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Treatment of neuropathic pain after peripheral nerve and brachial plexus traumatic injury
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.250699
Keywords: Brachial plexus, chronic pain, dorsal root entry zone procedure, neuropathic pain
In adults, peripheral nerve and brachial plexus injuries typically produce severe impairment in the affected limb.[1],[2] The annual incidence of such injuries is growing,[1],[3] and the percentage of those patients who experience neuropathic pain ranges from 67 and 95%, depending on the study.[1],[4],[5],[6] Among patients with cervical root avulsions, neuropathic pain is reported by 80-90% patients,[3],[6],[7],[8],[9],[10],[11],[12] with up to 30% ultimately considering their pain to be both intense and chronic.[1],[6],[8] Managing nerve injury-associated pain is complex and requires multidisciplinary teams of trained personnel to achieve satisfactory pain relief and a good quality of life, and to facilitate rehabilitation of the patient into the work force. Treatment should be initiated early and be both aggressive and progressive, beginning with drugs like tricyclic antidepressants and calcium channel ligands, combined with non-pharmacological therapies like physiotherapy, occupational therapy, interventional procedures, neurostimulation, and psychotherapy. In those patients with very severe or treatment-refractory pain, neurosurgical options must be considered. The primary aims of the current paper are to describe and analyze scenarios associated with pain as a result of peripheral nerve and plexus injuries, the pathophysiological mechanisms behind them, and the various therapeutic options that are available.
Brachial plexus and peripheral nerve injuries can be associated with any combinations of nociceptive, neuropathic and avulsion pain syndromes,[6],[12] and even with complex regional pain syndromes (CRPS) and phantom limb pain.[2],[5] Nociceptive pain is a protective physiological response by the nervous system, essential to preserving body integrity and detecting imminent threats and real tissue injury.[6],[12],[13],[14] It is associated with direct lesions involving the musculoskeletal system[6],[15] and with muscular disfunction secondary to myofascial syndromes characterized by painful spasms and muscular contractures.[6],[12] Neuropathic pain develops because the underlying lesion or disease affects the somatosensory system. It is caused by a peripheral nerve injury and its associated central nervous system (CNS) changes.[6],[12],[13],[14],[15],[16] Its symptoms can be 'negative', as is hypesthesia, thermal or mechanical anesthesia, hypalgesia and the loss of vibratory sense. In addition, its symptoms can be 'positive', including paresthesia, dysesthesia, hyperesthesia, allodynia and pain.[6],[13] Neuropathic pain caused by postganglionic brachial plexus lesions can arise from abnormal nerve regeneration, painful neuroma formation, and the compression of brachial plexus structures by fibrous tissues.[5],[12] However, with preganglionic lesions, whether or not the pain develops and its severity, also may be related to the number of axons affected [Figure 1].[5],[6],[8],[11],[17]
Neuropathic pain can appear immediately or as long as several months after the traumatic injury, and its intensity usually increases over time,[11],[12] related to the sympathetic nervous system plasticity mechanisms.[18] Early-onset pain that is severely intense from the beginning is highly suggestive of deafferentation pain, secondary to the avulsion of multiple roots.[1],[5],[7],[8],[11],[14] The pain is generally described as a constant burning and crushing sensation, associated with paroxysmal and unpredictable electrical shocks and throbbing throughout the affected limb.[3],[5],[8],[10],[11],[12],[14],[17] It occurs with such an intensity that it forces patients to cease certain activities.[3] Some pain is usually perceived in the hand, no matter which root is affected.[3],[5],[7],[8],[12] Some patients with C5 avulsion describe the shoulder pain. With C6 lesions, the pain is predominantly perceived in the thumb and index finger; while, with C7, C8 and T1 avulsions, the pain radiates from the elbow to the hand and is difficult to specifically localize.[3],[10],[11] The pain usually worsens with climate changes and improves during social events and recreational activities.[15] Chronic regional pain syndrome (CRPS) may be difficult to distinguish from chronic neuropathic pain. Both may have a sudden-onset burning and dysesthesia, and a distal distribution. However, the latter also may be associated with an excessive autonomic response, which can include sudden color changes in the affected limb; increased sweating followed by abrupt skin pallor and coldness; and, trophic disturbances involving the skin, hair and nails. A further distinctive characteristic is extreme sensitivity in the limb, to the point where the patient will withdraw it from even the slightest, lightest touch, even when distracted by the examiner.[19]
Peripheral nociceptor sensitization Nociceptors are peripheral receptors localized in the free endings of type C unmyelinated fibers and type A delta myelinic fibers. Sensitization is a special feature of nociceptors, which involves an increased excitability of the receptor. This in turn induces an increased responsiveness to nociceptive stimuli.[13] Once an axon is damaged, Wallerian degeneration occurs in the distal portion of the nerve. Both the axon and its myelin sheath experience degradation, whereupon the tissue becomes infiltrated with inflammatory cells that release pro-inflammatory and neural growth factors that augment the perception of painful stimuli (hyperalgesia) and lower the threshold for pain (allodynia).[6],[13],[14],[20] Peripheral ectopic discharges Postganglionic brachial plexus lesions are characterized by persistent connections between dorsal ganglia and central nervous system (CNS) neurons. With these lesions, increased and permanent neuronal activity should be related to the generation of ectopic ganglionic action potentials.[6],[20] Paresthesias and dysesthesias are caused by spontaneous discharges among A delta fibers, while disturbed excitability of type C fibers produces burning and shooting pain. Likewise, a rise in the number of sodium channels in the damaged nerve fibers disturbs neural transmission and promotes the development of pathologic connections between regenerating axons, a process called ephaptic coupling; this, in turn, causes short circuits of excitation in nociceptive neurons.[11],[13] Dorsal horn changes Central sensitization is a mechanism of pain amplification and of enhancing its chronic nature that increase the degree of the injury sustained by the somatosensory system.[6],[13],[18],[20] It involves the sensitization of glutamate N-methyl-D-aspartate (NMDA) receptors in the dorsal horn, with long-term changes.[13],[14],[20] Root avulsion is the lesion that has the strongest association with CNS plasticity changes.[6],[14],[18],[19] The sudden disconnection of the roots from the spinal cord produces primary changes in the affected segment, due to neuronal death, and secondary alterations related to the inflammatory response with the release of cytokines, and glial cell activation.[6],[13] These alter the substantia gelatinosa and Lissauer tract, which comprise the first point of integration of the input from primary sensory afferents.[5],[6] The dorsal root entry zone (DREZ) lesioning procedure specifically involves a neurosurgeon surgically entering the spinal cord to silence any damaged areas of pain-signaling nerve cells, to provide pain relief for patients with root avulsions.[6],[8],[19],[21] For some authors, the hyperactive state of the spinal cord neurons, due to lack of inhibition caused by spinal cord structural changes, could explain the persistent pain, regardless of the initial peripheral mechanisms responsible for it.[5],[6],[8],[9],[13],[14],[19],[21],[22] Others claim that the development of pain is mediated by non-avulsed roots, which could explain the improvement in pain observed after the primary, early root repair of brachial plexus injuries.[7] Cortical changes Functional imaging of the brain has demonstrated neuroplasticity processes within the brain cortex in patients with neuropathic pain syndromes.[11],[13] After peripheral nerve injuries, there is loss of the affector input to the sensorimotor cortex, resulting in changes in the somatotopic organization of body parts in both the sensory and motor cortices.[23] Some patients with complete brachial plexus lesions perceive limb movements, in addition to pain. This phenomenon, known as phantom limb sensations,[9] is observed in approximately 40% of patients with brachial plexus avulsions, though it is infrequent among those with other peripheral nerve injuries.[6] It also is associated with the reorganization of cortical areas related to the affected corporal segment. The extent of cortical reorganization is closely linked to the intensity of pain.[6],[9],[11],[13]
Achieving adequate control of pain and its associated symptoms is the primary objective of treatment, along with trying to avoid psychological deterioration and mood changes, and preserving sleep.[12],[24] The management should be a staged process [Figure 2].
Pharmacological treatment is generally the initial step in chronic pain management for peripheral nerve lesions.[12],[16],[25] Such treatment targets the use of CNS-acting drugs. Tricyclic antidepressants [TCA] (e.g., amitriptyline, nortriptyline), calcium channel ligands (e.g., pregabalin, gabapentin), other anticonvulsants (e.g., carbamazepine, clonazepam) and neuroleptic drugs have strong analgesic effects in ameliorating this type of pain.[5],[11] Based upon the pharmacological principle of potentiation synergy, it is strongly recommended that two or more drugs are combined. Combining a tricyclic antidepressant and either pregabalin or gabapentin is widely considered as the first-line pharmaceutical treatment, with certain opioids, other antidepressants and other anticonvulsants reserved for second-line therapy.[4],[11],[26],[27] Treatment usually is initiated with gabapentin or pregabalin, either alone or with a tricyclic antidepressant[4],[5],[11],[12],[19] If no improvement is observed after 6 to 8 weeks, other drugs should be considered, including other anticonvulsants like carbamazepine and lamotrigine, second line antidepressants like venlafaxin and duloxetine, and ultimately, an opioid analgesic.[11],[12] Calcium channel ligands: pregabalin and gabapentin The mechanical allodynia observed in patients with neuropathic pain might be caused by an increase in type N calcium channels among the central terminations of dorsal horn afferent neurons.[28] Gabapentin acts on gamma amino butyric acid (GABA) synapses by blocking voltage-dependent calcium channels. It is recommended that a low dose is used initially, typically 300 mg daily for 3 to 4 days, followed by gradually increasing the dose up to a maximum daily dose of 1200 mg thrice daily.[25] Its adverse effects include sleepiness, vertigo, ataxia, headache, weight gain, peripheral edema and asthenia.[26],[28] Pregabalin is the first anticonvulsant with documented efficacy in the treatment of peripheral and central neuropathic pain.[16],[26],[28] With this drug, the recommended starting dose is 50-75 mg per day, after which its dose also can be increased gradually to a maximum daily intake of 600 mg, divided into either two or three doses.[25] Its most common adverse effects are drowsiness, peripheral edema and dry mouth. Such side effects usually are mild and dose-dependent, often resolving with lowering of the dose, and certainly subside after the medication is discontinued.[26],[28] Antidepressants (serotonin-noradrenaline re-uptake inhibitors, SNRIs) The efficacy of SNRIs in treating neuropathic pain[4],[16] is independent of their antidepressant effects.[25],[26],[28] The anti-depressants used most frequently are TCAs — especially amitriptyline or nortriptyline — due to their effect on sodium channels, and inhibition of noradrenalin and serotonin re-uptake. They also antagonize muscarinic, histaminergic and alpha-adrenergic receptors, which explains their diverse adverse effects, which include a dry mouth, cognitive alterations, constipation, urinary retention, sedation, weight gain, orthostatic hypotension, and QT interval prolongation.[25],[26],[28] Contraindications to their use are closed-angle glaucoma, benign prostatic hypertrophy, and a history of myocardial infarction.[28] As with the previously-mentioned drugs, low doses are recommended initially, often beginning with 10-25 mg at night to reduce the risk of daily sedation, followed by slowly increasing the dose, as needed.[25],[26],[28] Effective analgesic doses generally are from 50 to 150 mg per day.[25],[28] An improved sleep, mood and anxiety are additional potential benefits of these drugs.[28] Other antidepressants that may be used for the second-line treatment include other inhibitors of serotonin and noradrenalin re-uptake, like duloxetine and venlafaxin. Opioids Opioid use is generally only considered when patients with neuropathic pain experience no more than a very limited response to first-line drugs. However, they are a good choice for acute neuropathic pain.[4],[25],[26] Tramadol, oxycodone and methadone are the opioids with the most published evidence supporting their efficacy in reducing neuropathic pain.[26] Tramadol is both a mu opioid receptor agonist and inhibitor of serotonin and noradrenaline re-uptake.[28] Oxycodone is the opioid with the most published clinical trials documenting its efficacy for neuropathic pain; as such, it is the drug listed in most clinical guidelines.[26] Opioids act at different levels of the peripheral and central nervous system. At the supra-spinal level, they interact with mu receptors within the peri-aqueductal gray substance (PGS), where they block pain transmission. At the spinal level, opioids inhibit dorsal horn neuronal impulses evoked by C fibers and local interneurons. At the peripheral level, the local application of opioids can have an effect similar to local anesthetics in a high concentration.[29] The most common adverse effects of opioid analgesics are nausea, constipation and sedation. It is recommended that the treatment starts with low doses, followed by a gradual upward or downward titration, as indicated, in association with laxatives and antiemetics.[26] Tramadol has its own unique adverse effects, including seizures, and serotonin syndrome[29] when combined with other SNRI-like antidepressants, monoamine oxidase inhibitors, antipsychotics, antiemetics and some analgesics.[30],[31] It also can trigger manic episodes in patients with a bipolar disorder.[32] Topical treatments Patches and lotions containing lidocaine for topical application can reduce hyperalgesia and allodynia[16] by acting upon the sodium channels over-expressed at the injured peripheral nerve endings. As systemic absorption is minimal with this route of administration, the likelihood of adverse effects is low, the most frequent undesirable effect being mild local skin reaction.[26] Capsaicin is an alkaloid derived from hot chili peppers that interacts with transient receptor potential cation channel subfamily V member 1 (TRPV1) receptors at the endings of type C fibers, producing desensitization to chemical, mechanical and thermal stimuli[33],[34] and, thereby, reducing pain transmission to the central nervous system.[34] Capsaicin and lidocaine are indicated as adjuvant therapies for patients with neuropathic pain, experiencing significant levels of dysesthesia, hyperalgesia and/or allodynia.[12],[13] Local anesthetics also can be very useful for administering of nerve blocks.[12] Non-pharmacological measures A follow-up with a psychotherapist with experience in treating patients suffering from chronic pain is strongly recommended.[12],[25] Some patients report a reduction in the intensity of pain when they use alcohol or marijuana, as well as with occupational therapy, acupuncture, physiotherapy, hypnosis and transcutaneous electrical nerve stimulation (TENS).[25] The last of these methods is a special form of low-frequency electrical stimulation designed to reduce pain. Its objective is to achieve neuromodulation, based upon Melzack and Wall's gate control theory of pain. It has a very low rate of adverse effects and complications.[5],[11],[12],[35] Although an initial success with TENS can be observed in up to 60-65% of patients, such benefits often wane over time, with only 20-30% of patients still reporting any meaningful analgesic effect after one or two months of treatment.[5],[35] Surgery The primary determinant of surgical success in treating neuropathic pain is the correct selection of patients.[21],[26] There are four basic options for the surgical management of neuropathic pain: decompression, reconstruction, ablation and modulation. The aim of decompressive procedures is to relieve peripheral nerves or roots from compression caused by the scar tissue, ligaments, tendons or tumors. Reconstructive techniques attempt to restore functional connectivity between the peripheral and central nervous system. Such reconstruction can be achieved directly by joining two damaged nerve endings or by performing nerve transfers. Both of these techniques can be performed with or without the use of nerve grafts. The ablative procedures include neurectomies, dorsal rhizotomy, dorsal ganglionectomy and dorsal root entry zone (DREZ) lesioning. Lastly, neuromodulation techniques seek to modify afferent or efferent neural pathways by administering either electrical stimuli (stimulators) or drugs (intrathecal pumps).[12] Primary nerve repair Neurolysis and nerve repair procedures, with or without grafts, can be sufficient to reduce pain caused by traumatic lesions affecting the peripheral nerves or the brachial plexus, even in some cases where root avulsions coexist.[5],[7],[8],[11],[27] Nerve transfers can achieve alleviation of painful syndromes in some patients, particularly with postganglionic injuries and partial avulsions.[5],[11],[17],[19],[27] Usually, pain begins to decrease, and may disappear, some months after the surgical intervention, even before motor and sensory recovery is observed.[11],[12],[17] DREZ lesioning Lesioning of the dorsal root entry zone (DREZ) is the method of choice to treat pain from brachial plexus root avulsions that fails to respond to pharmacological treatment and primary nerve repair.[5],[8],[10],[11],[12],[21],[36],[37] It is based on the concept of interrupting dorsal horn ascending pathways.[8],[12],[15],[16],[17],[18],[19],[21] This procedure is effective at relieving pain in 70 to 90% of patients,[8],[9],[10],[11],[12],[21],[27],[37] being particularly effective at reducing the paroxysmal component of avulsion pain.[11] Post intervention, pain may gradually reappears. However, according to several authors, 50 to 70% of patients report the presence of continued analgesia on a long-term basis.[5],[9],[12],[27] Among patients in whom the pain does recur, it usually is of tolerable intensity (approximately 20% of the original level of pain intensity) and is controllable with appropriate drugs.[12] Peripheral nerve stimulation Peripheral nerve stimulation achieves neuromodulation via implantation of a device directly onto the affected nerve, producing an electrical current to reduce pain.[38] The success rate of this approach ranges from 70 to 80% when treating post-surgical nerve lesions, injection injuries, and refractory compressive neuropathies.[39],[40],[41] Between 10 and 15% of patients experience some mild complication like a wound infection or electrode migration,[15],[40],[41] though some patients report undesirable muscular contractions as a result of repeated nerve stimulation. The use of this approach is not universally accepted, despite its having existed for many years and being a documented effective option for isolated nerve injuries. Spinal cord stimulation Spinal cord stimulation might act via the gate control theory of pain proposed by Melzack and Wall in 1965,[42] but its true mechanism of action is not completely known. The procedure entails implanting electrodes within the posterior epidural space, at the cervical or dorsal spinal cord level, that in turn are connected to an impulse generator.[5],[30] The indications for such a device include painful nerve lesions refractory to other treatments.[21],[26],[42] However, when complete root avulsion occurs, this approach generally is relatively ineffective due to the degeneration of target fibers up to the brainstem.[5],[10],[11],[21],[27] This method is an option for pain due to non-avulsive brachial plexus injury, and could be an option in those patients with persisting pain despite the performance of DREZ lesioning.[11] Cortical and deep-brain stimulation This procedure is reserved for those patients with neuropathic pain that fails to respond to any other form of treatment, amongst whom the reported success rates range from 36 to 45%.[11],[43] This approach also might be a good option as an adjuvant treatment in those patients with persistence of the continuous component of the avulsion pain after the DREZ lesioning.[11] In such patients, improvement could be related to cortical modulation of structures within the thalamus and cingulum that play an important role in maintaining the continuous component of avulsion pain.[11] Another hypothesis is that pain relief after cortical modulation is a response to the cortical activation of structures within the anti-descending nociceptive system.[43] Deep-brain stimulation of thalamic nuclei has also been used as a treatment modality for refractory avulsion pain and other refractory neuropathic pain disorders.[11],[43],[44] Intrathecal drug infusions Intrathecal infusions of analgesic medication are not usually adopted in patients with benign neuropathic pain, though they are commonly employed in treating oncological neuropathic pain.[45] Different drugs can be used, including opioids, calcium channel antagonists, NMDA antagonists, GABA agonists, alpha-2-adrenergic agonists, acetylcholinesterase inhibitors and somatostatin analogues.[15],[21],[27]
Neuropathic pain is very frequent among patients with a peripheral nerve or brachial plexus injury, with an incidence ranging from 67 to 95% overall, and from 80 to 90% when root avulsion has occurred. Several mechanisms are involved in the generation of neuropathic pain, including peripheral nociceptor sensitization, peripheral ectopic discharges, central sensitization with changes in the dorsal horn of the spinal cord, and cortical reorganization. The treatment must be multidisciplinary, starting with pharmacological measures (TCA, calcium channel inhibitors) in combination with non-pharmacological strategies like the use of TENS, topical agents, and physiotherapy, among others. A wide variety of surgical options exist. However, the most widely-used and accepted are primary nerve repair, DREZ lesioning for avulsion pain, spinal cord stimulation for non-avulsion neuropathic pain, and modulation by peripheral nerve stimulators. In refractory cases, other available options include deep brain and cortical stimulation. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Figure 1], [Figure 2]
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