TREATMENT. Reviews. Clinical features of postherpetic neuralgia The severity of the pain in postherpetic

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1 PATHOPHYSIOLOGY AND TREATMENT 1 Reviews -HERPETIC NEURALGIA: AND TREATMENT Howard L. Fields, M.D., Ph.D.* (JJSPC Vol.6 No.1, 1 `9, 1999) Clinical features of postherpetic neuralgia The severity of the pain in postherpetic neuralgia sory and neuropathological studies and pharmacological interventions. Compared to patients who have had acute zoster but have recovered without (PHN) is frequently sufficient to completely disrupt the lives of otherwise healthy individuals. The pain appears as the acute viral infection subsides and persists, often indefinitely. Thus, even if VZV infection were completely eliminated tomorrow, there would still be hundreds of thousands of individuals with severe PHN. No numbers or words can adequately describe the daily torture they endure. It is essential that we find a satisfactory treatment for this problem as soon as possible. One approach to developing a treatment is to determine the mechanisms of the pain and then devise rational interventions to mitigate those mechanisms. The essential first step in this process is to study the clinical features of the patients. Patients with PHN report one or more of the following ; a steady, deep aching pain that often has an abnormal quality, a lancinating pain that is brief, intense and often described in terms reminiscent of trigeminal neuralgia, and, finally, allodynia which is the induction of a sharp pain by light, moving, cutaneous stimuli. In individual patients, the most unpleasant aspect of their pain may be either continuous deep aching pain, lancinating pain, or allodynia. What insight we currently have into the mechanisms of PHN has come from a combination of sen- persistent pain, patients with PHN characteristically have dermatomal areas of cutaneous scarring and sensory loss'. Head and Campbe112~ reported extensive damage in dorsal root ganglia (DRG) supplying the affected dermatomes in 21 cases of HZ. Subsequent pathological studies have also demonstrated loss of nerve fibers in the affected segments3~5~. This is not surprising since the latent viral nucleic acid resides in dorsal root ganglion (DRG) cells which sustain the brunt of the attack during viral reactivation. The sensory deficits and evidence of DRG cells and their peripheral clinical investigators of destruction axons have led some to propose that it is the anatomical disruption of primary afferents and consequent deafferentation of their target dorsal horn neurons that leads to the development of pain1'6'. Although it is clear that both sensory deficit and loss of primary afferent neurons are present in most PHN patients, evidence supporting the deafferentation hypothesis is not conclusive because investigators correlated loss of primary have not directly the pain and allodynia with the anatomical of f erents and the sensory deficits. For example, only one of Head and Holmes 21 patients was reported to have had PHN2'. None the less, ideas about the mechanism of PHN pain have continued to center around the idea that primary afferent loss, i.e. deafferentation, is central to pain development. *Neurology, University of California, San Francisco 1

2 Two clinical patterns in PHN challenge the notion of deafferentation as the sole cause of pain : irritable nociceptor and deafferentation Although it is likely that deaf f erentation does play a role in some patients, for others, it is probably a minor factor. We began to address this issue in 1989 using detailed patient reports, clinical sensory examination, thermography, and skin infiltration with local anesthetic7'. Although some of our PHN patients had profound sensory loss, in many, particularly those with pronounced allodynia, sensory loss was minimal to undetectable. Furthermore, there was usually a spatial separation between the areas of most profound sensory loss and the reported location of the patient's most severe pain and allodynia. The pain was often most pronounced in a zone of transition between areas of significant sensory loss and the adjacent normally innervated skin. Using quantitative sensory testing we demonstrated that some patients with severe PHN and pronounced allodynia have normal thermal sensory thresholds in their region of greatest pain8'. Furthermore, in the allodynic subgroup of PHN patients, we found a highly significant inverse correlation between pain severity and sensory loss. Using skin punch biopsy, we found that thermal sensitivity is directly correlated with density of cutaneous innervation in the area of most severe pain9'. This directly supports the idea that, for most PHN patients, pain severity is associated with relative preservation rather than loss of primary afferents. Although these studies challenge the idea that deafferentation is the sole cause of pain in PHN it is important to point out that a minority of PHN patients complain primarily of a steady pain and have minimal or no allodynia. These patients differ from the allodynic group in that their area of maximal pain is spatially co-extensive with areas of profound sensory loss''. We believe that in patients with these latter clinical findings the mechanism producing their pain is different than in those patients whose most severe pain occurs in a region of prominent allodynia and minimal sensory loss. Consequently, we believe that there are at least two mechanisms contributing to pain in PHN. What are the possible causes of pain in PHN? Over the past decade enormous progress has been made in our understanding of the possible mechanisms that contribute to neuropathic pain. Through a combination of animal and human research, it has become clear that neuropathic pain can have a variety of causes. Possible mechanisms for the generation of pain and allodynia associated with peripheral nerve injury generally can be divided into two broad categorieslo,ll' : central and peripheral. CENTRAL NERVOUS SYSTEM MECHANISMS 1. Loss of large fiber afferent inhibition Large diameter primary afferents (Af) respond to light mechanical stimuli and in normal subjects produce innocuous sensations when active. Activity in these large diameter axons excites interneurons that inhibit the second-order pain-transmission cell. Conversely, when myelinated primary afferents are selectively blocked (e.g., by ischemic compression of a peripheral nerve), light mechanical or thermal stimuli to the skin innervated by the partially blocked nerve produce a sensation that has a poorly localized, tingly and/or burning dysesthetic quality. Furthermore, skin stimuli which would normally produce only mild pain produce exaggerated burning pain12'. These observations indicate that, under normal circumstances, input from myelinated fibers has a predominantly inhibitory effect on central pain transmission cells. In fact, selective stimulation of large myelinated primary afferents in peripheral nerve (or their central processes in the dorsal columns) inhibits nociceptive dorsal horn cells13'. Melzack and Wa1112' in their Gate Control Hypothesis proposed that the pain of nerve injury is due to selective damage to pain-inhibiting large diameter myelinated sensory axons. Even before Melzack and Wa1112' published their Gate Control Hypothesis, Noordenbos4' had proposed that PHN was due to predominant large fiber loss combined with activity in surviving small diameter nociceptor input. Whether there is a in fact predominant loss of large diameter myelinated primary afferents in PHN awaits patho- 2

3 PATHOPHYSIOLOGY AND TREATMENT 3 logical confirmation. Loss of large fiber evoked inhibition could also be brought about if central inhibitory mechanisms were damaged. In fact, there is significant shrinkage of the dorsal horn in PUN patients5'. However, although there is significant shrinkage, it is unclear what types of neurons, if any, are lost. In animal studies, peripheral damage of primary afferents does lead to signs of degeneration of deafferented spinal neurons. If this occurs in HZ, and some of the degenerating cells are inhibitory, their loss could lead to enhanced responsiveness to peripheral stimulation and an increase in spontaneous activity of central nervous system pain transmission neurons. Unfortunately, there is no direct evidence supporting this mechanism in PHN. 2. Deafferentation hyperactivity of central pain transmission neurons Deafferentation produces hyperactivity in dorsal horn cells. After dorsal roots are cut, many dorsal horn cells begin to fire spontaneously at high frequencies14'. Such a mechanism may underlie the pain that follows extensive denervating injuries. For example, pain is a characteristic sequela of the deafferentation produced by brachial plexus avulsion15~, and this pain seems to respond to surgical procedures which destroy nociceptive dorsal horn neurons16'. Although there are some reports of efficacy of this procedure for patients with PHN, it is hardly a standard procedure and there is little evidence to suggest that this mechanism contributes to PHN. 3. Aberrant connections due to reorganization of the central nervous system Damage to the peripheral or central nervous system results in deafferentation, sprouting of the central processes of surviving axons and the development of aberrant connections in the spinal cord. For example, surviving dorsal root axons make functional contact with spinal cord neurons that have been deprived of their normal input'''. The contribution to clinical pain syndromes of this type of anatomical rearrangement is unknown. It is of interest that following partial peripheral nerve injury, large myelinated primary of f erents which only respond to light mechanical stimuli sprout to contact neurons which normally respond to noxious stimulation18'. A process such as this could contribute allodynia in some cases of PHN. to the clinical finding of 4. Central sensitization : summation, secondary hyperalgesia and allodynia An important process contributing to neuropathic pain is central sensitization. Mendell and Wali'9' observed that when identical noxious stimuli are repeatedly applied to the skin, there is a progressive build-up in the response of dorsal horn neurons; a phenomenon called wind-up (also see20o. This central sensitization is a physiological process initiated by massive, prolonged or repeated noxious input. Both neural peptides such as substance P21l and excitatory amino acids acting at the NMDA receptor22,23) contribute to this phenomenon. In normal human subjects, slowly repeated noxious stimuli are associated with a progressive increase in intensity of perceived pain24~. This process, called summation, is exaggerated in some patients with neuropathic of wind-up. Summation pain, and may be the subjective correlate is blocked by NMDA antagonists in normal human subjects25~. As reported by Noordenbos, summation is a consistent finding in most PHN patients. The NMDA antagonist has been shown, in a small controlled Ketamine clinical trial, to both relieve the pain and to reduce summation in patients with postherpetic neuralgia26'. Unfortunately, the side effects of the drug preclude its long term use for outpatients. The effectiveness in suppressing summation of dextromethorphan, another commercially available NMDA antagonist, suggests that it (or a pharmacologically related drug) will be useful for PHN patients25'. Large diameter primary afferents are sensitive to innocuous light stimuli and normally produce only innocuous tactile sensations when active. However, with central sensitization these large diameter fibers become capable of inducing pain. This phenomenon called secondary hyperalgesia to distinguish it from sensitization of primary afferent nociceptors (primary hyperalgesia). The human psychophysical corre- is 3

4 late of secondary hyperalgesia is allodynia, a situation in which light mechanical stimuli produce pain. This type of allodynia is a dynamic process which is triggered and maintained by input from C-fiber nociceptors. It subsides quickly when the nociceptor input that sustains it is removed. In some cases of PHN, allodynia (like wind-up and summation) also appears to depend on nociceptor input since it subsides when topical agents are used to reduce nociceptor input27'. Furthermore, as with summation and secondary hyperalgesia in normal subjects, it appears to have an NMDA receptor mediated component26'. It is important to point out that secondary hyperalgesia and the allodynia it produces can be observed in subjects without nerve damage. It is a normal physiological response to intense nociceptive input. The available evidence supports the hypothesis that in some patients with PHN, a nociceptor driven central sensitization contributes significantly to allodynia. PERIPHERAL MECHANISMS 1. Ectopic impulse generation When the sciatic nerve is cut and allowed to regenerate and form a neuroma, spontaneous activity develops in the dorsal root axons innervating the neuroma28,29). Similarly, within hours after damaging the small diameter nociceptive axons innervating the cornea, these axons become spontaneously active3o) When a peripheral nerve is damaged, in addition to the regenerating peripheral terminals a region near the dorsal root ganglion (which is distant from the site of injury) becomes capable of generating "spontaneous" impulses31,32) An important advance in research on neuropathic pains is the development of partial nerve injury models33'. Many of these nerve damage models appear to produce pain and to share clinical features with human painful nerve injuries. Importantly, spontaneous (ectopic) activity in small diameter primary afferents is a common feature in these models3o,34,35) As will be discussed below, we feel that ectopic impulse generation in intact but abnormally hyperactive primary afferent nociceptors is a major contributor to pain in most patients with PHN. 2. Enhanced adrenergic sensitivity In addition to their spontaneous ectopic impulse activity, damaged nociceptive afferents innervating a neuroma can be excited by iv. adrenaline or by stimulation of sympathetic efferents that have regenerated into the neuroma36'. Furthermore, Sato and Perl37' have shown that sympathetic activity can sensitize identified nociceptors following damage to the nerve in which they run. Ultrastructural studies have demonstrated that regenerating axonal sprouts come into close apposition with each other during post-traumatic regeneration38'. Since some of these regenerating sprouts are derived from small diameter primary afferents and others from sympathetic postganglionic axons, this feature may provide an anatomical substrate for the sympathosensory activation. There is some evidence that nociceptors in painful skin of PHN patients have enhanced adrenergic sensitivity39'. 3. Inflammation of the nerve trunk The connective tissue sheath of peripheral nerves is innervated by sensory fibers, the nervi nervorum, which enter the sheath with the blood vessels which supply the nerve. Some of these fine diameter primary afferents are nociceptors4o~42> These nervi nervorum are a potential source of pain in diseases of peripheral nerve. The acute pain of a herniated inflamed disc or the pain accompanying an infection of nerve such as acute leprous neuropathy are probably due to the physiological activation of the nervi nervorum43) Although it is likely that inflammation contributes to the pain of acute zoster, which has a pronounced inflammatory component, there is little evidence of ongoing inflammation in DRGs or peripheral nerve in PHN. Furthermore, the pain of PHN tends to begin as the acute inflammation subsides. WHICH NEURAL MECHANISMS CONTRIBUTE TO PAIN IN PHN? The weight of available evidence supports the notion that there are at least two distinct mechanisms that contribute to the pain of PHN. For most PHN 4

5 PATHOPHYSIOLOGY AND TREATMENT 5 relief for some PHN patients46,47) This finding is important because it suggests that prostanoid sensitization of the peripheral terminals of nociceptive primary afferents contributes to the pain of PHN. Fourth, capsaicin causes burning pain and then relief in some patients with PHN. Capsaicin, the active ingredient of hot chili peppers, is a neurotoxin that first activates and then desensitizes unmyelinated sensory axons, predominantly nociceptors48). Capsaicin is currently available in a 0.075% preparation (Zostrix HP). One controlled trial has shown that this preparation does reduce the pain of postherpetic neuralgia compared to vehicle49). Capsaicin preparations often produce intolerable burning, so many patients discontinue its use50). The important point is that since capsaicin is relatively selective for activation and desensitization of nociceptors, the fact that it can produce burning and then relief provides strong support for the idea that nociceptor activity, rather than disruption, produces pain in PHN. In this regard, the study by Bjerring et al51) is important. Using quantitative thermal sensory testing and subjective pain ratings in patients with PHN, they showed that capsaicin induced pain relief was temporally correlated with elevation of heat pain threshold. This directly ties inactivation of primary afferent nociceptors to pain patients, anatomically intact, abnormally hyperactive primary afferent nociceptors play a major role in pain generation (the irritable nociceptor type). In these patients, allodynia is due to central sensitization of pain transmission neurons that is initiated and sustained by nociceptor input. A different mechanism produces pain in those PHN patients with constant pain in a region of profound sensory loss (deafferentation type). In these patients, pain results from a change in the functional connectivity and activation state of central nervous system pain transmission neurons produced by deafferentation. We discuss the supporting evidence for each of these two mechanisms below. Evidence that supports the irritable nociceptor hypothesis First, in the allodynic form of PHN the inverse correlation of sensory deficit and degree of anatomical denervation with the magnitude of pain severity strongly favors a causal role of nociceptor activity and is evidence against a primary role for deaff erentation in this patient group. Furthermore, in these patients there is often a spatial separation of the region of allodynia and greatest pain intensity from the region of most profound sensory loss. Second, lidocaine by intravenous infusion produces significant relief for patients with postherpetic neuralgia44). In vitro studies have shown that ectopic relief. Fifth, in the allodynic form of PHN the painful impulses generated by damaged primary afferent nociceptors are abolished by concentrations of local anesthetics much lower than that required for blocking normal axonal conduction30,45> Thus, the response to lidocaine of PHN pain supports the concept that ectopic impulse generation plays a role in pain generation. Our demonstration27) that lidocaine, topically applied to the painful skin (but not to unaffected skin), produces a significant analgesic effect is important because it strongly supports the idea that the lidocaine effect is local and peripheral and, thus, that spontaneous activity arising in skin primary afferents skin is often warm on thermography, consistent with the release of vasoactive neuropeptides from spontaneously active small diameter primary afferents. Many unmyelinated primary afferent nociceptors contain neuropeptides (e.g., Substance P and Calcitonin Gene-related peptide) that can produce a local inflammatory process (vasodilatation, plasma extravasation, accumulation of white blood cells and hyperalgesia). These peptides can be released during activation of primary afferent nociceptors and they contribute to the neurally mediated cutaneous wheal and flare produced by noxious stimuli. Ochoa and his produces pain. Third, topical application colleagues have reported clinical cases in which C- of aspirin or a nonsteroidal anti-inflammatory drug produces profound pain fiber nociceptors are chronically sensitizedll). Recordings of C-fibers in his patients suggest that the sensi- 5

6 tization is in part maintained by antidromic release of some neuromediator (e.g., substance P) from the peripheral terminals of C-nociceptors. Whether this mechanism is at work in PHN is unknown, however, short of actually recording from nociceptors in PHN patients, it will be difficult to answer this question. Evidence that supports a deafferentation mechanism 1, Some patients have pain in an area of profound sensory loss. 2, The pain in these patients is not relieved by infiltration of the painful skin with local anesthetic. THERAPY OF PHN Antidepressants Although many different therapeutic approaches have been used to treat PHN, only antidepressants have been proven effective in randomized, double blind, placebo-controlled studies52'53) The response rate to amitriptyline in PHN averages 60 percent, though patients seldom have complete relief of pain. Desipramine has been used extensively in PHN. It appears to be as effective as amitriptyline and offers the possiblity of significantly reducing side effects such as sedation and dysphoria. Two studies comparing highly serotonergic antidepressants (clomipramine and zimelidine) with amitriptyline in the treatment of post - herpetic neuralgia found amitriptyline superior54'55) Amitriptyline has a large number of annoying (drowsiness, dry mouth, constipation) and potentially significant (memory impairment, orthostatic hypotension) side effects. In addition to its effects on central serotoninergic and noradrenergic neurotransmission, amitriptyline is strongly anticholinergic, antihistaminergic and anti-alpha adrenergic. By contrast, desipramine, a secondary amine tricyclic antidepressant, has potent effects on central noradrenergic neurotransmission but only weakly affects other neurochemical systems. As an antidepressant, it is as effective as amitriptyline, with fewer side effects, especially on memory. Other systemic drugs There have been anecdotal reports of occasional success with a wide variety of treatments; however, only tricyclics and opioids are of proven benefit. Unfortunately, even with optimal tricyclic therapy, most patients have significant residual pain. Contrary to early reports56' we have not found phenothiazines to be of benefit either alone or when added to an optimal dose of tricyclics. We have also found that most patients, even with lancinating, ticlike pain derive very little benefit from Phenytoin or Carbamazepine, even when pushed to toxic levels. Despite the relative ineffectiveness of phenytoin and carbamazepine, some of the newer anticonvulsants are promising. Preliminary reports indicate that gabapentin is particularly helpful for postherpetic neuralgia57'58). Because of its relatively benign sideeffect profile, gabapentin may replace tricyclics as first line treatment for postherpetic neuralgia. Topical Medications Some patients are helped by transcutaneous electrical stimulation and a few obtain transient relief with sympathetic blockade. One approach to PHN treatment has been topical application of capsaicin, a neurotoxic agent49~. Our experience with capsaicin cream (0.075%) is that some patients obtain significant but incomplete relief. However, many patients have found it to be useless and others have been unable to tolerate the burning sensation. As discussed above, many patients with persistent PHN have exquisite allodynia. In other words, very light stimuli which are innocuous when applied to normal skin areas, produce severe, usually shooting, pain. In most of these patients, infiltration of the trigger areas with a local anesthetic (1% lidocaine) provides complete or almost complete relief which may last for several days'). A topical preparation of lidocaine (5%) has provided very encouraging results27). Some patients have continued to obtain relief for over a year. Unfortunately, this preparation is not yet commercially available. Furthermore, it is important to point out that topical preparations are of little use to patients with the pure deafferentation form of PHN. It is of interest that topical application of aspirin (tablets crushed into a powder and dis- 6

7 PATHOPHYSIOLOGY AND TREATMENT 7 solved in chloroform) has also been reported to provide striking Opioids relief46,47> In the low doses usually prescribed (up to 60 mg codeine equivalent), opioids are of little benefit for most patients with PUN. Nonetheless, higher efficacy opioids do help some people. A recent study has proven the efficacy of oxycodone in PFIN59'. When other approaches are exhausted and the patients are still reporting significant pain, I do not hesitate to use oral opiate medications. REFERENCES 1) Nurmikko T, Wells C, Bowsher D : Sensory dysfunction in postherpetic neuralgia. In : Touch, temperature, and pain in health and disease : mechanisms and assessments. Progress in pain research and management, Vol.3, J Boivie, P Hansson, and U Lindblom (eds). Seattle, IASP Press, 1994, ) Head H, Campbell AW : The pathology of herpes zoster and its bearing on sensory localization. Brain 23 : , ) Zacks SI, Langf itt TW, Elliott FA : Herpetic neuritis : A light and electron microscopic study. Neurology 14 : , ) Noordenbos W : Pain, Amsterdam : Elsevier,1959, ) Watson CPN, Deck JH, Morshead C, et al : Postherpetic neuralgia : further post-mortem studies of cases with and without pain. Pain 44 : , ) Baron R, Sauger M : Postherpetic neuralgia : are C- nociceptors involved in signalling and maintenance of tactile allodynia? Brain 116 : , ) Rowbotham MC, Fields HL : Post-herpetic neuralgia : the relation of pain complaint, sensory disturbance, and skin temperature. Pain 38 : , ) Rowbotham MC, Fields HL : The relationship of pain, allodynia and thermal sensation in post-herpetic neuralgia. Brain 119 : , ) Rowbotham MC, Yosipovitch G, Connolly MK, et al : Cutaneous innervation density in the allodynic form of postherpetic neuralgia. Neurobiol Disease 3 : , ) Fields HL, Rowbotham MC : Multiple mechanisms of neuropathic pain : a clinical perspective. In : Proceedings of the 7th World Congress on Pain, Vol.2, GF Gebhart, DL Hammond and TS Jensen (eds). Seattle, IASP Press, 1994, ) Cline MA, Ochoa J, Torebjork HE : Chronic hyperalgesia and skin warming caused by sensitized C nociceptors. Brain 112 : , ) Melzack R, Wall PD : Pain mechanisms : a new theory. Science 150 : , ) Hillman P, Wall PD : Inhibitory and excitatory factors influencing the receptive fields of lamina 5 spinal cord cells. Exp Brain Res 9 : , ) Lombard MC, Larabi Y : Electrophysiological study of cervical dorsal horn cells in partially deafferented rats. In : Advances in Pain Research and Therapy, JJ Bonica, et al (eds). New York, Raven Press, 1983, ) Wynn-Parry CB : Pain in avulsion lesions of the brachial plexus. Pain 9 : 41-53, ) Nashold BS Jr, Ostdahl RH : Dorsal root entry zone lesions for pain relief. J Neurosurg 51 : 59-69, ) Devor M, Wall PD : Plasticity in the spinal cord sensory map following peripheral nerve injury in rats. J Neurosci 1 : , ) Shortland P, Woolf CJ : Chronic peripheral nerve section results in a rearrangement of the central axonal arborizations of axotomized. A beta primary afferent neurons in the rat spinal cord. J Comp Neurol 330 : 65-82, ) Mendell LM, Wall PD : Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibers. Nature 206 : 97-99, ) Price DD, Hayes RL, Ruda MA, et al : Spatial and temporal transformations of input to spinothalamic tract neurons and their relation to somatic sensations. J Neurophysiol 41 : , ) Levine JD, Fields HL, Basbaum AL : Peptides and the primary afferent nociceptor. J Neurosci 13 : , ) Davies AM, Lodge LH : Evidence for involvement of N-methylaspartate receptors in "wind-up" of class 2 neurons in the dorsal horn of the rat. Brain Res , ) Dickenson AH : NMDA receptor antagonists as analgesics. In : Progress in Pain Management and Research, Vol.1, HL Fields and JC Liebeskind (eds). Seattle, IASP Press, 1994, ) Price DD, Hu JW, Dubner R, et al : Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain 3 : 57-68, ) Price DD, Mao J, Frenk H, et al : The N-methyl-Daspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man. Pain 59 : , ) Eide PK, Jorum E, Stubhaug A, et al : Relief of postherpetic neuralgia with the N-methyl-D-aspartic acid 7

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