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Management of Peripheral Nerve Neuralgia
CHAPTER 4
Management of Peripheral Nerve Neuralgia ANDREW C. ZACEST, MBBS, MS, FRACS, FFPMANZCA
HISTORICAL BACKGROUND The characteristic clinical features of pain of presumed peripheral nerve origin were described by physicians in the early 19th century and remain accurate to this day.1 These include the unique quality of neuropathic pain as well as sensory dysfunction and tenderness over the nerve particularly at points of compression. The term “neuralgia” was originally used as a descriptive term for all painful disorders attributed to peripheral nerves and was originally classified as a disease or “neurosis” or “nervous affection.” Later in the 19th century, classifications included neuralgia within the “hyperesthesias” and as a “functional” disorder of the nervous system, typically one of exclusion, made in the absence of evidence of a primary lesion of the nervous system. Not surprisingly, the term neuralgia came to be used loosely for a variety of conditions and a psychogenic origin was commonly inferred.2 During the course of the American Civil war, Silas Weir Mitchell coined the term “causalgia” to describe severe pain following traumatic nerve injury. Now termed complex regional pain syndrome, Mitchell noted that pain “in the shape of neuralgia” commonly follows nerve injury, is variable in presentation and intensity, often develops in a delayed fashion, and may involve other nerve territories. As noted earlier, Mitchell reported that the severity of the pain may lead some physicians to suspect the patient of “magnifying his pains.”3 Although peripheral nerve surgery was not routinely performed at this time, nerve resection was described with questionable benefit and amputation was frequently requested by patients. Although neuromas were described in the 17th century, Odier in 1811 described the sensitivity of the bulbous stump of the proximal portion of a transected nerve and Wood in 1828 named the terminal end bulb of an injured nerve a neuroma (cited in Ref. 4). Resection of neuromas back to good nerve was reported in
1886 by Richardson (cited in Ref. 5) and further developed with surgical experience of the treatment of peripheral nerve injury from the World Wars I and II. In 1921, Platt reported his results of “operations for causalgia,” including nerve resection and suture, intraneural injection of quinine and urea, and neurolysis, noting the best result for the former and worse for the latter.6 In the absence of obvious trauma, the pathophysiology of neuralgia was hypothesized to be due to “inflammation,” and the discovery and report of nervi nervorum by Victor Horsley in 1884 furthered this idea and the diagnosis of “neuritis” took favor.7 Weschler later proposed the term neuropathy as being more appropriate for nerve degeneration in the absence of inflammation in 1938.8 The current International Association for the Study of Pain (IASP) taxonomy from 1979 defines neuralgia as pain in the distribution of a nerve9 although, at the present, peripheral neuropathic pain, which may be due to several etiologies including secondary to peripheral nerve injury, is the current term.10 A recurring theme throughout the evolution of the concept of neuralgia to neuropathic pain has been the role of psychosocial factors, including Ochoa’s “psychogenic pseudoneuropathy”11 better explained today in terms of the sociopsychobiologic experience of pain. Most importantly, this concept has led to an appreciation of a multidisciplinary approach to assessing and treating patients with complex peripheral neuropathic pain.
PATHOPHYSIOLOGY OF PERIPHERAL NEUROPATHIC PAIN The pathophysiology of peripheral neuropathic pain following injury is complex and evolving but has been well summarized in recent publications and is the result of both experimental animal models and human 27
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data.10,12,13 After peripheral nerve injury, the key processes occurring at the periphery include ectopic neuronal firing, upregulation of sodium channels on injured fibers, neurogenic inflammation, increased expression of transient receptor potential V1 and adrenoreceptors on uninjured surrounding nerves, and Wallerian degeneration as well as regrowth of nerve fibers due to release of nerve growth factor, leading to peripheral sensitization. At the dorsal root ganglion (DRG), there is increased neurotransmitter release, proliferation of satellite glial, astrocyte, microglial and Schwann cells, and upregulation of ion channels.14 Within the spinal cord, central sensitization of second-order neurones occurs coupled with dysfunction of inhibitory interneurones and descending modulatory control systems. There is proliferation of glial and microglial populations, as well as an increase in membrane channel and excitatory neurotransmitters, resulting in pain in extraterritorial regions. Within the brain, neoplastic changes have been demonstrated in multiple locations, including the anterior cingulate cortex after experimental peripheral nerve injury in animals and also in patients with chronic neuropathic pain.15 An appreciation of this cascade of local, regional, and central pathophysiologic changes, which can arise from a peripheral nerve problem, helps in understanding the clinical presentation of patients and how specific therapies (pharmacology or interventions) may or may not work in treating patients with ostensibly simple peripheral nerve neuralgia. Neuromas develop as part of the normal repair process after nerve injury or as a result of chronic damage to nerves and may or may not be painful. Factors that appear to be associated with the development of a painful neuroma are the severity of nerve damage, superficial location, mechanosensitivity, and chronic injury or compression, e.g., from scar and contribute to increased nociceptor sensitivity, central sensitization, chemosensitivity to catecholamines due to upregulation of receptors and ectopic firing as discussed above. The high rates of chronic postsurgical pain are highly correlated with nerve damage and neuroma formation, for example, with nerve ingrowth into hernia mesh more likely in patients requiring explants for pain.16 The typical development of a painful neuroma over time from the onset of injury raises the possibility of prevention particularly with elective surgery and suggests that most neuromas do not cause symptoms and that early intervention including nerve repair or pharmacotherapy may help to prevent development.17
The pathology of nerve entrapment, the most common cause of peripheral neuropathic pain in humans, is incompletely understood because of the difficulty in obtaining human tissue. Chronic nerve compression has been associated with Schwann cell proliferation, apoptosis, demyelination, and remyelination in animal models in contrast to nerve injury in which Wallerian degeneration occurs.18 Other mechanisms include impaired microcirculation, small diameter axonal loss, sensory axon dysfunction, and distal reduction in intraepidermal nerve density.19 These processes may predate the injury to a peripheral nerve but may be important contributors to ongoing symptoms, including the pain following the injury. Of the nonsurgical causes of painful peripheral neuralgia or neuropathy, diabetes is the most common in the community, but a long differential diagnosis exists, including inherited channelopathies, neoplastic, metabolic, drugs, toxic, nutritional, infectious, and small fiber neuropathy. The pathophysiology of diabetic neuropathy is multifactorial but involves metabolic, vascular, autoimmune, and altered neurotrophic support and free-radical cascades with chronic hyperglycemia underpinning them all.13 Given the wide prevalence of diabetes and therefore neuropathy in the community, this is likely to be an important factor in pathology.
PATIENT ASSESSMENT The key question for a surgeon in assessing a patient with peripheral neuralgia or neuropathic pain is to what degree is the pathophysiology peripheral, e.g., localized neuroma or generalized. In addition, even if there is evidence of central sensitization, is there a significant peripheral component that would benefit from a peripheral intervention, which is usually less invasive and cheaper and may have the prospect of long-term benefit. The assessment involves combining the input from the history, clinical examination, and investigations to formulate a diagnosis of the etiology and pathophysiologic mechanisms involved in the patient’s pain syndrome. The history of the patient with peripheral neuropathic pain needs to be thorough to determine the likely etiology and possible pathophysiology, symptom complex of which pain may or may not be the main problem, a functional or impairment assessment, progression or resolution of symptoms, response to prior treatments, medical history including diabetes and cancer, pain history, patient expectations, and the psychosocial milieu including work.
CHAPTER 4 Management of Peripheral Nerve Neuralgia In the absence of a history of trauma, there is an extensive differential diagnosis of the causes of painful peripheral neuropathy as discussed earlier that should be worked through. Entrapment neurologic syndromes are usually straightforward, of slow onset, and progressive but may be atypical. In the acute setting conditions that mimic peripheral neuropathy including lumbar disc herniation, brachial neuritis, lumbar plexitis, or postherpetic neuralgia should be considered if the diagnosis is not clear and a neurology consult is sought for second opinion. In the setting of a history of trauma or surgery details of the evolution of symptoms, prior treatment records including operation notes will be essential to isolate the neural structures. Typically, there will be sensory disturbance or dysfunction as part of the nerve injury even if pain is not immediately apparent. In the case of prior nerve surgery, there may have been a period of pain relief before which the current symptoms are returned or not. The separation of nociceptive, neuropathic, or mixed components of pain on history is important in the trauma or postoperative situation, as the treatment of these will be very different. For example, the typical history of a patient with neuroma following hernia surgery, i.e., localized distal numbness, focal tenderness with distal radiation of pain into the nerve territory, or a paroxysmal or burning quality, will be very different to one with periostitis pubis.20 Although uncommon, nerve sheath tumors are typically benign and usually minimally symptomatic until large enough. However, if pain without a history of trauma and particularly with progressive neurologic symptoms is a prominent part of the history, a malignant nerve sheath tumor21 needs to be considered and urgently investigated. Physical examination of the patient with peripheral neuropathic pain must not only detail the neurologic deficit related to the putative injured peripheral nerve but also consider whether other neurologic diagnoses are present or possible to account for the pain, i.e., is the pain concordant with the one nerve? Even with the same peripheral nerve, two points of pathology may be possible particularly at points of compression. Quantitative sensory testing is being increasingly used particularly in research settings to document sensory and pain thresholds and may give insight into the pathophysiologic mechanisms, e.g., peripheral or central operant in the particular patient.10,12 They can also be repeated as should all neurologic examinations to document change or response to therapy. Signs beyond the distribution of the peripheral nerve in question, e.g.,
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allodynia, where a normally painless stimulus is painful, suggest central sensitization has occurred. Typical examination findings for a neuroma are a tender lump along the course of a peripheral nerve, sensitive to percussion with Tinel sign and often associated with distal sensory disturbance in the injured nerve. Combined with relief of symptoms from local anesthetic block, this finding is very supportive of neuroma and may be sufficient to therefore recommend surgery for exploration and removal of neuroma.20 Tinel sign may also be used at points of nerve compression in suspected entrapment and also to monitor recovery of nerve regrowth at the distal end as the paresthesia evoked implies that sensory axons are continuous with the central nervous system.
INVESTIGATIONS Electromyography (EMG) and nerve conduction studies can help to support or refute the clinical diagnosis of peripheral nerve dysfunction but have limitations and need to be performed at appropriate time intervals depending on the pattern of injury. The extent of nerve injury, as well as muscle denervation and reinnervation, can be characterized particularly over time. Conduction amplitudes and velocities can assess nerve damage from trauma or entrapment as well as the presence of polyneuropathy with the exception of small fiber neuropathy. Spinal root avulsion, upper motor neurone pathology, and primary muscle disease can also be differentiated by using EMG. Neuroimaging of the patient with peripheral nerve neuralgia is helpful in supporting the clinical history and examination findings. Ultrasound is an effective, cheap, and real-time tool in demonstrating neuromas and peripheral nerve tumors; however, differentiation may be difficult but is usually based on history.17 Nerve entrapment, subluxation, and nerve volume can also be assessed reliably. Interestingly, in a recent study, ultrasound was found to be more sensitive and equivalent specificity and better showed multifocal lesions compared with MRI.22 Ultrasound can also be used preoperatively and intraoperatively to localize lesions. MRI may be useful for entrapment syndromes, traumas, masses, and acquired or hereditary demyelinating polyneuropathies in peripheral nerve disorders23 and does have greater resolution for visualizing neural structure using multiplanar reconstruction and showing relationship to adjacent structures. Concomitant spinal imaging can be performed in cases where there is a differential diagnosis. Muscle and joint relations as well as changes in muscle bulk, which may occur in
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denervation, can be clearly seen. For peripheral nerve tumors, which may be painful, MRI is clearly the modality of choice and can distinguish benign from malignant lesions.21 With nerve injury, diffusion tensor imaging (DTI) sequences can track axonal degeneration and regeneration following grafting to supplement clinical evaluation.24 Nerve caliber, flattening or swelling, can also be assessed and be correlated with the clinical syndrome.
TREATMENT The treatment of peripheral neuropathic pain is directed by the results of the diagnostic formulation and can be broadly considered in terms of pharmacologic, functional, surgical, and neuromodulation options. Management should occur in the context of or with the availability of a multidisciplinary team. Most patients referred with peripheral neuropathic pain will already be on pharmacotherapy, which may include tricyclic antidepressants, anticonvulsants, gabapentinoids, opioids, norepinephrine reuptake inhibitors, lignocaine, and capsaicin patches as prescribed. A detailed review of pharmacotherapy for peripheral neuropathic pain is beyond the scope of this chapter; however, numerous reviews have determined that many patients do not receive appropriate treatment for neuropathic pain, and only a minority of patients have an adequate response to drug therapy.25,26 In spite of these limitations and pending results of more specific phenotypically driven pharmacologic trials using Qualitative Sensory Testing (QST), optimization of drug therapy should be attempted in all patients, as this may be sufficient in some patients. Physical therapy may also be prescribed to minimize deconditioning and retrain muscles in patients with peripheral neuropathic pain with modest but variable benefit according to a recent metaanalysis.27 Surgical treatment for pain secondary to nerve entrapment in the nontraumatic setting is usually straightforward, provided the diagnosis is concordant with nerve conduction findings and the nerve decompression is thorough, which are the two most common causes of failure. More difficult situations may arise with a history of trauma, focal pain without neurologic symptoms, advanced axonal damage, workers’ compensation or litigation, diabetes, or history of chronic pain. Simple decompression may also be combined with transposition of the nerve if position is an important component of the neural compression. Preoperative screening questionnaires to assess the patient pain experience and evaluate risk factors for poor surgical outcomes may be helpful.28
Surgical treatment of peripheral nerve neuroma is based on the premise that a significant proportion of the patient’s pain complaint is related to the neuroma or that this peripheral source of the pain is a significant contributor to a centralized process. The latter scenario may occur, for example, in a patient with postamputational pain with a stump neuroma. Successful removal of a neuroma may obviate the need for more complex pain interventions.4 Patient selection for surgery is the most important factor in predicting outcomes from neuroma surgery. A discrete clinical nerve syndrome, palpable lump, positive Tinel sign, concordant imaging, distal pain relief following local anesthetic block, and satisfactory psychosocial evaluation will give the best chance of a positive surgical finding and improvement postoperatively.4,17,20,29,30 The surgical strategies available for neuroma resection depend on the location of the neuroma in the nerve, particularly if it is on a distal sensory or mixed sensory motor nerve with preserved motor function (neuroma-in-continuity). In the former situation the neuroma can be excised, the distal sensory nerve sacrificed, and the stump reimplanted into a more favorable location but usually bone or muscle. A variety of technical nuances to deal with the sectioned end have been proposed, including ligation alone, diathermy of the cut end, proximal nerve crush, and nerve transposition into muscle or intermuscular planes without tension.4,17,20,29e31 Neuromas that occur in an amputation stump, the so-called “stump neuromas,” are another category of neuroma and may be addressed surgically only if a discrete lesion can be identified, relief can be achieved with local anesthetic block, and sufficient tissue can cover the cut end. In the author’s experience, a more diffuse pain syndrome within the stump is more common. The outcomes from neuroma surgery treatment have been sobering historically with high likelihood of pain recurrence even with initial good outcomes; however, improvements in patient selection and surgical techniques have occurred. Follow-up in the literature has typically been short, and patient populations have been heterogeneous. The trend toward patientreported outcomes and quality-of-life measures will allow better comparison between studies in the future. Burchiel reported a 44% surgical success defined by reduction in pain by 50% with mean follow-up of 11 months in a cohort of patients with preoperatively and intraoperatively defined neuroma that could be resected and relocated.29 Those patients with neuromas-in-continuity who underwent neurolysis
CHAPTER 4 Management of Peripheral Nerve Neuralgia alone had no improvement, but those with compression that could be relieved and transposed could improve. Zacest et al. reported 3-year follow-up of patients who underwent resection of ilioinguinal nerve for posthernia pain, most of which had a neuroma identified intraoperatively and noted return of pain was common (68%) although some degree of pain relief was also achieved in 67%.20 Domeshek et al. reported improvement in four patient-rated qualities, including pain, depression, disability and quality of life, in 70 patients who underwent neuroma resection, proximal crush, and transposition as well as decompression of associated nerve compression and were followed up at 24 months with a questionnaire and interview. Neuromas attached to large sensorimotor nerves were dissected off the main trunk. For all patients combined, the Visual Analog Pain Score dropped from 6.74 to 5.1 postoperatively (P < .001) and the degree of improvement was greater for patients with higher pain scores and depression. Ninety percent of patients had chronic pain for 6 months, suggesting that chronic sensitization was probably present. The authors of the last paper conclude that statistically significant improvements in patientreported pain and quality of life can occur following surgery in a center with expertise; however, many of the patients will continue to have chronic pain. The modest results from surgery reported above have led others to avoid surgical intervention altogether or recommend other interventions for patients with intractable peripheral neuropathic pain following trauma or surgery. Moreover, in many patients, perhaps most, in this group, there may be scarce macroscopic evidence of a structural lesion. Available interventions may range from peripheral lesional procedures at the peripheral nerve level or DRG level or neuromodulation strategies from the peripheral nerve level to spinal cord level. Each approach (lesion vs. neuromodulation) presents advantages and disadvantages that need to be carefully weighed in the individual patient. Theoretically, at least, in the likely situation that the patient with peripheral pain has developed some degree of central sensitization neuromodulation strategies would seem the better long-term strategy. Although a number of local lesional treatments have been trialed for suspected or proven neuromas, including repeated steroid injection, botulinum toxin, tumor necrosis factor inhibitor, phenol, cryotherapy, and radiofrequency (RF), the results are variable with recurrent pain. Their main advantages are low cost, minimal intervention, and repeatability, and if they only reduce the pain from a peripheral pain generator may be a valuable adjuvant to more comprehensive strategies.17
31
Peripheral nerve stimulation (PNS) is a neuromodulation technique in which electrical stimulation is applied to peripheral nerves to ameliorate chronic pain through preferential activation of myelinated fibers inducing long-term depression in synaptic efficiency. Initially developed in the 1960s as a percutaneous technique using an electrode over a peripheral nerve, and later as a surgical electrode, less invasive options include transcutaneous electrical stimulation, percutaneous electrical stimulation (PENS) using electrical stimulation of needles, or most recently noninvasive PENS or external non invasive percutaneous electrical stimulation (PENS). A recent prospective observation study enrolled 76 patients with a variety of conditions (postherpetic neuralgia, causalgia, and postsurgical pain) for a single treatment with a 21-gauge needle with maintenance of pain improvement for 3e6 months.32 A sham-controlled trial of EN-PENS is currently in progress.33 The potential advantages of PENS or EN-PENS are its minimally invasive nature, low side effect profile, and ability to be repeated in patients who might not be ideal candidates for implantable neurostimulators. Whether these therapies are capable of providing longterm relief for peripheral-based intractable pain is yet to be determined. PNS has also been successfully used for pain relief of painful stumps and neuromas in a number of case reports and recent small series.34e36 In the latter study, high-frequency stimulation (10 kHz) was used, resulting in nerve conduction block without paresthesia from the painful neuroma with patients reporting the greatest degree of pain relief they had ever experienced compared with other therapies. This is further evidence of peripherally mediated central pain and that peripheral therapies may help such patients. DRG stimulation has recently been demonstrated to be effective in treatment of neuropathic pain, including complex regional pain syndrome,37 phantom limb pain,38 and postsurgical pain syndrome39 with results maintained beyond a year. The relative advantages of this new target include the ability to cover areas difficult to target with conventional spinal cord stimulation (SCS), such as the groin, foot, and back with lower voltages required, minimizing unnecessary limb stimulation and patient preference. Although the present results are very promising, the longer-term outcomes are awaited. SCS has been the mainstay of neuromodulation therapy for neuropathic pain for the last three decades and has the advantage of being testable, reversible, and adjustable. Moreover, if it can be determined or is suspected that central sensitization has occurred, then the spinal cord would appear to be a logical place to
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target. Although there have been many technologic advances in lead design and stimulation parameters including conventional tonic, high frequency, and burst, a percutaneous trial with stimulation coverage of the painful area can be performed simply as an outpatient to assess therapeutically whether a permanent system may be an option. Although the highest levels of evidence for benefit of SCS have been for spinal-origin pain,40,41 phantom limb and neuroma pain have been treated successfully with SCS since 1969; however, the data derived chiefly from case reports and surgical series have been variable.42,43 Central neuromodulation, including deep brain stimulation and motor cortex stimulation, has been used for refractory neuropathic pain but is not approved by the Food and Drug Administration because of lack of evidence.44 With the explosion of neuromodulation options discussed above and the reluctance of many practitioners to create an irreversible lesion in a patient with neuropathic pain, lesional options including standard RF, root or ganglion section, once practiced historically, have fallen out of favor. An exception may be pulsed RF, which delivers a pulsed RF current of 42 C to the neural target and results in less tissue destruction. Its efficacy in neuropathic pain, despite a recent metaanalysis, suggests a potential benefit in some conditions but little in others.45
CONCLUSION The optimum treatment of the patient with peripheral neuropathic pain, depending on the etiology and pain phenotype, will range from simple pharmacotherapy to consideration of peripheral surgery, including regional lesioning, and then to neuromodulation options within a multidisciplinary framework. Given the pathophysiologic cascade that occurs following peripheral nerve injury, some degree of central sensitization is likely in most patients. In spite of this reality, a peripheral source may be amenable to surgical intervention and is worth considering although the outcomes are modest and the chance of recurrent pain is high. Neuromodulation strategies, if successful, appear to hold the best current hope of longer-term pain control but are rarely curative and require regular maintenance. Such therapies are best provided within a multidisciplinary pain clinic. In the future, better understanding of the pathophysiology of peripherally driven neuropathic pain and how this manifests in clinical pain phenotypes using tools such as QST testing will allow a more personalized approach to obtaining better pain outcomes for our patients.
REFERENCES 1. Armstrong J. On rheumatism and the diagnosis of gout and rheumatism. Lancet. 1825;7:65e69. 2. Quintner JL, Bove GM. From neuralgia to peripheral neuropathic pain: evolution of a concept. Reg Anesth Pain Med. 2001;26(4):368e372. 3. Mitchell SW, Morehouse GR, Keen WW. The classic. Gunshot wounds and other injuries of nerves by S. Weir Mitchell, M.D., George R. Morehouse, M.D., and William W. Keen, M.D. Clin Orthop Relat Res. 1982;(163):2e7. 4. Burchiel KJ, Israel Z,H. Surgical treatment of painful peripheral nerve injuries. In: Burchiel KJ, ed. Surgical Management of Pain. New York: Thieme; 2002:654e665. 5. Little KM, et al. An eclectic history of peripheral nerve surgery. Neurosurg Clin N Am. 2004;15(2):109e123. 6. Platt H. The surgery of the peripheral nerve injuries of warfare. Br Med J. 1921;1(3147):596e600. 7. Horsley V. Preliminary communications on the existence of sensory nerves and nerve endings in nerve trunks, the true “nervi nerorum”. BMJ. 1884;1(1204):166. 8. Wechsler I. Multiple peripheral neuropathy versus multiple neuritis. JAMA. 1938;110(23):1910e1913. 9. Bonica JJ. The need of a taxonomy. Pain. 1979;6(3):247e248. 10. Baron R, et al. Peripheral neuropathic pain: a mechanismrelated organizing principle based on sensory profiles. Pain. 2017;158(2):261e272. 11. Ochoa JL. Essence, investigation, and management of “neuropathic” pains: hopes from acknowledgment of chaos. Muscle Nerve. 1993;16(10):997e1008. 12. Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9(8):807e819. 13. Jay GW, Barkin RL. Neuropathic pain: etiology, pathophysiology, mechanisms, and evaluations. Dis Mon. 2014;60(1):6e47. 14. Guha D, Shamji MF. The dorsal root ganglion in the pathogenesis of chronic neuropathic pain. Neurosurgery. 2016; 63(suppl 1):118e126. 15. Jaggi AS, Singh N. Role of different brain areas in peripheral nerve injury-induced neuropathic pain. Brain Res. 2011;1381:187e201. 16. Bendavid R, et al. A mechanism of mesh-related postherniorrhaphy neuralgia. Hernia. 2016;20(3):357e365. 17. Rajput K, Reddy S, Shankar H. Painful neuromas. Clin J Pain. 2012;28(7):639e645. 18. Pham K, Gupta R. Understanding the mechanisms of entrapment neuropathies. Review article. Neurosurg Focus. 2009;26(2):E7. 19. Schmid AB, et al. The relationship of nerve fibre pathology to sensory function in entrapment neuropathy. Brain. 2014;137(Pt 12):3186e3199. 20. Zacest AC, et al. Long-term outcome following ilioinguinal neurectomy for chronic pain. J Neurosurg. 2010;112(4): 784e789. 21. Wasa J, et al. MRI features in the differentiation of malignant peripheral nerve sheath tumors and neurofibromas. Am J Roentgenol. 2010;194(6):1568e1574.
CHAPTER 4 Management of Peripheral Nerve Neuralgia 22. Zaidman CM, et al. Detection of peripheral nerve pathology: comparison of ultrasound and MRI. Neurology. 2013;80(18):1634e1640. 23. Kwee RM, et al. Accuracy of MRI in diagnosing peripheral nerve disease: a systematic review of the literature. Am J Roentgenol. 2014;203(6):1303e1309. 24. Simon NG, Kliot M. Diffusion weighted MRI and tractography for evaluating peripheral nerve degeneration and regeneration. Neural Regen Res. 2014;9(24):2122e2124. 25. Attal N, Bouhassira D. Pharmacotherapy of neuropathic pain: which drugs, which treatment algorithms? Pain. 2015;156(suppl 1):S104eS114. 26. Finnerup NB, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162e173. 27. Ginnerup-Nielsen E, et al. Physiotherapy for pain: a metaepidemiological study of randomised trials. Br J Sports Med. 2016;50(16):965e971. 28. Tang DT, et al. Nerve entrapment: update. Plast Reconstr Surg. 2015;135(1):199ee215e. 29. Burchiel KJ, Johans TJ, Ochoa J. The surgical treatment of painful traumatic neuromas. J Neurosurg. 1993;78(5): 714e719. 30. Domeshek LF, et al. Surgical treatment of neuromas improves patient-reported pain, depression, and quality of life. Plast Reconstr Surg. 2017;139(2):407e418. 31. Brunelli GA. Prevention of damage caused by sural nerve withdrawal for nerve grafting. Hand Surg. 2002;7(2): 163e166. 32. Rossi M, et al. A novel mini-invasive approach to the treatment of neuropathic pain: the PENS study. Pain Physician. 2016;19(1):E121eE128. 33. Johnson S, et al. A randomised, patient-assessor blinded, sham-controlled trial of external non-invasive peripheral nerve stimulation for chronic neuropathic pain following peripheral nerve injury (EN-PENS trial): study protocol for a randomised controlled trial. Trials. 2016;17(1):574. 34. Cornish PB. Successful peripheral neuromodulation for phantom limb pain: an update. Pain Med. 2016;17(5): 991.
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35. Meier K, et al. Peripheral neuromodulation for the treatment of postamputation neuroma pain: a case report. A A Case Rep. 2017;8(2):29e30. 36. Soin A, Fang ZP, Velasco J. Peripheral neuromodulation to treat postamputation pain. Prog Neurol Surg. 2015;29: 158e167. 37. Deer TR, et al. Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial. Pain. 2017;158(4):669e681. 38. Eldabe S, et al. Dorsal root ganglion (DRG) stimulation in the treatment of phantom limb pain (PLP). Neuromodulation. 2015;18(7):610e616; discussion 616e617. 39. Liem L, et al. One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain. Neuromodulation. 2015;18(1):41e48; discussion 48e49. 40. Kumar K, et al. The effects of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation. Neurosurgery. 2008;63(4):762e770; discussion 770. 41. North RB, et al. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: a randomized, controlled trial. Neurosurgery. 2005;56(1):98e106; discussion 106e107. 42. Aiyer R, et al. A systematic review on the treatment of phantom limb pain with spinal cord stimulation. Pain Manag. 2017;7(1):59e69. 43. Viswanathan A, Phan PC, Burton AW. Use of spinal cord stimulation in the treatment of phantom limb pain: case series and review of the literature. Pain Pract. 2010;10(5): 479e484. 44. Moore NZ, Lempka SF, Machado A. Central neuromodulation for refractory pain. Neurosurg Clin N Am. 2014;25(1): 77e83. 45. Shi Y, Wu W. Treatment of neuropathic pain using pulsed radiofrequency: a meta-analysis. Pain Physician. 2016; 19(7):429e444.
Management of Peripheral Nerve Neuralgia ANDREW C. ZACEST, MBBS, MS, FRACS, FFPMANZCA
HISTORICAL BACKGROUND The characteristic clinical features of pain of presumed peripheral nerve origin were described by physicians in the early 19th century and remain accurate to this day.1 These include the unique quality of neuropathic pain as well as sensory dysfunction and tenderness over the nerve particularly at points of compression. The term “neuralgia” was originally used as a descriptive term for all painful disorders attributed to peripheral nerves and was originally classified as a disease or “neurosis” or “nervous affection.” Later in the 19th century, classifications included neuralgia within the “hyperesthesias” and as a “functional” disorder of the nervous system, typically one of exclusion, made in the absence of evidence of a primary lesion of the nervous system. Not surprisingly, the term neuralgia came to be used loosely for a variety of conditions and a psychogenic origin was commonly inferred.2 During the course of the American Civil war, Silas Weir Mitchell coined the term “causalgia” to describe severe pain following traumatic nerve injury. Now termed complex regional pain syndrome, Mitchell noted that pain “in the shape of neuralgia” commonly follows nerve injury, is variable in presentation and intensity, often develops in a delayed fashion, and may involve other nerve territories. As noted earlier, Mitchell reported that the severity of the pain may lead some physicians to suspect the patient of “magnifying his pains.”3 Although peripheral nerve surgery was not routinely performed at this time, nerve resection was described with questionable benefit and amputation was frequently requested by patients. Although neuromas were described in the 17th century, Odier in 1811 described the sensitivity of the bulbous stump of the proximal portion of a transected nerve and Wood in 1828 named the terminal end bulb of an injured nerve a neuroma (cited in Ref. 4). Resection of neuromas back to good nerve was reported in
1886 by Richardson (cited in Ref. 5) and further developed with surgical experience of the treatment of peripheral nerve injury from the World Wars I and II. In 1921, Platt reported his results of “operations for causalgia,” including nerve resection and suture, intraneural injection of quinine and urea, and neurolysis, noting the best result for the former and worse for the latter.6 In the absence of obvious trauma, the pathophysiology of neuralgia was hypothesized to be due to “inflammation,” and the discovery and report of nervi nervorum by Victor Horsley in 1884 furthered this idea and the diagnosis of “neuritis” took favor.7 Weschler later proposed the term neuropathy as being more appropriate for nerve degeneration in the absence of inflammation in 1938.8 The current International Association for the Study of Pain (IASP) taxonomy from 1979 defines neuralgia as pain in the distribution of a nerve9 although, at the present, peripheral neuropathic pain, which may be due to several etiologies including secondary to peripheral nerve injury, is the current term.10 A recurring theme throughout the evolution of the concept of neuralgia to neuropathic pain has been the role of psychosocial factors, including Ochoa’s “psychogenic pseudoneuropathy”11 better explained today in terms of the sociopsychobiologic experience of pain. Most importantly, this concept has led to an appreciation of a multidisciplinary approach to assessing and treating patients with complex peripheral neuropathic pain.
PATHOPHYSIOLOGY OF PERIPHERAL NEUROPATHIC PAIN The pathophysiology of peripheral neuropathic pain following injury is complex and evolving but has been well summarized in recent publications and is the result of both experimental animal models and human 27
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data.10,12,13 After peripheral nerve injury, the key processes occurring at the periphery include ectopic neuronal firing, upregulation of sodium channels on injured fibers, neurogenic inflammation, increased expression of transient receptor potential V1 and adrenoreceptors on uninjured surrounding nerves, and Wallerian degeneration as well as regrowth of nerve fibers due to release of nerve growth factor, leading to peripheral sensitization. At the dorsal root ganglion (DRG), there is increased neurotransmitter release, proliferation of satellite glial, astrocyte, microglial and Schwann cells, and upregulation of ion channels.14 Within the spinal cord, central sensitization of second-order neurones occurs coupled with dysfunction of inhibitory interneurones and descending modulatory control systems. There is proliferation of glial and microglial populations, as well as an increase in membrane channel and excitatory neurotransmitters, resulting in pain in extraterritorial regions. Within the brain, neoplastic changes have been demonstrated in multiple locations, including the anterior cingulate cortex after experimental peripheral nerve injury in animals and also in patients with chronic neuropathic pain.15 An appreciation of this cascade of local, regional, and central pathophysiologic changes, which can arise from a peripheral nerve problem, helps in understanding the clinical presentation of patients and how specific therapies (pharmacology or interventions) may or may not work in treating patients with ostensibly simple peripheral nerve neuralgia. Neuromas develop as part of the normal repair process after nerve injury or as a result of chronic damage to nerves and may or may not be painful. Factors that appear to be associated with the development of a painful neuroma are the severity of nerve damage, superficial location, mechanosensitivity, and chronic injury or compression, e.g., from scar and contribute to increased nociceptor sensitivity, central sensitization, chemosensitivity to catecholamines due to upregulation of receptors and ectopic firing as discussed above. The high rates of chronic postsurgical pain are highly correlated with nerve damage and neuroma formation, for example, with nerve ingrowth into hernia mesh more likely in patients requiring explants for pain.16 The typical development of a painful neuroma over time from the onset of injury raises the possibility of prevention particularly with elective surgery and suggests that most neuromas do not cause symptoms and that early intervention including nerve repair or pharmacotherapy may help to prevent development.17
The pathology of nerve entrapment, the most common cause of peripheral neuropathic pain in humans, is incompletely understood because of the difficulty in obtaining human tissue. Chronic nerve compression has been associated with Schwann cell proliferation, apoptosis, demyelination, and remyelination in animal models in contrast to nerve injury in which Wallerian degeneration occurs.18 Other mechanisms include impaired microcirculation, small diameter axonal loss, sensory axon dysfunction, and distal reduction in intraepidermal nerve density.19 These processes may predate the injury to a peripheral nerve but may be important contributors to ongoing symptoms, including the pain following the injury. Of the nonsurgical causes of painful peripheral neuralgia or neuropathy, diabetes is the most common in the community, but a long differential diagnosis exists, including inherited channelopathies, neoplastic, metabolic, drugs, toxic, nutritional, infectious, and small fiber neuropathy. The pathophysiology of diabetic neuropathy is multifactorial but involves metabolic, vascular, autoimmune, and altered neurotrophic support and free-radical cascades with chronic hyperglycemia underpinning them all.13 Given the wide prevalence of diabetes and therefore neuropathy in the community, this is likely to be an important factor in pathology.
PATIENT ASSESSMENT The key question for a surgeon in assessing a patient with peripheral neuralgia or neuropathic pain is to what degree is the pathophysiology peripheral, e.g., localized neuroma or generalized. In addition, even if there is evidence of central sensitization, is there a significant peripheral component that would benefit from a peripheral intervention, which is usually less invasive and cheaper and may have the prospect of long-term benefit. The assessment involves combining the input from the history, clinical examination, and investigations to formulate a diagnosis of the etiology and pathophysiologic mechanisms involved in the patient’s pain syndrome. The history of the patient with peripheral neuropathic pain needs to be thorough to determine the likely etiology and possible pathophysiology, symptom complex of which pain may or may not be the main problem, a functional or impairment assessment, progression or resolution of symptoms, response to prior treatments, medical history including diabetes and cancer, pain history, patient expectations, and the psychosocial milieu including work.
CHAPTER 4 Management of Peripheral Nerve Neuralgia In the absence of a history of trauma, there is an extensive differential diagnosis of the causes of painful peripheral neuropathy as discussed earlier that should be worked through. Entrapment neurologic syndromes are usually straightforward, of slow onset, and progressive but may be atypical. In the acute setting conditions that mimic peripheral neuropathy including lumbar disc herniation, brachial neuritis, lumbar plexitis, or postherpetic neuralgia should be considered if the diagnosis is not clear and a neurology consult is sought for second opinion. In the setting of a history of trauma or surgery details of the evolution of symptoms, prior treatment records including operation notes will be essential to isolate the neural structures. Typically, there will be sensory disturbance or dysfunction as part of the nerve injury even if pain is not immediately apparent. In the case of prior nerve surgery, there may have been a period of pain relief before which the current symptoms are returned or not. The separation of nociceptive, neuropathic, or mixed components of pain on history is important in the trauma or postoperative situation, as the treatment of these will be very different. For example, the typical history of a patient with neuroma following hernia surgery, i.e., localized distal numbness, focal tenderness with distal radiation of pain into the nerve territory, or a paroxysmal or burning quality, will be very different to one with periostitis pubis.20 Although uncommon, nerve sheath tumors are typically benign and usually minimally symptomatic until large enough. However, if pain without a history of trauma and particularly with progressive neurologic symptoms is a prominent part of the history, a malignant nerve sheath tumor21 needs to be considered and urgently investigated. Physical examination of the patient with peripheral neuropathic pain must not only detail the neurologic deficit related to the putative injured peripheral nerve but also consider whether other neurologic diagnoses are present or possible to account for the pain, i.e., is the pain concordant with the one nerve? Even with the same peripheral nerve, two points of pathology may be possible particularly at points of compression. Quantitative sensory testing is being increasingly used particularly in research settings to document sensory and pain thresholds and may give insight into the pathophysiologic mechanisms, e.g., peripheral or central operant in the particular patient.10,12 They can also be repeated as should all neurologic examinations to document change or response to therapy. Signs beyond the distribution of the peripheral nerve in question, e.g.,
29
allodynia, where a normally painless stimulus is painful, suggest central sensitization has occurred. Typical examination findings for a neuroma are a tender lump along the course of a peripheral nerve, sensitive to percussion with Tinel sign and often associated with distal sensory disturbance in the injured nerve. Combined with relief of symptoms from local anesthetic block, this finding is very supportive of neuroma and may be sufficient to therefore recommend surgery for exploration and removal of neuroma.20 Tinel sign may also be used at points of nerve compression in suspected entrapment and also to monitor recovery of nerve regrowth at the distal end as the paresthesia evoked implies that sensory axons are continuous with the central nervous system.
INVESTIGATIONS Electromyography (EMG) and nerve conduction studies can help to support or refute the clinical diagnosis of peripheral nerve dysfunction but have limitations and need to be performed at appropriate time intervals depending on the pattern of injury. The extent of nerve injury, as well as muscle denervation and reinnervation, can be characterized particularly over time. Conduction amplitudes and velocities can assess nerve damage from trauma or entrapment as well as the presence of polyneuropathy with the exception of small fiber neuropathy. Spinal root avulsion, upper motor neurone pathology, and primary muscle disease can also be differentiated by using EMG. Neuroimaging of the patient with peripheral nerve neuralgia is helpful in supporting the clinical history and examination findings. Ultrasound is an effective, cheap, and real-time tool in demonstrating neuromas and peripheral nerve tumors; however, differentiation may be difficult but is usually based on history.17 Nerve entrapment, subluxation, and nerve volume can also be assessed reliably. Interestingly, in a recent study, ultrasound was found to be more sensitive and equivalent specificity and better showed multifocal lesions compared with MRI.22 Ultrasound can also be used preoperatively and intraoperatively to localize lesions. MRI may be useful for entrapment syndromes, traumas, masses, and acquired or hereditary demyelinating polyneuropathies in peripheral nerve disorders23 and does have greater resolution for visualizing neural structure using multiplanar reconstruction and showing relationship to adjacent structures. Concomitant spinal imaging can be performed in cases where there is a differential diagnosis. Muscle and joint relations as well as changes in muscle bulk, which may occur in
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denervation, can be clearly seen. For peripheral nerve tumors, which may be painful, MRI is clearly the modality of choice and can distinguish benign from malignant lesions.21 With nerve injury, diffusion tensor imaging (DTI) sequences can track axonal degeneration and regeneration following grafting to supplement clinical evaluation.24 Nerve caliber, flattening or swelling, can also be assessed and be correlated with the clinical syndrome.
TREATMENT The treatment of peripheral neuropathic pain is directed by the results of the diagnostic formulation and can be broadly considered in terms of pharmacologic, functional, surgical, and neuromodulation options. Management should occur in the context of or with the availability of a multidisciplinary team. Most patients referred with peripheral neuropathic pain will already be on pharmacotherapy, which may include tricyclic antidepressants, anticonvulsants, gabapentinoids, opioids, norepinephrine reuptake inhibitors, lignocaine, and capsaicin patches as prescribed. A detailed review of pharmacotherapy for peripheral neuropathic pain is beyond the scope of this chapter; however, numerous reviews have determined that many patients do not receive appropriate treatment for neuropathic pain, and only a minority of patients have an adequate response to drug therapy.25,26 In spite of these limitations and pending results of more specific phenotypically driven pharmacologic trials using Qualitative Sensory Testing (QST), optimization of drug therapy should be attempted in all patients, as this may be sufficient in some patients. Physical therapy may also be prescribed to minimize deconditioning and retrain muscles in patients with peripheral neuropathic pain with modest but variable benefit according to a recent metaanalysis.27 Surgical treatment for pain secondary to nerve entrapment in the nontraumatic setting is usually straightforward, provided the diagnosis is concordant with nerve conduction findings and the nerve decompression is thorough, which are the two most common causes of failure. More difficult situations may arise with a history of trauma, focal pain without neurologic symptoms, advanced axonal damage, workers’ compensation or litigation, diabetes, or history of chronic pain. Simple decompression may also be combined with transposition of the nerve if position is an important component of the neural compression. Preoperative screening questionnaires to assess the patient pain experience and evaluate risk factors for poor surgical outcomes may be helpful.28
Surgical treatment of peripheral nerve neuroma is based on the premise that a significant proportion of the patient’s pain complaint is related to the neuroma or that this peripheral source of the pain is a significant contributor to a centralized process. The latter scenario may occur, for example, in a patient with postamputational pain with a stump neuroma. Successful removal of a neuroma may obviate the need for more complex pain interventions.4 Patient selection for surgery is the most important factor in predicting outcomes from neuroma surgery. A discrete clinical nerve syndrome, palpable lump, positive Tinel sign, concordant imaging, distal pain relief following local anesthetic block, and satisfactory psychosocial evaluation will give the best chance of a positive surgical finding and improvement postoperatively.4,17,20,29,30 The surgical strategies available for neuroma resection depend on the location of the neuroma in the nerve, particularly if it is on a distal sensory or mixed sensory motor nerve with preserved motor function (neuroma-in-continuity). In the former situation the neuroma can be excised, the distal sensory nerve sacrificed, and the stump reimplanted into a more favorable location but usually bone or muscle. A variety of technical nuances to deal with the sectioned end have been proposed, including ligation alone, diathermy of the cut end, proximal nerve crush, and nerve transposition into muscle or intermuscular planes without tension.4,17,20,29e31 Neuromas that occur in an amputation stump, the so-called “stump neuromas,” are another category of neuroma and may be addressed surgically only if a discrete lesion can be identified, relief can be achieved with local anesthetic block, and sufficient tissue can cover the cut end. In the author’s experience, a more diffuse pain syndrome within the stump is more common. The outcomes from neuroma surgery treatment have been sobering historically with high likelihood of pain recurrence even with initial good outcomes; however, improvements in patient selection and surgical techniques have occurred. Follow-up in the literature has typically been short, and patient populations have been heterogeneous. The trend toward patientreported outcomes and quality-of-life measures will allow better comparison between studies in the future. Burchiel reported a 44% surgical success defined by reduction in pain by 50% with mean follow-up of 11 months in a cohort of patients with preoperatively and intraoperatively defined neuroma that could be resected and relocated.29 Those patients with neuromas-in-continuity who underwent neurolysis
CHAPTER 4 Management of Peripheral Nerve Neuralgia alone had no improvement, but those with compression that could be relieved and transposed could improve. Zacest et al. reported 3-year follow-up of patients who underwent resection of ilioinguinal nerve for posthernia pain, most of which had a neuroma identified intraoperatively and noted return of pain was common (68%) although some degree of pain relief was also achieved in 67%.20 Domeshek et al. reported improvement in four patient-rated qualities, including pain, depression, disability and quality of life, in 70 patients who underwent neuroma resection, proximal crush, and transposition as well as decompression of associated nerve compression and were followed up at 24 months with a questionnaire and interview. Neuromas attached to large sensorimotor nerves were dissected off the main trunk. For all patients combined, the Visual Analog Pain Score dropped from 6.74 to 5.1 postoperatively (P < .001) and the degree of improvement was greater for patients with higher pain scores and depression. Ninety percent of patients had chronic pain for 6 months, suggesting that chronic sensitization was probably present. The authors of the last paper conclude that statistically significant improvements in patientreported pain and quality of life can occur following surgery in a center with expertise; however, many of the patients will continue to have chronic pain. The modest results from surgery reported above have led others to avoid surgical intervention altogether or recommend other interventions for patients with intractable peripheral neuropathic pain following trauma or surgery. Moreover, in many patients, perhaps most, in this group, there may be scarce macroscopic evidence of a structural lesion. Available interventions may range from peripheral lesional procedures at the peripheral nerve level or DRG level or neuromodulation strategies from the peripheral nerve level to spinal cord level. Each approach (lesion vs. neuromodulation) presents advantages and disadvantages that need to be carefully weighed in the individual patient. Theoretically, at least, in the likely situation that the patient with peripheral pain has developed some degree of central sensitization neuromodulation strategies would seem the better long-term strategy. Although a number of local lesional treatments have been trialed for suspected or proven neuromas, including repeated steroid injection, botulinum toxin, tumor necrosis factor inhibitor, phenol, cryotherapy, and radiofrequency (RF), the results are variable with recurrent pain. Their main advantages are low cost, minimal intervention, and repeatability, and if they only reduce the pain from a peripheral pain generator may be a valuable adjuvant to more comprehensive strategies.17
31
Peripheral nerve stimulation (PNS) is a neuromodulation technique in which electrical stimulation is applied to peripheral nerves to ameliorate chronic pain through preferential activation of myelinated fibers inducing long-term depression in synaptic efficiency. Initially developed in the 1960s as a percutaneous technique using an electrode over a peripheral nerve, and later as a surgical electrode, less invasive options include transcutaneous electrical stimulation, percutaneous electrical stimulation (PENS) using electrical stimulation of needles, or most recently noninvasive PENS or external non invasive percutaneous electrical stimulation (PENS). A recent prospective observation study enrolled 76 patients with a variety of conditions (postherpetic neuralgia, causalgia, and postsurgical pain) for a single treatment with a 21-gauge needle with maintenance of pain improvement for 3e6 months.32 A sham-controlled trial of EN-PENS is currently in progress.33 The potential advantages of PENS or EN-PENS are its minimally invasive nature, low side effect profile, and ability to be repeated in patients who might not be ideal candidates for implantable neurostimulators. Whether these therapies are capable of providing longterm relief for peripheral-based intractable pain is yet to be determined. PNS has also been successfully used for pain relief of painful stumps and neuromas in a number of case reports and recent small series.34e36 In the latter study, high-frequency stimulation (10 kHz) was used, resulting in nerve conduction block without paresthesia from the painful neuroma with patients reporting the greatest degree of pain relief they had ever experienced compared with other therapies. This is further evidence of peripherally mediated central pain and that peripheral therapies may help such patients. DRG stimulation has recently been demonstrated to be effective in treatment of neuropathic pain, including complex regional pain syndrome,37 phantom limb pain,38 and postsurgical pain syndrome39 with results maintained beyond a year. The relative advantages of this new target include the ability to cover areas difficult to target with conventional spinal cord stimulation (SCS), such as the groin, foot, and back with lower voltages required, minimizing unnecessary limb stimulation and patient preference. Although the present results are very promising, the longer-term outcomes are awaited. SCS has been the mainstay of neuromodulation therapy for neuropathic pain for the last three decades and has the advantage of being testable, reversible, and adjustable. Moreover, if it can be determined or is suspected that central sensitization has occurred, then the spinal cord would appear to be a logical place to
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target. Although there have been many technologic advances in lead design and stimulation parameters including conventional tonic, high frequency, and burst, a percutaneous trial with stimulation coverage of the painful area can be performed simply as an outpatient to assess therapeutically whether a permanent system may be an option. Although the highest levels of evidence for benefit of SCS have been for spinal-origin pain,40,41 phantom limb and neuroma pain have been treated successfully with SCS since 1969; however, the data derived chiefly from case reports and surgical series have been variable.42,43 Central neuromodulation, including deep brain stimulation and motor cortex stimulation, has been used for refractory neuropathic pain but is not approved by the Food and Drug Administration because of lack of evidence.44 With the explosion of neuromodulation options discussed above and the reluctance of many practitioners to create an irreversible lesion in a patient with neuropathic pain, lesional options including standard RF, root or ganglion section, once practiced historically, have fallen out of favor. An exception may be pulsed RF, which delivers a pulsed RF current of 42 C to the neural target and results in less tissue destruction. Its efficacy in neuropathic pain, despite a recent metaanalysis, suggests a potential benefit in some conditions but little in others.45
CONCLUSION The optimum treatment of the patient with peripheral neuropathic pain, depending on the etiology and pain phenotype, will range from simple pharmacotherapy to consideration of peripheral surgery, including regional lesioning, and then to neuromodulation options within a multidisciplinary framework. Given the pathophysiologic cascade that occurs following peripheral nerve injury, some degree of central sensitization is likely in most patients. In spite of this reality, a peripheral source may be amenable to surgical intervention and is worth considering although the outcomes are modest and the chance of recurrent pain is high. Neuromodulation strategies, if successful, appear to hold the best current hope of longer-term pain control but are rarely curative and require regular maintenance. Such therapies are best provided within a multidisciplinary pain clinic. In the future, better understanding of the pathophysiology of peripherally driven neuropathic pain and how this manifests in clinical pain phenotypes using tools such as QST testing will allow a more personalized approach to obtaining better pain outcomes for our patients.
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35. Meier K, et al. Peripheral neuromodulation for the treatment of postamputation neuroma pain: a case report. A A Case Rep. 2017;8(2):29e30. 36. Soin A, Fang ZP, Velasco J. Peripheral neuromodulation to treat postamputation pain. Prog Neurol Surg. 2015;29: 158e167. 37. Deer TR, et al. Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: a randomized comparative trial. Pain. 2017;158(4):669e681. 38. Eldabe S, et al. Dorsal root ganglion (DRG) stimulation in the treatment of phantom limb pain (PLP). Neuromodulation. 2015;18(7):610e616; discussion 616e617. 39. Liem L, et al. One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain. Neuromodulation. 2015;18(1):41e48; discussion 48e49. 40. Kumar K, et al. The effects of spinal cord stimulation in neuropathic pain are sustained: a 24-month follow-up of the prospective randomized controlled multicenter trial of the effectiveness of spinal cord stimulation. Neurosurgery. 2008;63(4):762e770; discussion 770. 41. North RB, et al. Spinal cord stimulation versus repeated lumbosacral spine surgery for chronic pain: a randomized, controlled trial. Neurosurgery. 2005;56(1):98e106; discussion 106e107. 42. Aiyer R, et al. A systematic review on the treatment of phantom limb pain with spinal cord stimulation. Pain Manag. 2017;7(1):59e69. 43. Viswanathan A, Phan PC, Burton AW. Use of spinal cord stimulation in the treatment of phantom limb pain: case series and review of the literature. Pain Pract. 2010;10(5): 479e484. 44. Moore NZ, Lempka SF, Machado A. Central neuromodulation for refractory pain. Neurosurg Clin N Am. 2014;25(1): 77e83. 45. Shi Y, Wu W. Treatment of neuropathic pain using pulsed radiofrequency: a meta-analysis. Pain Physician. 2016; 19(7):429e444.