A Medicolegal Perspective on Neuropathic Pain
The sensation of pain evolved to protect the body from actual and potential harm (1, 2). However, in neuropathic pain, which is caused by a lesion or disease of the somatosensory nervous system (1-5), this protective function is lost (2). Instead, the perceived pain is spontaneous and manifests without any outside stimulus (1, 3). The aetiology of neuropathic pain varies widely, and includes injuries and lesions to the brain and spinal cord, peripheral neuropathy arising from diabetes mellitus or as a result of chemotherapy due to cancer, trigeminal neuralgia, peripheral nerve injury, and post-stroke pain (2-5). As there is no agreed definition of neuropathic pain, estimating the prevalence of the condition is difficult (3), but most studies agree that it lies somewhere in the range of 3–17% of the population (2-5), and occurs more frequently in women and in patients aged over 50 years (3, 5). As well as pain-related symptoms, neuropathic pain can result in depression, sleep disturbance and physical limitations (4); thus, it can have a significant impact on a patient’s psychological wellbeing and quality of life (3, 5).
There is no single diagnostic test to identify neuropathic pain as patients suffer from sensory abnormalities that occur in different combinations, depending on the condition and mechanism by which the pain arises (1, 4). However, several characteristics distinguish neuropathic from inflammatory, or nociceptive, pain (5). Signs and symptoms frequently associated with the condition include allodynia (pain arising from a usually benign stimulus), hyperalgesia (an increase in the perception of pain above normal levels) and paresthesia (the perception of sensations described by the patient as similar to pin-pricks, tingling, itching and reduced or lost sensitivity) (1, 3, 4).
The exact cause of neuropathic pain remains unclear, although several mechanisms have been suggested. The human body contains several different types of sensory neurones, with those used to detect painful stimuli being called nociceptors. These neurones have receptors and ion channels that, when triggered to a sufficient degree, transmit a pain signal to the spinal cord. Most of these neurones only respond to a single, very specific, stimulus. For example, a neurone may register physical touch but not extreme heat or cold (2). Both injury and inflammation increase neuronal responsiveness and it is likely that this is a key factor behind the sensations experienced by patients with neuropathic pain (2, 4). This theory is borne out by the finding that injection of the anaesthetic lidocaine at painful foci in patients with neuropathic pain greatly diminishes allodynia (2).
Animal studies have clearly demonstrated that nerve injury or disease can lead to changes to spinal or supraspinal neuroplasticity, resulting in central sensitisation, the symptoms of which mirror those associated with neuropathic pain. This may be due to phenotypic changes in touch fibres or increased activity of excitatory amino acid transmission, and it is also likely that the activation of nonneuronal cells, such as glia, also contributes to this process. Nerve injury may also impair endogenous inhibitory mechanisms of nociception, which may increase postinjury nerve sensitivity. Given the heterogeneous nature of neuropathic pain, it is likely that a single condition will be made up of subgroups of patients with different pain mechanisms, and that in some patients, multiple mechanisms may be responsible (1, 4).
Despite advances in the understanding of the causes of neuropathic pain, successful treatment remains a challenge. There are currently no drugs specifically aimed at treating it, and management strategies usually target the clinical symptoms rather than the underlying causes (5). Over half of all patients with chronic pain who are receiving prescription medication have reported that this does not always give adequate pain relief, and around 15% of those who have stopped medication cite side effects as the reason (2).
Several repurposed drugs are recommended for the treatment of neuropathic pain. First-line options include gabapentinoid anticonvulsive medications, serotonin-norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) (1, 2, 4, 5). Second-line treatments include weak opioid analgesics, such as tramadol and tapentadol, along with topical applications of lidocaine or capsaicin patches for peripheral neuropathic pain (1, 4, 5). Due to issues with long-term use and possible dependency, strong opioids such as oxycodone and morphine are reserved for a third-line option for both central and peripheral conditions, while botulinum toxin type A-haemagglutinin complex is recommended only for peripheral pain (3-5).
A major issue with pharmacological treatment is that the efficacy of these drugs is variable and overall, only modest effects have been achieved (2). It is usually necessary to treat between two and eight patients to see a 50% reduction in pain in one patient (2, 4). Therefore, it is important that patients understand that treatment is unlikely to be curative and some residual pain may remain (4). Nevertheless, good results have been reported for some drugs when used for certain conditions. Gabapentinoids are particularly beneficial for pain related to diabetes, herpetic neuralgia, spinal cord injury and phantom limb syndrome, while TCAs have also been used successfully in patients with pain following nerve or spinal cord injury, herpetic neuralgia and postpartum pain (3).
Another drawback is that side effects are common. These include dizziness, sedation and peripheral swelling for the gabapentinoid group, nausea for SNRIs and anticholinergic effects, such as dry mouth and constipation for TCAs (4, 5). Furthermore, TCAs are contraindicated in patients with some cardiac conditions, glaucoma or prostate hypertrophy. As SNRIs are associated with increased blood pressure and cardiac conduction abnormalities, they must also be used with caution in patients with cardiac disease (3, 4).
While cannabis-related medications may have a role in the treatment of neuropathic pain, this remains unclear, as the potential benefits and harms have not yet been fully established and results from studies have been conflicting (3, 5). Similarly, the efficacy of herbal medicines such as nutmeg, St John’s wort or various compounds used in traditional Chinese medicine remains controversial (1, 5).
A variety of non-pharmacological interventions are also available, and these can be especially useful for patients whose pain has not responded to pharmacologic treatment (4, 5). These include physical and psychological therapies, spinal cord stimulation, nerve blockade, surgery and transcranial magnetic stimulation (2-5). As with the pharmacological treatment options, evidence for the efficacy of these interventions is generally limited (4, 5). For example, spinal cord or dorsal column stimulation can provide effective pain relief for several neuropathic pain conditions, but only in around 50% of patients. Research into variations of this technique, involving burst and high-frequency stimulation, may improve its efficacy (3). Exercise therapy, particularly when combined with psychological therapy, has a moderate beneficial effect on both physical activity and quality of life, while cognitive behavioural therapy has little benefit in terms of actual pain relief but is very effective in improving mood and diminishing catastrophising. Interestingly, psychological therapies delivered by internet showed a similar efficacy in reducing pain, depression and anxiety as interventions delivered by a more conventional face-to-face route (5).
The recent increase in the understanding of neuropathic pain means that additional treatment options are likely to be developed in the future, some of which may target specific disease processes (2, 4). Researchers are currently exploring the possibility of selectively controlling the excitability of neurones that respond to specific stimuli using either chemo- or optogenetic tools. Some mutations in the sodium ion channel NaV1.7 produce congenital insensitivity to pain without producing serious systemic complications. This suggests that selective inhibition of NaV1.7 could lead to pain relief without associated neurological side effects. This targeted approach is preferable to oral medication, which results in the whole body being exposed to the drug. For example, a recent trial in patients with trigeminal neuralgia found that selective NaV1.7 inhibition led to fewer treatment failures and a greater improvement in pain score, when compared to placebo. However, while clinical trials have started, viable treatment options are not likely in the near future (2).
As an alternative to targeting the neurone itself, another option may be to focus on spinal cord transmission between first- and second-order neurones (2). Ziconotide acts by blocking presynaptic calcium channels, leading to inhibition of neurotransmission. However, in order to prevent systemic side effects, the drug must be administered intrathecally, requiring the implantation of a minipump. N-methyl-D-aspartate receptors, which are involved in synaptic transmission as well as neuroplasticity, are being investigated as an alternative target for pain management. Furthermore, as neuroinflammation appears to play an important role in the development of neuropathic pain, inhibition of this process offers another potential therapeutic option (3).
Neuropathic pain is a relatively common condition that can have a significant impact on a patient’s quality of life. As the aetiology is highly variable, diagnosis and treatment are challenging, and many currently available interventions do not provide adequate pain relief. Patient education encompassing both the expected course of the diagnosed condition and the limitations of current treatment options will help to manage expectations (4). Recent advances in the understanding of the changes in the nervous system that give rise to neuropathic pain have identified novel targets for treatment. Clinical trials are ongoing and it is likely that new therapeutic options will be available in the future. In the meantime, an individualised approach using a combination of different therapies in a personalised treatment plan may provide more benefit than a single-drug approach (3, 4).
References
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2. St John Smith E. Advances in understanding nociception and neuropathic pain. J Neurol. 2018;265(2):231-8.
3. Cavalli E, Mammana S, Nicoletti F, Bramanti P, Mazzon E. The neuropathic pain: An overview of the current treatment and future therapeutic approaches. Int J Immunopathol Pharmacol. 2019;33:2058738419838383.
4. Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc. 2015;90(4):532-45.
5. Szok D, Tajti J, Nyári A, Vécsei L. Therapeutic Approaches for Peripheral and Central Neuropathic Pain. Behav Neurol. 2019;2019:8685954.
