Introduction

Imagine waking up one day and feeling pain that will not go away, no matter what you do to subdue it. This is what most people with neuropathic pain go through every day. Chronic pain brought on by nerve damage or malfunction is known as neuropathic pain (NP). Neuropathic pain affects many people and is estimated to have a prevalence of 6.9% to 10% in the general population.¹ Every basic action becomes a chore when a patient has neuropathic pain, which can have a devastating effect on their quality of life and is frequently linked to psychological distress.² Traditional treatments are usually disappointing for this kind of pain. They usually have limited efficacy and may include associated side effects that often make patients feel worse.³ In the context of alternative therapies, medicinal cannabis takes over in this situation. Medical cannabis is only used for therapeutic purposes, as opposed to recreational cannabis, which is typically used for enjoyment. Tetrahydrocannabinol (THC) and cannabidiol are two examples of the active molecules found in medical cannabis, known as cannabinoids, which have been shown to reduce inflammation and relieve pain.⁴ Although the legal status of medicinal cannabis varies greatly, it is currently being accepted as a legitimate treatment for a variety of illnesses, including neuropathic pain, in several nations. A review of current research on medicinal cannabis use as a potential alternative treatment for neuropathic pain syndromes is presented here, bringing some hope to these patients.

Pathophysiology of Neuropathic Pain

The pathophysiology of NP includes complex interactions between central and peripheral systems that cause allodynia, or pain from ordinarily harmless stimuli, and hyperalgesia, or a heightened sensitivity to painful stimuli.⁵ Neuropathic pain injury or damage to nerves causes changes in the afferent fibres, especially in unmyelinated C fibres, Aδ fibres, and myelinated Aβ fibres.⁶ This is a form of injury that leads to enhanced neuronal excitability and ectopic activity, where nerves start firing in a very abnormal way. Excitotoxicity and increased amplification of pain signals are caused by further dysregulation of neurotransmitters, including glutamate, which results from excessive glutamate release.⁷ On the other hand, an imbalance with the inhibitory neurotransmitter GABA reduces the body's ability to efficiently regulate pain.

Pharmacology of Medical Cannabis

Medicinal cannabis elicits its pharmacological properties from the endocannabinoid system (ECS), integral to the regulation of several physiological processes, which include the sensation of pain and the associated inflammatory responses.⁸ The two main cannabinoid receptors, CB1 and CB2, are at the core of the ECS. The majority of CB1 receptors are found on neurones, where they influence the release of different neurotransmitters and take part in neurotransmission. They mostly interact with THC (tetrahydrocannabinol). On the other hand, CB2 receptors are mainly expressed within the peripheral immune system and participate in the processes of regulating inflammation and immune responses.^9,10 The ECS is a very complex system that works to maintain homeostasis within the body, whereas the cannabinoids from cannabis act via their receptors to express their therapeutic benefits. 

The pharmacokinetic steps for THC and CBD would fall under different phases: 

• Absorption
• Distribution
• Metabolism
• Excretion

The two active cannabinoids in cannabis are taken up through different modes of consumption, such as inhalation, the oral route, and topical application.¹¹

Mechanisms of Cannabis in Alleviating Neuropathic Pain

One of the major mechanisms of action involves the activation of CB1 receptors, which in turn results in dampening the nociceptive signalling. The binding of THC to these receptors diminishes the forward transmission of pain signals at both the peripheral and central nervous system levels, hence decreasing the perception of pain.¹¹ Besides, cannabis has shown remarkable anti-inflammatory actions through the activation of CB2 receptors, mainly present in immune cells. Cannabis acts by turning on the receptors to decrease neuroinflammation, a major promoter for the persistence of chronic pain, inhibiting pro-inflammatory cytokines such as NO, TNF-α, and IL-1β.¹² A reduction in inflammation reduces pain and further creates an environment much more appropriate for neuronal functioning and recovery. Cannabis also exerts neuroprotection against neurone damage caused by oxidative stress.¹³ This becomes of essence in conditions presenting with neuropathic pain, where it would appear that oxidative stress enhances neuronal injury. 

Clinical Evidence for Cannabis in Neuropathic Pain Management

There has been ample scrutiny of clinical evidence for the use of cannabis in the management of neuropathic pain through several systematic reviews and meta-analyses regarding both efficacy and safety. Overall, the comprehensive review of the current status of the clinical trials suggests that medicines derived from cannabis will achieve important improvements in pain intensity, sleep, and psychological well-being compared with a placebo. For instance, a review reported that, compared to a placebo, cannabis was associated with a 30% or greater number of patients achieving relief from pain.¹⁴ Further, cannabis-based medicines have shown promise in reducing the intensity of classic pharmacological therapy, such as opioids, which are often associated with significant side effects and risks of addiction.¹⁵ At the same time, it is beyond doubt that, while cannabis does have several benefits, the strength of evidence varies greatly from study to study, and a large number of trials suffered from small sample sizes and serious methodological limitations. Therefore, while cannabis seems promising for neuropathic pain management, further studies are necessary to establish its role in the clinical setting.

Safety, Tolerability, and Adverse Effects

Toxicity testing for safety and tolerability is especially required for neuropathic pain, both for acute and chronic toxicity. Acutely, the most common adverse effects that are experienced after the use of cannabis include coughing fits, anxiety, paranoia, panic attacks, fainting, and vomiting.¹⁶ Individual characteristics may show a wide variation wherein some may enjoy euphoria or heightened sensory perception while others may suffer from adverse responses. Patients are generally advised to avoid driving after the consumption of cannabis, as coordination and reaction time may be impaired.¹⁷ Understanding these temporary effects is important to anyone considering using cannabis to manage their pain, as it prepares them to expect and manage any immediate adverse reactions they may encounter. Furthermore, long-term use of cannabis is said to lead to an increased risk of addiction. About 9% of adults using cannabis have been shown to become dependent, which increases further to about 17% when this drug has been initiated at a tender age, with 25%-50% who use it daily addicted.¹⁸ As such, proper attention and regulation must be addressed to ensure that the drug is rendered safe for patients as its usage increases. This includes laying down clear guidelines regarding dosage, formulation, and usage patterns to minimise risks and maximise therapeutic benefits.

Societal and Legal Considerations

The regulatory environment regarding medical cannabis varies significantly among the sub-regions and reveals the different cultural views, legal systems, and health policies that each exhibits. In countries like Canada and Germany, for example, medical cannabis is legally recognised, and its use is regulated, providing persons suffering from certain ailments access to cannabis products on prescription.^19,20 On the other hand, countries like Malaysia and Iran exercise very severe bans on even the minimum utilisation of cannabis, such as medical uses.^21,22 Apart from regulatory issues, much stigma attributed to cannabis use remains one of the more significant barriers to treatment for many candidates. The common misconception that cannabis is a recreational substance often blinds the masses from the possibility of such medicinal benefits.

Future Directions in Research and Therapy

Future studies and treatments for neuropathic pain with cannabis should be more focused on aspects of personalised medicine and adjunctive treatment with cannabis, combined with other conventional modes of treatment. Of these, one very attractive avenue of research involves determining how genetic factors influence individual responses to cannabinoids. Consequently, the furtherance of clinical trials becomes an important feature of future research into cannabis therapy for neuropathic pain. Rigorous, placebo-controlled, long-term studies should be designed to ensure the proper safety and efficacy of cannabis-based treatments.

Conclusion

Clinical evidence, so far, increasingly supports the use of cannabis in the treatment of NP by showing not only its various mechanisms but also relevant patient benefits. It follows from the studies that cannabis is capable of effectively acting on pain pathways, reducing inflammation, and providing neuroprotection in pursuit of improved overall pain management. For instance, it has been demonstrated through systematic reviews and meta-analyses that cannabis-based medicines considerably reduce pain intensity, with the majority of patients experiencing at least a 30% reduction in symptoms of pain. More importantly, these data suggest that cannabis might prove to be an effective substitute or adjunctive therapy for those patients who respond inadequately to conventional pharmacological pain management. Beneficial clinical results support cannabis as a possible treatment for neuropathic pain and offer hope for patients who have not found symptom relief with previous treatments.

While promising clinically, there is a need to balance the view of medical cannabis use. Evidence upholds its efficacy; however, certain gaps must be studied in detail for a full understanding of long-term safety and the optimal dosing strategy of cannabis therapy. In this respect, current studies particularly need to press toward the resolution of uncertainties and the investigation of genetic determinants influencing individual response to cannabinoids.