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Neurogenic Pain: Diagnosis and Treatment
Pain that arises from the nervous system is termed "neurogenic." Peripheral neurogenic pain may follow transient pressure upon or stretching of a peripheral nerve or root, or reflect sustained damage to a nerve ("neuropathic pain") such as in polyneuropathy, entrapment neuropathy, or after herpes zoster.1 Neurogenic pain may have a central origin such as stroke, multiple sclerosis, or trauma, especially of the spinal cord. Diagnosis Correct diagnosis allows tailoring treatment to the pathophysiologic mechanisms that trigger and maintain the painful condition. Assessing the pain location, intensity, quality, time course, precipitating and relieving factors, as well as its impact on physical and psychosocial function is the first step in clinical analysis.2 Diagnosis depends upon, first, the neuroanatomical distribution of the pain and, second, evidence of sensory dysfunction involving a peripheral nerve, plexus, nerve root or central pathway. If the affected nerve or pathway is mixed motor and sensory, then weakness, muscle atrophy, or reflex abnormalities may be additional clues to neural involvement. The diagnosis may be obvious but sometimes a thorough neurological examination is needed to uncover the neurogenic origin of the pain. A pain drawing made by the patient frequently gives a good indication of the neuroanatomic distribution and quality of the pain (Fig 1).
regardless of modality. Sensory dysfunction may be manifested as hypo. increasing pain to normally painful stimuli (hyperalgesia) or pain due to normally nonpainful stimuli (allodynia) (Fig 2). Abnormal sensory function in neurogenic pain states can. SENSORY ABNORMALITIES IN PATIENTS WITH NEUROGENIC PAIN . hypoesthesia occurs without an increase in stimulus detection threshold (thin line).Figure 1 Impaired sensation is often evident during a careful examination. with a lowered threshold. Figure 2. and occasionally (thin line). Occasionally. Temporal and spatial sensory dysfunction are also common (Table 1). be described in terms of stimulus strength and sensation magnitude. (B) Elevated stimulus perception threshold. Adapted from Lindblom and Ochoa32 Table 1.and hyperesthesia often seen in neurogenic pain states. Evoked sensation hyperpathic syndrome (thick line) often has a paresthetic or dysesthetic character or is frankly painful instead of the normal sensation evoked by the applied stimulus.and/or hyperesthesia for one or more modalities. (A) Hypoesthesia ("Hypo" thick line) consists of both increased perception threshold and reduced sensation magnitude at suprathreshold stimulus strengths. (C) Hyperesthesia can also occur separately with a steeper slope. together with an increase in slope of the magnitude/stimulus relation is typical for the combination of hypo.
e. and altered sweating. Careful clinical examination to identify the spatial distribution of sensory abnormalities and other problems should always precede QST.Quantitative Hypoesthesia Hyperesthesia Allodynia Paresthesia Dysesthesia Dyslocalization Radiation Hypoalgesia Hyperalgesia Qualitative Spatial Temporal Abnormal latency Abnormal aftersensation Abnormal summation It is important to test all somatosensory modalities since dysfunction confined to a single modality may otherwise escape detection. Conventional clinical sensory testing uses a cotton swab or camel’s-hair brush for light touch. and one object each for cold and warm. Bedside clinical assessment guides the sites and methods of QST employed. QST of different sensory modalities is mandatory to profile somatosensory function. nails. and viscera) are lacking. Because tests of deep sensation (e. thermal non-nociceptive and nociceptive perception thresholds. in subcutaneous tissue.3 Such signs of dysautonomia may also be found with sympathetically independent pain. pinprick for mechanically evoked pain. Methods now exist to directly quantify tactile perception and vibratory thresholds. or other tissue should be sought if sympathetically maintained pain is suspected.. Quantitative sensory testing (QST) to assess perception thresholds for different modalities has been refined in recent years. muscle. Skin temperature should be measured since it may suggest pain-associated dysautonomia as part of a specific pain condition. If nerve damage is limited to deeper tissues..4 When "bedside" testing is inconclusive. Provocative maneuvers may be needed in cases of intermittent mechanical stress upon nerves or roots because sensory dysfunction may not be apparent at rest.g. one can only examine sensory function in a nerve or tract that has a cutaneous representation. figure writing for tactile discrimination. the second diagnostic criterion cannot be applied and the diagnosis of neurogenic pain remains tentative and based on indirect evidence.g. and atrophy of skin. discoloration. Treatment TENS . and pinch.or pressure-pain thresholds. when any form of skin contact during sensory testing evokes pain. Other dysautonomic signs such as edema.
The anticholinergic and antihistaminergic effects of antidepressants may also contribute to the analgesic effects of these drugs. In central neurogenic pain. and amitriptyline in particular. Prior to TENS trial in a patient with a pacemaker. Neurosurgical ablation or stimulation techniques are also important therapeutically.Treatment for patients with peripheral neurogenic pain begins with transcutaneous electrical nerve stimulation (TENS).and low-frequency stimulation techniques are tried. the cardiologist should be consulted.5 When both high. TENS will benefit some patients with peripheral neurogenic pain. Because there are no predictors for choice of medication. clinical anecdotes. Drugs The number of carefully designed treatment trials for neurogenic pain is low. Antidepressants in general. the current strategy is a "trial and error" procedure that yields clear improvement in only a minority of patients with central or peripheral neurogenic pain. provide analgesia in a . The medical arsenal for treating neurogenic pain (Table 2) is based on a mixture of observations from clinical studies. TENS is less effective. and experimental findings. PHARMACOTHERAPY OF NEUROGENIC PAIN Antidepressants Amitriptyline Clomipramine Desipramine Imipramine Maprotiline Paroxetine Carbamazepine Phenytoin Valproate Clonazepam Baclofen Mexiletine Including topical agents Capsaicin Oral Transdermal Anticonvulsants Antiarrhythmics Local anesthetics Topical Opioids Antidepressants are believed to potentiate the effect of biogenic amines in endogenous pain-relieving systems. Detailed discussion of these specialized methods will appear in a future issue of Pain: Clinical Updates. Table 2. Strategies for treating sympathetically maintained pain were described in an earlier Pain: Clinical Updates3 and will not be repeated here.6 Occasionally TENS worsens pain. Reported side effects are limited to allergic reactions to the electrode gel and interference with cardiac pacemakers.
require input from the periphery to be maintained. The existence of possible longterm benefits of repeated blocks remains to be systematically explored. Mexiletine.9 Leijon and Boivie. The possibility that hyperexcitable central neurons have increased susceptibility to systemically absorbed local anesthetics cannot. intravenous lidocaine 1 to 5 mg/kg/hr) have also been reported in post-herpetic neuralgia. Anticonvulsants. were formerly the initial treatment in neurogenic pain (peripheral or central) if symptoms were paroxysmal and allodynia or hyperalgesia were present.10 suggesting that antidepressants’ efficacy for neurogenic pain depends mainly on noradrenergic uptake inhibition. phenytoin are the most commonly used in doses equivalent to those for antiepileptic treatment.12 For unclear reasons. amitriptyline should be the first choice. Such a balance is typically reached at a dosage of 75 to 150 mg of amitriptyline or maprotiline per day. In patients with painful diabetic neuropathy the selective serotonin uptake blocker fluoxetine was no more effective than placebo. Long-term pain relief for up to six days was achieved by Arner et al. The current view seems to be that in these conditions.g. has shown promise in early studies for alleviating both peripheral16 and central17 neurogenic pain in a daily dose of about 10 mg/kg.9 and painful diabetic polyneuropathy. allodynia and dysesthesia) may. found a correlation between plasma amitriptyline concentration and pain relief in patients with central post-stroke pain. . Future trials should subdivide patient groups based on a thorough examination. Among the antiepileptic drugs15 carbamazepine and.20 and central neurogenic pain. Signs of central dysfunction found during examination (e. Spontaneous discharge of damaged peripheral or central neurons. or disinhibited. Controlled studies using these drugs are rare. an oral antiarrhythmic lidocaine analogue. predictors of favorable outcome using local anesthetics are not yet defined. trigeminal neuralgia excluded. treatment of neurogenic pain should be based on the balance of pain relief and side effects rather than plasma concentration of the drug and its metabolites. In practice. local anesthetics.8. perhaps using meticulous sensory analysis to search for predictors of successful treatment.11 however.21 As with other treatment modalities for neurogenic pain. Benefits from systemically administered local anesthetics (e..10 two conditions in which multiple pathophysiologic mechanisms may produce pain.18 after single blocks in patients with painful mononeuropathies. drugs such as "membrane-stabilizing" antiepileptics. be excluded.g. particularly carbamazepine. to some extent.19 painful diabetic neuropathy. therefore.subgroup of patients with peripheral7-10 and central11 neurogenic pain states. pain relief during antidepressant therapy for postherpetic neuralgia seems not to be correlated with drug dosage or plasma concentration. The use of mexiletine stems from observations of analgesia in painful neuropathy during systemic lidocaine administration but controlled studies are needed to judge its value in neurogenic pain states. and antiarrhythmics may reduce the excitability of neurons by interfering with initiation of the action potential. hyperexcitable central neurons may perpetuate certain neurogenic pain states. Antidepressant trials in peripheral neurogenic pain have focused on postherpetic neuralgia7. a peripheral block with local anesthetic often removes the pain18. of course.14 In such cases and when antidepressant therapy fails or is poorly tolerated..13. Even though patients with painful mononeuropathy seem to have signs of central dysfunction on examination.
27 Another recent hypothesis used to explain relative or total opioid insensitivity in chronic neurogenic pain is an increase in synthesis of the neuropeptide cholecystokinin (CCK) within the spinal cord as a result of peripheral nerve damage. Although the long-term benefits of opioids for chronic neurogenic pain are not well established. Ketamine. EMLA) that penetrate the skin is a recent therapeutic alternative for neuropathic pain with localized hyperalgesia and allodynia. . it may be possible to develop NMDA receptor antagonists that produce analgesia without intolerable side effects. some patients appear to respond well.24 Opioid therapy for neurogenic pain is controversial. Uncontrolled studies on post-herpetic neuralgia22 suggest that.23 The clinical impression. Drugs to inhibit NO production are a natural goal for future research. It is not known whether subpopulations of NMDA receptors are "pain-specific.26 Clinical evidence of relative opioid insensitivity of neurogenic pain is consistent with the experimental finding of a reduction of opioid receptors in the spinal cord dorsal horn after peripheral nerve damage.Topical application of local anesthetics (lidocaine and prilocaine in combination. at present. has recently been found to decrease the pain of postherpetic neuralgia. however. neurotransmitter. Drug interaction with GABA transmission has been reported to alleviate different neurogenic pain conditions. offset opioid analgesia." If such subpopulations do exist. in such cases. a logical clinical approach is to initiate and titrate opioid dosage according to individual needs. except for baclofen treatment of trigeminal neuralgia. clinical anecdotes.31 in part as a mediator of the cellular responses to NMDA receptor activation.g. Recently. The novel neurotransmitter gas nitric oxide (NO) has recently been recognized as playing an important role in nociceptive processing in the spinal cord. Gamma-aminobutyric acid (GABA) is a widely distributed. causing activation and subsequent inhibition of small-diameter nociceptive fibers.29 Pain was reduced but there were prominent psychiatric side effects. topical capsaicin (the active ingredient in hot peppers) may be indicated.. therefore.30 NMDA receptors mediate long-term excitatory effects of nociceptive transmission but these receptors also are present in areas of the CNS unrelated to pain or nociception.26 Therefore.25.28 CCK exerts opioid antagonist effects and could.19. The analgesic action of capsaicin is thought to be due to its ability to release substance P. an anesthetic that also acts as an NMDA receptor blocker. is that such drugs (e. The medical arsenal for treating neurogenic pain is based on a mixture of observations from clinical studies. the first report of intrathecal administration of an N-methyl-D-aspartate (NMDA) antagonist to a patient with neurogenic pain was published. clonazepam or baclofen) do not give substantial relief. primarily inhibitory. and experimental findings.
Current drug and nondrug therapies for patients with chronic neurogenic pain offer substantial pain relief to no more than half of those afflicted with such pain. 12. et al. . In addition. 326–1250–1256. et al. 1:9–11. 32:671–673. Pain Digest 1993. placebo-controlled. Per Hansson. 17: 321–339. N Engl J Med 1992. . 17. Pain 1990. Recent findings indicate that stimulation techniques and pharmacological treatments. 5. 1(3):1–4. Neurology 1991. et al. Leijon G. 8. have therapeutic potential to normalize altered responsiveness of the CNS. Neurogenic Pain Unit Department of Rehabilitation Medicine Karolinska Hospital/Institute Stockholm. Wall PD. Watson CP. This knowledge offers many possible approaches for pharmacological intervention (e. et al. 16. PhD. J Neurosci 1990. Lancet 1988. 1(1):9–19. 41:1024–1028. Pain 1983. Arner S. knowledge of pathophysiologic mechanisms underlying neurogenic pain has grown exponentially during the last decade. 7. et al. Carr DB. Mohamed SA. Degard A. 1(4):14.g. Developing techniques to manipulate mechanisms of neural plasticity is a crucial task for future pain research. 6:163–174. et al. Pain 1990. Swerdlow M. 48:29–36. 14. et al. Hansson P. Pain Clin Update 1993. Per E. Lombard M-C. Effective new drugs to treat neurogenic pain conditions are therefore desperately needed. alone or in combination. 37:589–596. 2. 4. Awerbuch G. Pain Clin Update 1994. are therefore desperately needed. Pain Clinic 1986. 1989. 11. Neurology 1982. 42:131–133. 10. 9. Rowbotham MC. et al. Conclusion Current drug and nondrug therapies for patients with chronic neurogenic pain offer substantial pain relief to no more than half of those afflicted with such pain. Effective new drugs . double-blind studies with long-term follow-up are needed to conclusively judge the efficacy of current therapies. 2(l):1–4. Pain Clin Updates 1993. et al. On the bright side. Max MB. Watson GP. et al. 13. Sweden References 1. 19. 187–191. 43:287–297. Pain 1909. Turk DC. 3:36–42. Max MB. Max MB. 15. 6.. DDS Associate Professor. Neurology 1987. 36:27–36. Sjökund BH. 3:23–26. et al. Pain Digest 1993. et al. neurotransmitter antagonists given singly or with other drugs to decrease excitability at the membrane level or inhibit different steps of the nociceptive transmission process). 3. Acknowledgments The support of Karolinska Institute Foundation is gratefully acknowledged. Pain 1992. . Pain 1979. Leijon G. 18. 55:129–133. MD.
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