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Neuropathic pain can be debilitating and often difficult to treat due to its variable nature in patients, their unique responses to treatment, as well as comorbid conditions that may mask the underlying pain mechanism. Neuropathic pain can be treated with non-pharmacological, pharmacological, and interventional treatment. Treatment can also exists as a combination of different treatments personalized for each patient, taking into account their medical history and adverse side effects. Many guidelines exist for neuropathic pain treatment, such as the one created by the International Association for the Study of Pain (IASP) and Neuropathic Pain Special Interest Group (NeuPSIG) for stepwise pharmacological treatment management[1]. Other guidelines include stepwise treatment, progressing from lower adverse risks and side effects, such as starting with non-pharmacological methods, to pharmacological methods, and finally to interventional treatment[2]. Research for different areas of treatment is still ongoing as many treatments available are still ineffective for a large proportion of patients. New therapeutic targets such as inhibition of astrocyte activation and a transdermal delivery system of pharmacological drugs are currently being investigated.

Non-pharmacological treatment

  • Exercise

  • One classically prescribed treatment is exercise, known to effectively reduce chronic pain without serious side effects[3,4]. For example, short term exercise can upregulate endogenous brainstem opioids, resulting in neuropathic pain reduction, specifically for thermal and tactile hypersensitivity[5]. In addition, exercise has also been shown to reduce hypersensitivity from nerve injuries in rodent models[6]. These rodent models are successful model organisms for neuropathic pain, as many of the positive results are reflected in humans as well[7,8]. In addition, short-term running was found to reduce allodynia and help the regeneration of peripheral nerves[9]. Normal regular functioning was subsequently increased after exercise.

  • Phantom limb mirror therapy

  • Phantom limb pain occurs when there is perceived neuropathic pain originating from a missing limb or region of the body[10]. In 1996 mirror therapy was discovered by Ramachandran and Rogers-Ramachandran, where a “virtual reality box”, or a mirror box, was used to superimpose an image of an intact limb at the position of the phantom limb, and subsequent movement of the mirror limb resulted in kinetic sensations in the phantom[11]. Mirror neurons in the brain also fired during observation of movement[12] and are also implicated in the modulation cortical somatosensory input by blocking pain perception[13,14].

  • Eye movement desensitization and reprocessing (EMDR)

  • EMDR is a form of psychotherapy that alternates between using bilateral sensory stimulation, such as repetitive eye movements, and paying attention to specific memories[5], specifically focusing on the traumatizing aspects of the memory and reprocessing them into a less distressing memory[15]. These memories may include post-traumatic experiences that may cause phantom pain, and can be rewired for the relief of cognitive and somatic symptoms[16]. EMDR can be explained using the conditioning theory: a traumatic stimulus is usually accompanied with fear or terror, for example during post-traumatic stress disorder, and therefore escape or avoidance behaviour is usually enforced[17]. This unconditioned behavior is then presented simultaneously with a new distracting stimulus, such as eye movements or even an auditory or visual stimulus[17]. The patient then learns to maintain awareness of the traumatic event while performing these eye movements, thus conditioning the stimulus and learning to cope with the traumatic memory[17]. Anxiety decreases as desensitization occurs and the patient learns they do not need to resort to avoidance or escape behaviour[17]. EMDR has been shown to be successful in the treatment of pain and psychological symptoms of phantom limb over long term treatment[18].

Pharmacological treatment

Table adapted from Xu, B., Descalzi, G., Ye, H.-R., Zhuo, M. & Wang, Y.-W. Translational investigation and treatment of neuropathic pain. Molecular Pain 8, 15 (2012).

Pharmacological treatment can be used effectively to manage neuropathic pain. However it should be noted that pharmacological treatment effectiveness is variable among patients. Notable pharmacological drugs with a high degree of efficacy for relief include antidepressants, anticonvulsants and opioids[19].
  • Antidepressants

  • Tricyclic antidepressants Tricyclic antidepressants are commonly used for their analgesic effects, which work by blocking peripheral noradrenergic receptors[20] or sodium channels[21]. The analgesic effects work in both normal and depressed patients, and thus depression is not required for effective pain management[22]. Other antidepressants include serotonin noradrenaline reuptake inhibitors (SNRIs) such as duloxetine and venlafaxine for diabetic peripheral neuropathy treatment[1].

  • Anticonvulsants

  • Gabapentin binds voltage gated calcium channels in the brain and reduces the release of several monoamine neurotransmitters in the blood[23]. It has been shown to be effective in treating allodynia[24,25] as well as reducing diabetic peripheral neuropathy[25]. There are mild to moderate adverse effects including dizziness and drowsiness[25] alongside its analgesic effects. Other types of anticonvulsants include pregabalin and carbamazepine.

  • Opioids

  • Opioid agonists, include morphine, oxycodone, and levorphanol. Opiods can be used to treat peripheral and central neuropathy[26], hyperalgesia[27], as well as diabetic neuropathy[28].Recent research has been investigating transdermal drug delivery systems for neuropathic pain treatment, including transdermal buprenorphine for chronic cancer pain[29,30], as well as central and peripheral neuropathic pain[30,31]. Although there are risks of drug abuse and addiction, it should be noted that because of high efficacy and regained functional rates, opioids can be a successful form of treatment when combined with careful monitoring and precise prescriptions[32].

  • Miscellaneous

  • Other types of medications may include topical patches such as lidocaine patch (5%), cannabinoids, and NMDA antagonists.
  • The lidocaine patch (5%) has analgesic effects that vary between patients. A recent study has suggested that patients with incomplete C-fiber degeneration may still have discharge from remaining C-fibers, and therefore can benefit from this type of topical lidocaine treatment, whereas others will have insufficient nerve-fiber blockage and less pronounced improvements[33].
  • Cannabinoids have been used extensively in pain therapy. For example allodynia can be treated using cannabinoid agonists which increase cannabinoid receptor expression and inhibit the activation of microglia and astrocytes seen after injury[34].
  • An NMDA receptor antagonist, 10% CNS5161, has recently been used in silicone pressure-sensitive adhesives that allow maximum skin permeation[35]. Other NMDA receptor antagonists such as ketamine, have also been used in percutaneous delivery systems[36].

Interventional treatment

Deep brain stimulation of the thalamus. Figure adapted from Asaad, W. & Eskandar, E. The movers and shakers of deep brain stimulation. Nature Medicine 14, 17–19 (2008).

  • Deep brain stimulation

  • Deep brain stimulation (DBS) is an invasive form of treatment that electrically stimulates deep brain structures, such as the ventral posterolateral nucleus of the thalamus[37] for peripheral neuropathic pain, or the periventricular gray area for central post-stroke pain[38]. Other targeted structures include the internal capsule to treat phantom limb pain and trigeminal neuropathic pain[39]. However the effectiveness of DBS is highly variable between patients, ranging from a high efficacy rates[38,40] to low efficacy rates[40]. There are several disadvantages as well, such as the development of tolerance and types of neuropathic pain that do not respond well to DBS, such as postherpetic neuralgia and pain caused by spinal cord lesions[39]. Further investigation and more evidence-based research are needed for this type of treatment.

  • Motor cortex stimulation

  • Motor cortex stimulation (MCS) is an invasive intervention that can be used to target more drug-resistant types of pain, such as trigeminal neuralgia[41], post-stroke pain[42], as well as peripheral neuropathy[43]. For example, MCS has been shown to treat hyperalgesia by stimulation of the nucleus zona incerta which inhibits pain symptoms[44].

  • Spinal cord stimulation

  • Spinal cord stimulation (SCS) is an invasive surgical intervention that can also be used for more long term relief of resistant forms of neuropathy[45]. SCS results in sustained pain relief, functional capacity and better health after just two years of treatment[46]. There is also evidence that the spinal serotonergic system is activated in SCS and involved in the inhibition of nociceptive processing by inducing GABA release[45]. GABA, an inhibitory transmitter, can be inhibited presynaptically at primary afferent terminals by GABA antagonists to inhibit pain signals[47]. SCS also releases serotonin and substance P when stimulated in the dorsal horn, both which are involved in pain management through the serotonergic descending pathways[48].

Treatment guidelines

Effective guidelines should include medical history, evaluation of treatment outcome tailored for each patient, as well as documentation of thorough research studies[43]. An example of a treatment guideline is the IASP Pain Special Interest Group Guidelines for treatment of neuropathic pain, or one that weighs the adversity of side effects as well as the level of efficacy and tolerability for each treatment type, such as in the Canadian Pain Society and EFNS guideline recommendations[2]. In addition, treatment guidelines can also be organized by assessing the possible underlying pain mechanism and targeting the originating cause of neuropathic pain using evidence-based results[1]. Combinational personalized drug therapy is used to maximize beneficial effects multiple drugs and minimize side effects due to lesser doses of each drug[1]. For example, the combination of gabapentin and nortriptyline was proven more effective when prescribed together and also resulted in fewer side effects, such as less sleep interference and better mood[42].

  • Stepwisepharm_NP.png
    Stepwise pharmacologic management of neuropathic pain. Table from Dworkin, R. H. et al. Pharmacologic management of neuropathic pain: Evidence-based recommendations. PAIN 132, 237–251 (2007).

Current research for new treatment

  • Inhibition of astrocyte activation therapy

  • Glial cells, astrocytes and microglia, are activated during neuropathic pain states, which may be due to the degeneration of sensory neurons[16]. During these states, proinflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF)[49] are induced in spinal cord glial cells and cause hypersensitivity[18]. It is suggested that inhibition of proinflammatory cytokines should be investigated as a new therapeutic target for pain[18].
    Increase of GFAP throughout the spinal cord such as around the dorsal horn, central canal, and ventral horn (not shown). Adapted from: Zhang, H., Yoon, S.-Y., Zhang, H. & Dougherty, P. M. Evidence That Spinal Astrocytes but Not Microglia Contribute to the Pathogenesis of Paclitaxel-Induced Painful Neuropathy. The Journal of Pain 13, 293–303 (2012).

  • There are also several lines of evidence that specify the inhibition of astrocyte activation as a new therapeutic target for pain management. Neuropathy induced by an effective chemotherapeutic drug paclitaxel shows that only spinal astrocytes are involved in neuropathy, and not microglia[20]. This was shown using glial fibrillary acidic protein (GFAP) in the spinal cord after paclitaxel injections in rat models. Another study also determined that only spinal astrocytes contributed to chronic pain by testing specific inhibitors for each type of glial cell in rats with virally induced postherapetic neuralgia[50]. Here there was significant increase in IL-1β in activated astrocytes, which induced phosphorylation of N-methyl-D-aspartic acid receptor (NMDAR), and resulted in strengthened pain transmission[50].

  • Spinal astrocyte activation was determined to be responsible for the maintenance phase of neuropathic pain in mice. Astrocyte activation was successfully metabolically inhibited using Bushi, a Japanese herbal medicine with similar analgesic effects as fluorocitrate[51,52]. Bushi was shown to reverse spinal astrocyte activation and inhibit the persistent maintenance phase of neuropathic pain. However the molecule targeted in the reversal of astrocyte activation is unknown[51]. Further research is required for this promising new therapeutic target.


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See Also

Neuropathic Pain and Treatment
Mechanisms of Neuropathic Pain
Causes and Genetic Variability in Neuropathic Pain
Signs, Symptoms, Diagnosis, and Comorbidities

External Links

The University of Toronto Centre for the Study of Pain
The Wasser Pain Management Centre at Mount Sinai Hospital
Comprehensive Pain Program at Toronto Western Hospital
Canadian Pain Society, Special Interest Groups Neuropathic Pain