Neuropathic pain
[7] The gold standard for diagnosing small fiber neuropathy as the etiology of neuropathic pain is skin biopsy.
[22] Certain classes of neuropathic pain may cause serious adverse effects necessitating hospital admission, for instance trigeminal neuralgia can present as a severe crisis where the patient may have difficulty talking, eating and drinking.
[26] Meta analysis of randomized clinical trials suggests that Lamotrigine is not useful for the majority of patients although it may have use in treatment of refractory cases.
[32] Dual serotonin-norepinephrine reuptake inhibitors in particular duloxetine, as well as tricyclic antidepressants in particular amitriptyline, and nortriptyline are considered first-line medications for this condition.
[34] Several opioids, particularly levorphanol, methadone and ketobemidone, possess NMDA receptor antagonism in addition to their μ-opioid agonist properties.
The d-isomer does not have opioid agonist action and acts as an NMDA receptor antagonist; d-methadone is analgesic in experimental models of chronic pain.
[38] Importantly, recent observational studies suggest a pain-relief benefit in non-cancer related chronic pain of reducing or terminating long-term opioid therapy.
[43] Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.
[46] Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (dura) has been used to treat pain.
As compared with spinal stimulation, which is associated with noticeable tingling (paresthesia) at treatment levels, the only palpable effect is pain relief.
[49] The N-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance.
Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance.
[50] Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half life (ketamine), weak activity (memantine) or unacceptable side effects (dextromethorpan).
Photoswitchable analogues of the anticonvulsant drug carbamazepine have been developed to control its pharmacological activity locally and on demand using light, with the purpose to reduce adverse systemic effects.
[51] One of these compounds (carbadiazocine, based on a bridged azobenzene) has been shown to produce analgesia with noninvasive illumination in a rat model of neuropathic pain.
Ziconotide is a voltage-gated calcium channel blocker which may be used in severe cases of ongoing neuropathic pain[52] it is delivered intrathecally.
[54] In animals a gene therapy for local transgenes encoding for GABA synthesizing-releasing inhibitory machinery has been demonstrated and was effective for months at a time.
It increases synaptically GABA-mediated neuronal inhibition in the spinal cord (or in the brain) via the induced expression of genes GAD65 and VGAT without any detected systemic or segmental side effects.
Repeated topical applications of capsaicin are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation.
[73] While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (dysesthesia including stabbing and burning pain) as well as neuropathic deficits (paresthesia),[74] the meta-analysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone".
[75] Benfotiamine is an oral prodrug of Vitamin B1 that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.
[78] The idea of origination of pain from the nerve itself, without any exciting pathology in other organs is presented by medieval medical scholars such as Rhazes, Haly Abbas and Avicenna.
Notably our understanding of these processes is largely driven by rodent models in part because studying these tissues in living adults is difficult.
During neuropathic pain, ectopic activity arises in the peripheral nociceptors and this appears to be due in part to changes in the ion channel expression at the level of the periphery.
There may be an increase in the expression or activity of voltage gated sodium and calcium channels which will support action potential generation.
Broadly speaking in neuropathic pain, neurons are hypersensitized, glia become activated and there is a loss of inhibitory tone.
The loss of inhibitory inputs may allow fibers to transmit messages via the spinothalamic tract thus causing pain in normally painless stimuli.
Brain derived neurotrophic factor, prostaglandins, TNF and IL-1β may be produced by microglia and cause changes in neurons that lead to hyperexcitability.
[88] During high frequency stimulation synapses conveying nociceptive information may become hyper efficient in a process that is similar although not identical to long-term potentiation.
In chronic nerve injury, there is redistribution and alteration of subunit compositions of sodium and calcium channels resulting in spontaneous firing at ectopic sites along the sensory pathway.
