Jovin Z. et al.

REVIEW ARTICLE UDC 616.8-009.7-07

ASSESSMENT OF NEUROPATHIC PAIN AND CLINICAL EVALUATION OF PATIENTS WITH SUSPECTED NEUROPATHIC PAIN PROCENA I KLINIKA EVALUACIJA PACIJENATA SA SUSPEKTNIM NEUROPATSKIM BOLOM Zita Jovin1, Milan Cvijanovi1, Miroslav Ilin1, Aleksandar Kopitovi1, Aleksandar Jei1

Abstract: Pain is an unpleasant sensory and emotional experience associated with existing or potential damage to the tissue or that is experienced as such. According to the current definition, the term neuropathic pain refers to pain that occurs as a direct consequence of a lesion or disease affecting the somatosensory system. Neuropathic pain is particularly problematic for its severity, chronicity and resistance to common analgesics. It affects around 2-3% of the general population, although the estimates vary widely. Evaluation of neuropathic pain includes neurophysiological tests, skin biopsy, quantitative sensory testing, physical examination and pain assessment. Neuropathic pain causes positive and negative symptoms and can occur spontaneously or following a provoking stimulus. A detailed medical history and thorough clinical evaluation aid localizing the damage to the neuraxis. Precise determination of localization, intensity, quality and pattern of pain are of the utmost importance. Key words: neuropathic pain, clinical evaluation Saetak: Bol je neprijatno senzorno i emocionalno iskustvo udrueno sa aktuelnim ili potencijalnim oteenjem tkiva ili je doivljeno kao takvo. Prema poslednjoj definiciji termin neuropatski bol odnosi se na bol koji nastaje kao direktna posledica lezije ili bolesti koja zahvata somatosenzorni sistem. Specijalno je problematian zbog njegove jaine, hroniciteta i rezistentnosti na uobiajene analgetike. Oko 2-3% populacije pati od njega, iako postoje razliiti podaci. Vrlo je vana procena neuropatskog bola koja podrazumeva neurofizioloke testove, biopsiju koe, kvantitativno senzorno testiranje, fizikalni pregled pacijenta i merenje bola. Uzrokuje pojavu negativnih i pozitivnih simptoma, spontanog i stimulusom izazvanog bola. Detaljna istorija bolesti, opsean kliniki pregled pomau u lokalizaciji oteenja unutar neuroaksisa. Vrlo je vano odrediti lokalizaciju, intenzitet, kvalitet i vremensku distribuciju bola. Kljune rei: neuropatski bol, klinika evaluacija

1 Clinic of Neurology, Clinical Center of Vojvodina, Novi Sad, Serbia.

Correspondence to: Zita Jovin,MD, Clinic of Neurology, Clinical Center of Vojvodina, Hajduk Veljka 1, 21000 Novi Sad, Serbia, E-mail: zitajovin@yahoo.com * Received: October 16, 2009; accepted June 6, 2010.

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INTRODUCTION Pain commonly originates from activation of primary nociceptive afferents by current or potential stimuli due to tissue damage and the processing of these activities within the nociceptive system. Pain is an unpleasant sensory and emotional experience associated with an existing or potential damage to the tissue, or that is experienced as such. Classification of pain according to the pathogenesis 1. nociceptive pain 2. neuropathic pain 3. psychogenic pain 4. idiopathic pain Classification of pain according to duration 1. acute pain 2. subacute pain 3. chronic pain In addition, pain can be initiated by activity generated within the nociceptive system without an adequate stimulation of its peripheral sensory endings. This type of pain is called neuropathic. DEFINITION According to the current definition, the term neuropathic pain refers to pain occurring as a direct consequence of a lesion or disease affecting the somatosensory system. (1). The term disease has replaced the previous term dysfunction that was poorly defined and could be wrongly interpreted, including normal plasticity of the nociceptive system. The term disease, however, suggests an identified disease process such as inflammation, autoimmune conditions, or chanalopathi-

es, whereas lesion indicates macro- or microscopically identified damage. The restriction to the somatosensory system is required since disease or lesion of other parts of the nervous system may cause other pain types that should not be confused with neuropathic pain, such as pain associated with spasticity and rigidity that is caused by activation of nociceptive afferents in the muscles (5). Neuropathic pain is described as burning, stabbing and electrical. It can be constant, aching, and paroxysmal. EPIDEMIOLOGY Epidemiology of neuropathic pain has not been studied thoroughly yet, partly due to a wide range of associated conditions. Chronic pain is not uncommon, although the prevalence in adults varies widely, from 2%-40%. Chronic pain comprises a nociceptive and a neuropathic component and is often multifactorial. The estimated 3.75 million cases of chronic neuropathic pain in the USA include various conditions, such as cancer pain, pain due to spinal cord injury, lumbar pain and phantom pain. Approximately 45% of patients registered in health care organizations in the USA have recurrent and persisting pain, from lumbar pain to facial pain, and more than 25% of pain clinic patients in Great Britain have neuropathic pain syndromes. Neuropathic pain associated with diseases such as diabetes mellitus and herpes zoster has been most extensively studied and described, however these conditions are not the main causes of neuropathic pain. Radiculopathy, which may be the main cause of many cases of lumbar pain, is likely the most common cause of pain originating in peripheral nerves. (4,5).

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Table 1 Clinical conditions associated with neuropathic pain

Central nervous system brain infarction cortical and subcortical spinal cord trauma demyelination syringomyelia and syringobulbia neoplastic and other compressive lesions trigeminal and glosopharyngeal neuralgia migraine* fibromyalgia* Peripheral nervous system nerve compression/entrapment neuropathies traumatic nerve injury ischemic neuropathies polyneuropathies (hereditary, metabolic, toxic, inflammatory, paraneoplastic, nutritional, vasculitic, infectious) plexopathies (neoplastic, autoimmune, postradiation, traumatic) nerve root compression postamputation stump and phantom pain postherpetic neuralgia cancer induced neuropathy (infiltration, chemotherapy induced, radiation induced, surgically induced)

TYPES OF NEUROPATHIC PAIN Neuropathic pain results from damage to the central and/or peripheral nervous system, an impending impairment or dysfunction, frequently in the absence of pain producing impulses. Damage to the nervous system causes loss of sensibility (negative symptoms), where the degree of loss approximates with the severity of impairment. A minority of cases present with different types of pain and dysesthesias (positive symptoms). Blocking of nerve conduction in neuropathic states causes nerve dysfunction that can result in numbness, weakness and loss of deep tendon reflexes in

the area of the involved nerve. Neuropathic conditions also cause aberrant symptoms of spontaneous and provoked pain. Spontaneous pain (continuous or intermittent) is commonly described as sharp, stabbing or burning. Pain provoked by a stimulus is characterized by hyperalgesia (increased pain induced by painful stimuli) and allodynia (pain caused by non-painful stimuli), that result from mechanical, thermal or chemical stimulation. These sensory abnormalities can spread outside the nerve distribution, which can lead to a false diagnosis of a functional or psychosomatic disorder (6).

Table 2 Sensory symptoms and signs associated with neuropathic pain

Symptoms/signs Allodynia Anesthesia Dysesthesia Hyperalgesia Hyperpathy Hypoesthesias Paresthesias Phantom pain Pain not caused by nociceptive stimulus (clothes, mild touch). Can be mechanical (e.g. mild pressure), dynamic (caused by non-painful stimulus shifting), or thermal (caused by nonpainful hot or cold stimuli) Loss of normal sensitivity in the affected area Spontaneous or provoked unpleasant abnormal sensation Exaggerated response to mild nociceptive stimulus Delayed and explosive responses to nociceptive stimulus Decrease in normal sensitivity Non-painful spontaneous abnormal sensation Painful sensation of the presence of a limb that has been removed (e.g. amputated limb), or pain in the absence of current injury

ASSESSMENT OF PAIN Pain is a complex experience dependent on cognitive, emotional and educational factors. It therefore demands tools that can measure it objectively. The following four degrees of objectivity can be 32

differentiated: 1. Laboratory tests that use quantitative means to measure objective response (neurophysiological tests and skin biopsy) 2. Quantitative sensory testing, which, although employing quantitative grading of stimuli, depends on the patients subjective assessment, 3. bedside evalu-

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ation that depends on the examiners experience and the patients ability and willingness to cooperate 4. Pain questionnaires that depend entirely on patients responses (7). NEUROPHYSIOLOGICAL TESTING Standard neurophysiological responses to an electrical stimulus, such as nerve conduction studies and somatosensory evoked potentials (SEP), can identify, localize and quantify damage along peripheral or central sensory pathways, however, they do not assess the function of nociceptive pathways (8). The leading approach currently is utilization of laser stimulators to emit heat-spreading impulses that selectively incite free nerve endings (A and C) in the superficial skin layer. Consensus of over 200 studies currently accepts that laser- evoked potentials (A- LEPs) are nociceptive responses. Late LEPs enable simpler and much more reliable neurophysiological assessment of the function of nociceptive pathways and are useful in the diagnosis of the peripheral and central neuropathic pain (8). Their major drawback in the clinical practice is their limited availability. Ultralate LEPs (referring to activation of C fibers) are technically much more difficult to record, and there are a few studies evaluating their usefulness in patients with neuropathic pain (9). The contact heat evoked potentials have been invented recently and still require clinical validation (10). BIOPSY Painful neuropathies typically and primarily affect small nerve fibers. Early detection of small fiber neuropathy by nerve biopsy may be fruitless, since the assessment of small fibers is troublesome and demands electronic microscopy. Percutaneous needle biopsy can quantify A and C nerve fibers by measuring density of intraepidermal nerve fibers (IENF). Damage to IENF is seen in various neuropathies that are characterized by small fiber axonal loss. Percutaneous needle biopsy is simple, minimally invasive and optimal for follow up. However, despite these advantages, it is useless in central pain and demyelinating neuropathies, and it is currently available only in several research centers (11).

QUANTITATIVE SENSORY TESTING (QST) QST is analysis of perception in response to external stimuli of controlled intensity. Detection and pain thresholds are determined by applying stimuli to the skin in an ascending and descending order of magnitude. Mechanical sensitivity for tactile stimuli is measured using plastic filaments, pinprick sensation with weighted needles, and vibration sensitivity with an electronic vibrameter. Thermal perception and thermal pain are measured using a probe that operates on a thermoelectric principle. QST has been used for early diagnosis and followup of small fiber neuropathies that cannot be assessed by standard nerve conduction studies, and has proved useful in early detection of diabetic neuropathy. QST is particularly suitable for quantification of mechanical and thermal allodynia and hyperalgesia and painful neuropathic syndromes, and it has been used in pharmacological studies of therapeutic efficacy to provoked pain (5). However, QST abnormalities do not provide a definite evidence of neuropathic pain, because QST shows changes also in non-neuropathic pain conditions, such as rheumatoid arthritis and inflammatory arthromyalgias. QST is time-consuming and therefore difficult to perform in clinical practice (5). CLINICAL EVALUATION A lot of symptoms, signs, and testing are needed in order to adequately and comprehensively define mechanisms involved in the development of a neuropathic pain syndrome. A detailed medical and surgical history is the first step in understanding pain etiology. Thorough clinical examination allows the clinician to integrate the patients current symptoms and start localizing the involved elements of the neuraxis. Identifying pain localization, quality, intensity and pattern is of utmost importance. Neurological examination comprises simple tests for the assessment of presence or absence of specific stimulus-provoked signs. Evaluation of sensibility, in particular in order to elicit hypoesthesia (numbness) or hyperesthesia (hyperpathy and/or allodynia), should be done carefully. 33

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Differentiation between mechanical and thermal allodynia may have clinical significance. Evaluation of reflexes, comprehensive motor studies and evaluation of the vegetative nervous system are necessary for understanding of neuropathy. MEASUREMENT OF PAIN Ancillary tools for assessment of pain characteristics are measuring instruments, i.e. pain scales, grading systems and questionnaires. Unidimensional scales are based on self-assessment of pain, they are easy to use, efficient and demand minimal effort from the examinee. They disadvantage is the insufficiently defined upper limit. The Numerical Rating Scale is commonly used scale. Patients are asked to rate their pain on a scale 0-10 or 0-5 (12). Visual Analogue Scale is not suitable for older patients with vision and cognitive deficits Descriptive scale is used to grade pain using descriptors, such as no pain, mild pain, moderate, severe, extreme. If presented verbally, it is easily understandable even to patients with advanced stages of dementia (13). Categorization scales enable patients to rate pain intensity using verbal or visual descriptors. Continuous application of pain rating scales enables monitoring therapeutic response, occurrence of new pain or worsening of existing pain (13). Mutidimensional pain assessment involves application of a range of different instruments (13). Brief Pain Inventory (BPI) evaluates pain and the patients subjective assessment of the effects of pain of daily activities and function. McGill Pain Questionnaire (MPQ) enables rating multiple dimensions of subjective experience (sensory, affective, evaluative) (13). Neuropathic Pain Scale (NPS) assesses eight qualities of neuropathic pain (sharp, dull, hot, cold, sensitive, itching, deep, superficial) and rates each with 0-10. 34

Depending on the purpose of measurement, i.e. general measurement of only chronic pain, measurement specific to certain pain syndrome or quality of life, various instruments for multidimensional pain assessment have been designed (e.g. Randall Chronic Pain Scale, Ronald-Morris Disability Scale, Sickness Impact Profile). Over the recent years several screening methods for differentiation of neuropathic and nociceptive pain have been accepted. Some of them, such as NPQ (Neuropathic Pain Questionnaire (14), ID Pain (15), i PainDETECT (20), employ only interview. The Leeds Assessement of Neuropathic Simptoms and Signs (LANSS) (16) and the Douleur Neuropathique en 4 Questions (DN4) (17) use both interview and various studies of tactile hypesthesia, soft touch pain, and these scales show better sensitivity and specificity than former, which implies the significance of clinical examination. CLINICAL EVALUATION OF PATIENTS WITH SUSPECTED NEUROPATHIC PAIN PATIENT HISTORY Pain intensity Pain scales Assessed at each visit in order to monitor therapeutic response Description of sensory symptoms (18) Quality of pain: burning, sharp, stabbing, cold, allodynia (pain induced by a light touch of clothes or bed sheets) Frequent non-painful sensations: pricking, tingling, itching, numbness Temporal variation Neuropathic pain commonly becomes more severe as the day advances (19) If the pain severity progresses over months, a neoplastic process should be suspected

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Functional impact Impact on sleep (19), self-care, daily activities, work, social and sexual function (20), mood and suicidal ideas (21) Previous treatment Neuropathic pain is usually resistant to acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) Adequate titrated doses of specific drugs should be determined and documented Alcohol and substance abuse History of dependence disorders can affect the decision about prescribing opioids and cannabinoids Previous dependence should be considered with a psychologist and/or psychiatrist Interaction of sedatives and alcohol and other substances should be considered CLINICAL EXAMINATION Motor examination Motor weakness can occur in the distribution of the involved nerve True weakness should be differentiated from antalgic weakness Deep tendon reflexes May be decreased or absent in the distribution of the affected nerve Sensibility examination Light touch, pin prick, vibration responses and proprioception can be reduced or absent in the affected nerve territory Sensory disturbance can expand outside the nerve innervation territory Dynamic allodynia (pain provoked by gently brushing the skin with a cotton ball) Thermal allodynia (burning sensation in response to an ice cube placed on the skin) Hyperalgesia to a pin prick test (exaggerated pain following a pin prick)

Pain on leg lifting suggests irritation of lumbar nerve roots Myofascial trigger points confirm existence of myofascial pain along with neuropathic Tinels sign (distally radiating paresthesias provoked by tapping of damaged or regenerated nervous fibers) Skin examination Changes in the skin temperature, color, sweating or hair growth suggest complex regional pain syndrome (CRPS) (22) Residual dermatomal scars may persist following herpes zoster infection Skin changes characteristic for diabetes mellitus SPECIAL TESTS CT and MRI Facilitate specific diagnosis (e.g. disk herniation, tumor infiltration) Electromyography and nerve conduction studies, other neurophysiological methods (SEP< LEP) Skin and nerve biopsy Quantitative sensory testing Three-phase bone scan May facilitate diagnosis of CRPS (22) Laboratory testing Additional tests to aid identifying causes of neuropathies, e.g. Glucose tolerance test, thyroid function, vitamin B12 levels, CD4+ T lymphocyte counts. CONCLUSION The cause of neuropathic pain often remains unknown despite thorough evaluation, and caution is needed before pronouncing pain idiopathic or psychogenic. Over the past years there have been huge advances in pain assessment. Assessment of the patient with suspected neuropathic pain should be directed towards excluding treatable conditions (e.g. spinal cord compressi35

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on, neoplasms), confirming the diagnosis of neuropathic pain and identification of clinical findings (e.g. insomnia, autonomic neuropathy) that can facilitate establishing an adequate treatment.

12. England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ, et al. Evaluation of distal symmetric polyneuropathy: The role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Muscle Nerve 2009;39:106115. 13. American Pain Society; National Pharmaceutical Council. Pain: Current Understanding of Assessment, Management, and Treatments. Continuing education program, 2006. Gleniev (IL): American Pain Society 14. Melzack R. The McGill Pain Questionnaire: Major Properties and Scoring Methods. Pain 1975;1:277-99. 15. Freynhagen R, Baron R, Gockel U, Tolle T . PainDETECT: A new screening questionnaire to detect neuropathic components in patients with back pain. Curr Med Res Opin 2006;22:19111920. 16. Bennett MI. The LANSS Pain Scale: The Leeds Assessment of Neuropathic Symptoms and Signs. Pain 2001; 92: 147157. 17. Bouhassira D, Attal N, Alchaar H, Boureau F, Bruxelle J, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:2936. 18. Bouhassira D, Attal N, Alchaar H, Boureau F, Bruxelle J, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:2936. 19. Odrcich M, Bailey JM, Cahill CM, et al. Chronobiological characteristics of painful diabetic neuropathy and postherpetic neuralgia: Diurnal pain variation and effects of analgesic therapy. Pain 2006;120:207-12. 20. Smith MT, Haythornthwaite JA. How do sleep disturbance and chronic pain interrelate? Insights from the longitudinal and cognitive-behavioral clinical trials literature.Sleep Med Rev 2004;8:119-32. 21. Haythornthwaite JA, Benrud-Larsen LM. Psychological aspects of neuropathic pain. Clin J Pain 2000;16:S101-5. 22. Kozin F, Soin JS, Ryan LM, et al. Bone scintigraphy in the reflex sympathetic dystrophy syndrome. Radiology 1981;138:437-43.

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1. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, et al. Neuropathic pain: Redefinition and a grading system for clinical and research purposes. Neurology 2008;70:16301635. 2. Max MB, Schafer SC, Culnane M, et al. Association of pain relief with drug side effects in postherpetic neuralgia: a single-dose study of clonidine, codeine, ibuprofen, and placebo. Clin Pharmacol Ther 1988;43:363-71. 3. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 1998;5:209-27. 4. Jensen TS, Gottrup H, Sindrup SH, et al. The clinical picture of neuropathic pain. Eur J Pharmacol 2001;429:1-11. 5. Cruccu G, Anand P, Attal N, Garcia-Larrea L,Haanpaa M, et al. EFNS guidelines on neuropathic pain assessment. Eur J Neurol 2004;11:153162. 6. Cruccu G, Aminoff MJ, Curio G, Guerit JM, Kakigi R, et al. Recommendations for the clinical use of somatosensory-evoked potentials. Clin Neurophysiol 2008;119:17051719. 7. Garcia-Larrea L, Convers P, Magnin M, AndreObadia N, Peyron R, et al. Laser-evoked potential abnormalities in central pain patients: The influence of spontaneous and provoked pain. Brain 2002;125:2766 2781. 8. Treede RD, Lorenz J, Baumgartner U. Clinical usefulness of laser-evoked potentials. Neurophysiol Clin 2003;33:303314. 9. Truini A, Galeotti F, Haanpaa M, Zucchi R, Albanesi A, et al. Pathophysiology of pain in postherpetic neuralgia: A clinical and neurophysiological study. Pain 2008;140: 405410. 10. Granovsky Y, Matre D, Sokolik A, Lorenz J, Casey KL. Thermoreceptive innervation of human glabrous and hairy skin: A contact heat evoked potential analysis. Pain 2005;115:238247. 11. Lauria G, Cornblath DR, Johansson O, McArthur JC, Mellgren SI, et al. EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral neuropathy. Eur J Neuro 2005;l12:747758.

Reviewers comment Review article by Z. Jovin et al. cannot be better timed to raise our awareness about a difficult subject of neuropathic pain. There is an urgent move to increase pain awareness throughout the world,

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from developed countries to developing countries. Immediately following the International Association of Pain Congress in Montreal , Canada, there will be a Pain Summit during the first week of September with wide participation, from practicing physicians, researchers, to drug companies and different civic and political organizations. The reason is that pain patients are underdiagnosed and undertreated. For us neurologist it is even more urgent, as we frequently deal with patients complaining of pain associated with peripheral or central nervous disorders. Understanding of peripheral neuropathic pain is still legging new strides in areas of nociceptive pain. Central pain is even bigger enigma, especially with finding of dissociated sensory loss in post-stoke and spinal cord injury pain patients. These findings and resulting hypotheses are against common sense of pathogenesis of usual pains-nociceptive pains. This is probably a main reason that there are no medications specifically developed to address this odd condition.

This excellent article comprehensively reviews the current state of the art definition, subtypes, and diagnostic approaches to neuropathic pain. It should help us better understand spectrum of neuropathic pain, choose a right diagnostic approach and hopefully lead to a better management of these difficult to treat patients with chronic pains and dysesthesias. Logical next step would be a review article about treatment options in neuropathic pain, which is even more formidable task.

Aleksandar Beric, MD, D.Sc Professor of Neurology, Neurosurgery and Orthopedic Surgery, NYU School of Medicine, New York

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