Medical Cannabis for Neuropathic Pain

Many cultures throughout history have used cannabis to treat a variety of painful ailments. Neuropathic pain is a complicated condition that is challenging to treat with our current medications. Recent scientific discovery has elucidated the intricate role of the endocannabinoid system in the pathophysiology of neuropathic pain. As societal perceptions change, and legislation on medical cannabis relaxes, there is growing interest in the use of medical cannabis for neuropathic pain.

Research and data from recent randomized controlled trials (RCTs) evaluating medical cannabis for the treatment of neuropathic pain has demonstrated the efficacy of medical cannabis for treating neuropathic pain, with number-needed-to-treat values similar to current pharmacotherapies.

Introduction

Despite a significant amount of research, the treatment of neuropathic pain remains a major challenge for pain specialists and primary care physicians. It has been estimated that 6–10% of the population suffers from pain with neuropathic signs and symptoms.

  • Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system.

In our experience, many patients continue to experience neuropathic pain symptoms despite adequate trials of analgesics from multiple classes of neuropathic agents. These treatment failures with anti-neuropathic pain agents may be due to lack of analgesic efficacy, intolerance, or contraindications to various classes of medications. Patients with poorly controlled neuropathic pain have significantly poorer health status and increased symptoms of anxiety and depression. On a societal level, neuropathic pain is associated with significant societal costs resulting from higher healthcare utilization, disability, and lost productivity.

Clinically, we have noticed a broad spectrum of symptoms described in patients with neuropathic pain, and similarly varied patient response to the available treatments. There have been many efforts to subtype neuropathic pain in order to predict treatment response based on clinical characteristics of the pain symptoms; however, developing effective, reproducible treatment plans for various neuropathic pain subtypes has proven difficult. We believe that a highly individualized treatment plan is the cornerstone of neuropathic pain treatment. Therefore, it is imperative that physicians treating neuropathic pain have an understanding of pain mechanisms, the efficacy of our standard therapies, and the data behind non-standard therapies on the horizon, including medical cannabis given its promising nature.

Mechanism of Neuropathic Pain

In neuropathic pain states, maladaptive changes occur in response to injury and result in the afferent pain pathways deviating from their normal function of alerting the brain to actual or potential tissue damage. The neuropathic pain syndrome is characterized by:

  • An increase in afferent nerve spontaneous activity, and
  • An exaggerated or abnormal response of the central or peripheral nervous system to afferent input or stimuli.

The initial injury to the central or peripheral nervous system that leads to neuropathic pain can be caused by various insults including physical trauma (herniated disc, compression by a tumor), toxin exposure (chemotherapy, alcohol, heavy metals), infection (HIV, herpes zoster), metabolic abnormalities (diabetes, vitamin deficiencies), and abnormal immune system activation (multiple sclerosis). Although neuropathic pain is a complex disorder seen in various disease states, there are likely common mechanisms occurring in response to nerve injury that may underlie the classic symptoms experienced in patients with neuropathic pain.

Increased Ectopic Activity

Patients with neuropathic pain often express sensations of spontaneous pain that indicate activity of nociceptive afferent fibers in the absence of a known stimulus. These ectopic discharges may originate from various points on the injured nerve, including the dorsal root ganglion (DRG), axon, nerve terminals, or neuroma formed after injury. In addition, apparently uninjured nerves near the site of injury can generate ectopic discharges because of abnormal nerve “cross talk” or ephaptic transmission.

Neuronal Sensitization

Neuropathic pain is further characterized by central and peripheral neuronal sensitization. Symptoms of neuronal sensitization include allodynia, a painful response to a typically non-noxious stimulus, and hyperalgesia, an exaggerated pain response to a normally painful stimulus. Sensitization likely shares similar mechanisms theorized to produce ectopic activity, but additional stimuli and maladaptive changes may occur.

Following nerve injury, inflammatory mediators, including calcitonin-gene related peptide (CGRP) and Substance P lead to increased vascular permeability. This results in localized edema and increased exposure of the nerve environment to prostaglandins, bradykinin, cytokines, and growth factors that are released from the injured nerve terminals and the surrounding cells. Exposure to this inflammatory milieu increases neuronal mechanical and chemical sensitivity to stimuli at the location of injury and in the DRG. In addition, it is hypothesized that exposure to growth factors leads to neuronal sprouting and neuroma formation, which themselves demonstrate decreased stimulation thresholds as described above. Peripheral nerve injury and inflammation also causes activation of glial cells within the spinal cord, which promotes central sensitization and contributes to the maintenance of the neuropathic pain state.

Descending Inhibitory Pathway

The role mood, emotional state, and memory associations play in pain perception is well documented. Serotonergic, dopaminergic, noradrenergic, glycinergic, and GABAergic pathways originate in various supra-spinal centers and project to the medullary and spinal dorsal horns where they modulate nociceptive signaling. In chronic pain, dysfunction of these modulatory pathways leads to decreased inhibition, and in some cases, potentiation of nociceptive signaling.

Dysfunction of descending pathways is not unique to neuropathic pain; however, the efficacy of antidepressant medications (tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors) in the treatment of neuropathic pain suggests that modulation of these pathways is an important consideration when treating patients experiencing neuropathic pain symptoms.

Treatment of Neuropathic Pain

There are a variety of pharmaceutical options for patients suffering from neuropathic pain symptoms, including, but not limited to anti-depressants, anti-epileptics, and opioids.

A meta-analysis of the more commonly used neuropathic pain agents demonstrated a number needed to treat ranging from 3.6 (TCAs) to 7.7 (pregabalin). However, as with all medications, both efficacy and side effect profiles must be taken into consideration when choosing a therapy. The same meta-analysis demonstrated a number needed to harm ranging from 11.7 (strong opioids—oxycodone, morphine) to 25.6 (gabapentin).

Many of the medications conventionally used to target neuropathic pain symptoms have significant side effect profiles and may be contraindicated in certain subsets of patients with co-existing diseases. Phyto-cannabinoids, derived from the flower of the Cannabis plant, as well as their synthetic derivatives have demonstrated exogenous activity within the neuropathic pain pathways previously described. Historical use of cannabis suggests it may offer a similar efficacy (NNT = 5.6) and comparable or improved side effect profile when compared to our currently accepted therapeutic options.

Medical Cannabis for Neuropathic Pain: Efficacious?

Nearly 20 years of clinical data supports the short-term use of cannabis for the treatment of neuropathic pain. Over that time about a dozen randomized double-blinded, placebo-controlled trials have demonstrated significant pain relief over placebo with results and tolerability profiles comparable to current pharmacologic therapies. The data includes multiple routes of cannabis administration, different cannabinoid ratios, and patients with diverse etiologies of neuropathic pain, and suggests potential for a wide range of applications of medical cannabis.

Multiple randomized controlled trials demonstrated efficacy of medical cannabis for treating neuropathic pain, with numbers needed to treat values similar to current pharmacotherapies. Although limited by small sample sizes and short duration of study, the evidence appears to support the safety and efficacy of short-term, low-dose cannabis vaporization and oral mucosal delivery for the treatment of neuropathic pain.

The results suggest medical cannabis may be as tolerable and effective as current neuropathic agents; however, more studies are needed to determine the long-term effects of medical cannabis use. Furthermore, continued research to optimize dosing, cannabinoid ratios, and alternate routes of administration may help to refine the therapeutic role of medical cannabis for neuropathic pain.

            Inhaled Cannabis

A small number of randomized controlled trials performed in the mid to late 2000’s evaluated the effectiveness of inhaled cannabis for treating neuropathic pain and generally yielded favorable results.

Cannabis cigarettes containing 3.56% THC were smoked three times daily for 5 days, and patients reported a 34% reduction in daily pain, with 52% of patients reporting > 30% reduction in pain, which is the generally accepted minimum pain reduction to be considered clinically significant in studies

            Cannabis-Based Medicinal Extracts

Initial efficacy studies performed in Europe comparing THC, CBD, and THC:CBD (1:1) extracts to placebo demonstrated significant reductions in mean pain severity scores and improvement in sleep measures in patients with neuropathic pain due to various etiologies including MS, spinal cord injury, brachial plexus injury, unilateral peripheral nerve injury, post-herpetic neuralgia, and complex regional pain syndrome (CRPS) type II.

These randomized, double-blinded, placebo-controlled trials suggest the efficacy of cannabis-based extracts for the treatment of neuropathic pain symptoms, while demonstrating tolerability in patients whose pain symptoms had been refractory to conventional therapy. Data suggests that cannabis-based medical extracts may be a useful adjuvant for some patients with neuropathic pain symptoms. 

Summation

Humans have utilized the analgesic benefits of cannabis for millennia, while more recently scientific evidence has implicated the ECS as having an integral role in the pathophysiology of neuropathic pain. Neuropathic pain is challenging to treat, and adverse effects often limit many pharmaceutical options. Randomised controlled trials conducted over the last two decades have demonstrated efficacy of medical cannabis comparable to current therapies for the treatment of neuropathic pain. This data is limited by small sample sizes and studies of short duration but appears to support the safety and tolerability of cannabis vaporization and oral mucosal delivery.

However, continued research is needed to assess functional outcomes in addition to reduced pain scores, evaluate long-term tolerability, optimal dosing and alternate routes of administration, and provide education and guidance for physicians.

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