Disease Study 2016 stated that chronic pain-related diseases are the leading cause of disability and disease burden globally (4) ; In the UK only, a survey from 2017 reported that 34% of adults in the UK are affected by some forms of chronic pain (5). As chronic pain is a condition that has psychological, emotional and social aspects, disciplines specialised in addressing the different dimensions of pain perception management have become popular; therapies such as hypnosis, acupuncture, CBT and massage therapy (36). Despite the existence of these alternative ways to deal with pain, pharmaceuticals are still extremely popular and among them one of the most prescribed classes of drugs are opiates.
Opiates are a double edge sword: although they are effective at reducing the symptoms, the risk of developing a physiological addiction is dangerously high (7). In the USA the prescription opiates abuse is at such a critical level to be considered an epidemic: deaths related to prescription opiates in 2010 was double of 2002 while 70% of drug related deaths in 2019 was linked to opiates (roughly 50.000 individuals) (8,9). In the UK the situation is not as dramatic as overseas, but prescription (and illegal) opioid related deaths are on the rise (10).
The lack of a side effect-free solution for managing chronic pain is putting many individuals on their knees; nevertheless, an ever-growing number of people who persisted in the quest for an effective alternative treatment for their condition are finding a possible solution in a herbal medicine native to Southeast Asia.
Kratom and its indole alkaloids
Kratom (Mytragina speciosa) is a widely cultivated tropical tree belonging to the Rubiaceae botanical family and indigenous to Southeast Asia. kratom has been used for centuries by the indigenous people of Southeast Asia both as a stimulant and a sedative. There are three main varieties of kratom whose names are given by the colour of the veins: green, white and red. Green strain kratom is said to be more potent of the other two, but the evidence is only anecdotal (39). Its leaves, which are usually chewed or consumed as tea or powder, contain psychoactive indole alkaloids which have shown to have a strong affinity with the opioid receptors in the central nervous system (11). These psychoactive compounds are mitragynine (the most abundant), 7-OH-mitragynine (the most bioactive), speciociliatine and corynantheidine. Most of the research has been conducted on mitragynine and 7-OH-Mitragynine, which appear to bind agonistically mainly to µ-, κ- and δ- opiate receptors, causing analgesia and euphoria. Interestingly, these molecules are structurally different from common opiates such as morphine and they have been called ‘atypical opiates’. This denomination has been given to them because they act as opiate receptor agonists without triggering the potentially harmful side effect common to opiate drugs use such as respiratory depression, sedation and constipation; this process is thought to happen because kratom indole alkaloids do not activate β-arrestin, a protein linked to cascade activation of opiates side effects (13). Because of this unique selective property, kratom could have a therapeutic potential as an opiate drug substitute in the mitigation of withdrawal syndrome (14).
Kratom for pain management
The first document on kratom as an opioid alternative was published in 1988 and it concludes by stating that kratom might be a successful substitute for methadone as a rehab strategy (15).
Following this study, experiments on mice confirmed that kratom alkaloids cause significantly lower addictive behaviors compared to morphine-addicted control groups (16), while individuals using kratom alongside other narcotics reported higher quality social life and improved management of withdrawal syndrome; in addition, kratom users alongside opiates report longer abstinence periods (up to one year) and have remarkably less chances to develop an opiate addiction (17,18,19).
In one online survey from 2017 involving 2798 American kratom users, 91% of them selected ‘pain management’ as a reason for using the herb, while another survey from the same year conducted by the American Kratom Association on 2867 individuals showed that 48% of participants used kratom to relieve pain and 10% used it as an opioid drug substitute (20, 21). Although specific studies on kratom and chronic pain management are still limited, there is significant evidence showing it to be a safer remedy compared to synthetic opioids when used long-term.
Dosage and safety
Kratom leaves can be consumed in different ways: hot infusions, chewed (the traditional way in Southeast Asia) and smoked. Most people take it in forms of pills, capsules, extract or as a powder mixed with a beverage (37, 40). A unique characteristic of kratom is to be both a stimulant and sedative depending on the dosage. A few grams of dried leaves, cause an excitatory response in the central nervous system, while larger doses (5+ g) give the opiate-like euphoria and sedation (12). In terms of safety, the available literature is controversial; although its use poses a risk of overdosing a thousand times smaller than opiates (25, 26), kratom use has been associated with liver toxicity and withdrawal syndrome. In a detailed report from 2020 on liver toxicity associated with kratom consumption the FDA flagged 25 individual cases related to the toxic effects of kratom on the hepatic system. 37% of the individuals concerned have taken 5g to 20g daily of kratom in a powdered form for an average of 21 days before starting to notice signs and symptoms of malaise, jaundice and dark urine; nevertheless, there is no information regarding the existence of pre-existing medical condition of the consumers, nor specific hepatotoxic mechanism have been identified in human and animal studies. It is postulated that some compounds other than mitragynine could be cytotoxic to hepatocytes although there is no clear evidence (38). On the other hand, other sources state that no cases of death have been confirmed to be caused by kratom alone and most of the fatalities associated with its intake also involved the clear overconsumption of other drugs. There are high chances then that the fatality cases signaled by the FDA and other organisations might be biased by inadequate postmortem toxicology data and testing protocols (25).
The symptomatic side effects of taking kratom are somewhat similar to the opiate ones; these include nausea, vomiting withdrawal symptoms such as hostility, aggression, aching of muscles and bones and insomnia with potential increase of tolerance to the herb (27, 28). Nevertheless, these symptoms are exceptionally milder compared to opiates, presenting with less intensity, the onset within about 12 to 16 hours and a duration of 1 to 3 days (26). In addition, a survey conducted on 2798 kratom users showed that less than 10% of participants developed the aforementioned withdrawal symptoms after one or more years of use (18).
How to safely use Kratom
Due to lack of research, there is no accepted standard safe dosage of kratom powder or extract but it is widely accepted that long-term use of kratom leaves for treating chronic pain and opiates withdrawal is not recommended due to its potential for addiction and hepatotoxicity (26). Nevertheless, short-term use of kratom leaf powder appears to be relatively safe; a survey involving more than 8000 individuals revealed that withdrawal symptoms are dose/frequency dependent and a dosage of 5g three times a day elicited the desired analgesic effects in most of the participants while causing severe side effects only in 0.65% of the population (40). Kratom quality is also another important factor to consider; due to the restricted regulations about the marketing of kratom products, most of the available kratom on the UK market is likely to come from the dark web or other illicit channels of trade. These unregulated products are a potential threat as they are likely to not have been subjected to quality tests, might not give the desired effects or could even be harmful (41). To safely consume kratom then only use it under the guidance of a qualified practitioner in countries where it is legal and subjected to quality controls; to start with a low dosage (no more than 15g a day) and to quit immediately if side effects start to appear.
The legal status of Kratom
The legal status of kratom varies from country to country. In Europe, for instance, it is legal in Belgium, Netherlands and Germany but illegal in Italy and Switzerland, while controlled In Denmark and Portugal. Even in the US different states have contradictory laws about kratom. In the UK, the 2016 Psychoactive Substance Act put a ban on all substances and herbs known to have psychotropic effects unless regulated. This turned kratom into an illegal substance and made it unavailable on the market (29).
This article evaluated the potential of Mitragyna speciosa, kratom leaves, as a substitute for opioid and opiate drugs in the management of chronic pain. Chronic pain is a condition which burdens both the individual and the medical system in most countries worldwide; commonly prescribed drugs for managing chronic pain are opioids and opiates, which effectively modulate the symptoms but cause undesirable side effects, cause addiction and increase the risk of death by overdose when used long-term
Mitragynine and 7-OH-Mitragynine, the predominant indole alkaloids in kratom leaves, act as opiate receptors agonist causing opiate-like euphoria, analgesia and sedation without depressing the respiratory system and posing a far lower risk of developing serious addiction and withdrawal symptoms. Despite its potential therapeutic benefits, various studies report side effects from kratom use such as hepatotoxicity and withdrawal symptoms. In conclusion, even though kratom appears to be an effective but less harmful remedy to manage chronic pain when compared to opiate drugs, its prolonged use could also have a negative impact on human health. In order to allow kratom to be legally prescribed, further pharmacological investigations on its safety and toxicity are required.
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