Is Nociceptor Activation by Alpha-1 Adrenoreceptors the Culprit in Sympathetically Maintained Pain?

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1 Focus Is Nociceptor Activation by Alpha-1 Adrenoreceptors the Culprit in Sympathetically Maintained Pain? James N. Campbell, *t Richard A. Meyer, *t and Srinivasa N. Raja_~ In certain patients, pain depends on sympathetic activity in the affected area. Sometimes referred to as reflex sympathetic dystrophy or causalgia, this disease is termed sympathetically maintained pain (SMP). Several lines of evidence support the hypothesis that in this disease alpha-1 adrenoreceptors develop in peripheral tissues (possibly at terminals of nociceptors), such that the release of norepinephrine from the sympathetic terminals activates the nociceptors and leads to the sensation of pain. This hypothesis stems from previous work with regional guanethidine block, stimulation of sympathetic ganglia, application of norepinephrine to the affected area, and oral sympatholytic drugs. Recent results from alpha~ agonists and antagonists in patients with and without SMP support this hypothesis. Intravenous phentolamine, a short-acting, competitive alphaadrenergic antagonist, produced pain relief that was highly correlated with relief obtained with a local anesthetic block of the sympathetic ganglia. This experiment supports the contention that SMP is mediated by an alpha-adrenoreceptor. Topical application of the alpha-2 agonist, clonidine, relieved hyperalgesia at the site of application presumably by reducing the release of norepinephrine. Injection of norepinephrine and the alpha-1 agonist phenylephrine into the clonidine-treated area produced marked pain and hyperalgesia. These results implicate the alpha-1 adrenoreceptor as the culprit in SMP. Key words- reflex sympathetic dystrophy, alpha-adrenoreceptor, hyperalgesia, nociceptors, causalgia, sympathetic From the Departments of *Neurosurgery and :~Anesthesiology and the tapp[ied Physics Laboratory, Johns Hopkins University, Baltimore, Maryland. Reprint requests: James N. Campbell, MD, Department of Neurosurgery, Johns Hopkins University School of Medicine, 6 North Wolfe Street, Meyer 7-113, Baltimore, MD nervous system, human, sympathetic blocking agents, clonidine, phentolamine, allodynia, adrenoreceptors O ne of the most intriguing painful conditions in humans relates to the association of pain and the sympathetic nervous system. In 1939, Leriche 17 first brought attention to this relationship when he reported that high periarterial "sympathectomy" relieved pain in certain soldiers injured in World War I. Three separate investigators had previously reported that resection of the sympathetic chain relieved pain in certain patients. 7,23.34 In many instances, the mere performance of a succession of anesthetic blocks of the sympathetic chain may afford pain relief. 3 Some clinicians debate the terminology regarding pain and the sympathetic nervous system. Clinicians have used the terms Sudeck's atrophy, reflex sympathetic dystrophy (RSD), and causalgia, among others, as labels for this syndrome. The main reason for this is that patients with pain, whether it is linked to the sympathetic nervous system or not, may present with similar signs and symptoms. Thus, a patient diagnosed to have RSD may or may not have pain that is dependent on sympathetic activity in the painful area. Roberts 27 suggested the term sympathetically maintained pain (SMP) to refer to the aspect of pain that depends on sympathetic activity in the painful area. A given patient may have SMP or sympathetically independent pain (SIP). Another possibility is that a given patient may have two components of pain, one that is sympathetically dependent and another that is sympathetically independenl It is not clear that RSD is a distinct entity as most clinicians APS Journal 1(1):3-11,

2 4 FOCUS/Campbell, Meyer, Raja use the term; rather RSD in different patients may involve a number of diseases with different underlying pathophysiological mechanisms. SMP is an operantly-based diagnosis for a subset of patients where the definition is unambiguous. Determining whether or not SMP is present is a well-defined task for the clinician. The outcome of that determination has im~ portant implications for treatment. HYPOTHESIS What is the mechanism by which activity in the sympathetic nervous system leads to pain? We propose that the site of interaction is in th e peripheral nervous system. Specifically, we postulate that, in SMP, alpha-1 adrenoreceptors become expressed on primary afferent nociceptors such that the release of norepinephrine by the postganglionic sympathetic terminals leads to activation of the nociceptors. PERIPHERAL RELEASE OF NOREPINEPHRINE CAUSES PAIN SMP by definition is eliminated by blockade of sympathetic efferent innervation of the painful area. Thus, an anesthetic blockade of the relevant sympathetic ganglia relieves pain in patients with SMP. Walker and Nulsen 39 and White and Sweet 41 observed that stimulation of the sympathetic chain evoked pain in patients with SMP, but not in those who did not have SMP. Moreover, Walker and Nulsen 39 noted that stimulation of the severed distal end of the sympathetic chain evoked pain in those diagnosed with SMP but not in other patients. This was the first demonstration that a substance(s) released from the sympathetic fibers evoked pain. These observations also substantiated the tenet that the efferent sympathetic fibers, rather than afferent fibers that may travel with the sympathetic fibers, account for SMP. Why did this stimulation evoke pain only in patients with SMP? Did patients with SMP release a substance from their sympathetic terminals different from that released in normal subjects, or were the effects of the normal transmitter different? Three independent lines of evidence suggest that norepinephrine released by the sympathetic fibers is critical in SMP. (1) The regional infusion of guanethidine relieves pain in SMP patients. ~2 Guanethidine is thought to act by depleting norepinephrine from the sympathetic terminals. (2) In patients whose pain had been relieved by either a sympathetic block or surgical sympathectomy (i.e., patients with SMP), an intracutaneous injection of norepinephrine into the previously painful area rekindled the pain and hyperalgesia.* However, norepinephrine injected intracutaneously into normal subjects induces little if any pain, and no hyperalgesia. 6 Therefore, an abnormal increase in the amount of norepinephrine released from sympathetic terminals is not likely the only reason for SMP. 3 Finally, oral administration of the alpha-adrenoreceptor blocking agents phenoxybenzamine 9 and prazosin 1 is reported to confer pain relief in patients with SMP. THE PHENTOLAMINE DIAGNOSTIC TEST FOR SMP The foregoing evidence suggests that SMP is a disease that arises from activation of receptors sensitive to norepinephrine, activation of which somehow leads to pain. Thus, in a sense, SMP is a receptor disease, the receptor being one that is activated by norepinephrine. Norepinephrine can act at two different classes of adrenergic receptors, alpha and beta. Since phenoxybenzamine and prazosin appear to relieve pain in SMP, the culprit should be the alpha receptor. Phentolamine is a short-acting, competitive alpha-adrenergic antagonist available for systemic use. Might intravenously administered phentolamine be an alternative means to diagnose (and perhaps treat) SMP? To answer this question, we compared the pain relief obtained following phentolamine administration wi(h that obtained following an anestlletic block of the sympathetic nervous system. 25 Twenty patients who presented with pain and hyperalgesia to mechanical and cooling stimuli in an extremity were included in our initial study. All patients had severe, disabling, ongoing pain for 6-12 months (mean, 37 months) due to traumatic or surgical injury, and in 1 patients a nerve injury could be documented. The sympathetic ganglion block and the phentolamine block were performed in random order on separate days. The sympathetic ganglion blocks were done under fluoroscopic guidance using a singleneedle technique. The adequacy of the sympathetic block was monitored with cutaneous temperature measurements on distal extremities of the blocked and unblocked sides. Sensory testing was done to verify that a somatic nerve block did not occur. Phentolamine was administered through an intravenous (IV) catheter inserted in an unaffected extremity. Patients were maintained in a supine position and hemodynamic parameters such as blood- * The definition of hyperalgesia used here follows that of Hardy et al. 1~ and refers to a lowered threshold for pain and increased pain to suprathreshold stimuli (i.e., the opposite of hypaigesia).

3 FOCUS/Campbell, Meyer, Raja 5 pressure and ECG were monitored. Two investigators were present during the block, one to monitor the patient's hemodynamic status and skin temperature and administer the drugs, and the other to obtain ratings of ongoing (stimulus-independent) and stimulus-evoked pain (i.e., pain evoked from gentle touch or cooling stimuli). The study was double-blind in the sense that neither the second investigator nor the patient knew when the drug was injected. The period before drug injection served as the placebo control period, and typically lasted about 3 minutes (minimum time, 15 minutes). For 2 of the 2 patients, the pain subsided during the saline infusion period; therefore they did not receive phentolamine. These two patients were considered to be placebo responders and were excluded from further analysis. The remaining 18 patients received 25 mg (n = 9) or 35 mg (n = 9) of phentolamine over a period of less than 5 minutes. Since one of the observed side effects of phentolamine administration in the initial series of patients (n = 8) was tachycardia, some patients were pretreated with 1-2 mg of propranolol (n = 1). An example of the time course of pain relief after phentolamine administration is shown in Figure 1. This patient had pain and hyperalgesia on the anterior and lateral aspects of the knee after arthroscopy. Pain ratings did not change after the administration of normal saline. After administration of 35 mg phentolamine, more than 8% of the patient's pain was relieved. Pain gradually returned to baseline levels over the course of about 7 hours. A surgical lumbar sympathectomy in this patient resulted in complete pain relief, which was still present at a 2-year followup examination. For the 18 patients who received both blocks, the maximum pain relief obtained from the phentolamine block was highly correlated to the maximum pain relief obtained from the sympathetic ganglion block (Fig. 2). Nine of the 18 patients had less than 3% pain relief from both blocks and might therefore be considered to have SIP. The other nine had 5% or more pain relief, therefore a component of their pain was considered to be SMP. Of these nine SMP patients, three had received propranolol and six had ns mg phenf.olamine 1 ) 1 O 3 i k 8 6 (- o I I-q < (1) EL 4- "-U Q m, > 2 I l I O " Time (min) Figure 1, Pain relief conferred from systemic phentolamine in a patient with SMP. Ratings of ongoing pain (filled circles) and pain evoked from light pressure (open circles) were made before and during saline and phentolamine administration. Pain decreased significantly after phentolamine but not after saline administration. Phentolamine was administered as six incremental doses up to a total dose of 35 rag. From Raja et al. 25 With permission. o o 2O o",9 1

4 6 FOCUS/Campbell, Meyer, Raja 1 9, 9,., 9, ~ propranolol ~ (1),-~- Ono propranolol _ /,~ ~o8._c- O_._ u ~ c 6 /~/~ C] E -6 4o E C ~"--"~u -~ 2, ~_., ~,.,,,, O Maximum % Pain Relief (L.A. sympathetic block) Figure 2. Maximum pain relief following phentolamine administration was correlated with maximum pain relief following local anesthetic block of the sympathetic ganglia for the 18 patients who received bloth blocks. A diagnosis of SMP is likely for patients who received substantial pain relief from both blocks. Propranolol (closed circles) was administered before phentolamine to the last 1 subjects in the study. From Raja et al. 2s With permission. not. the maximum pain relief achieved in these nine patients was similar. In other trials (unpublished) in which longer exposures to propranolol were given, patients with SMP did not achieve pain relief with propranolol. Therefore, blockade of the beta-adrenoreceptor with propranolol probably does not contribute to the pain relief in the phentolamine test. Phentolamine was equally effective in reducing ongoing and stimulus-evoked pain. All patients preferred the phentolamine test over the sympathetic ganglion block, mainly because phentolamine administration is painless. The main side effects observed were nasal stuffiness (n = 1), headache (n = 3), and dizziness (n = 2). An average of 65% of the maximum decrease in pain ratings was reported prior to the onset of nasal stuffiness in the patients who achieved greater than 5% pain relief with the phentolamine test. Thus, patients would have little clue as to when phentolamine was given. The phentolamine diagnostic test has many advantages over traditional diagnostic methods such as local anesthetic ganglion block and regional intravenous guanethidine: (1) Many of the false positive results that are obtained with ganglion blocks are avoided with the phentolamine test. False positive results can occur when the anesthetic spreads to the nearby nerve roots to produce a somatic blockade; afferent fibers that course with the sympathetic efferent fibers are anesthetized; and the dose of anesthetic used in ganglion blocks may be sufficient to produce a systemic analgesic effect. 29 (2) Similarly, the co-injection of lidocaine to attenuate pain from guanethidine may lead to a false positive result. (3) Ganglion blocks and regional guanethidine are more difficult to perform technically than the phentolamine test. Ganglion blocks require precise needle localization and in the lumbar area should ideally be done with aid of fluoroscopy. The IV regional block is more difficult to perform in the lower extremity because of greater mass and circumference of the limb. (4) A number'of complications have been reported with ganglion blocks, including pneumothorax, phrenic nerve injury, cardiac arrhythmias, laryngeal nerve injury, injury to the kidney, hemorrhage, and inadvertent intravascular or epidural injections. 2~ (5) With IV regional blocks, the guanethidine may escape into the systemic circulation, with resultant systemic hemodynamic effects. (6) Both the ganglion block and guanethidine procedures may cause the patient much pain. (7) Placebo effects are difficult to evaluate with ganglion blocks and regional guanethidine. The phentolamine test is easy to perform and well tolerated by patients. 2 Saline and drugs may be administered in a double-blinded fashion so that placebo effects may be assessed. In addition, conventional blocks assess the presence of SMP in the leg, arm, or even the face, but not in the trunk. Systemic phentolamine allows the clinician to test for SMP throughout the body in the course of the same test. Where is the likely site of action for phentolamine? Phentolamine appears to be capable of crossing the blood-brain barrier. Therefore the site of action of the phentolamine administered systemically could be either central or peripheral. 2e.43 Intrathecal administration of adrenergic agonists such as epinephrine results in behavioral signs of analgesia. 14,42 Thus, the effect of phentolamine at the level of the spinal cord would be a reversal of the analgesic effects of adrenergic agents. In contrast, intravenous phentolamine is an analgesic in patients with SMP. Therefore, phentolamine does not likely act at the spinal cord level. Our current regimen for delivering phentolamine is given in Table 1. Our present technique differs from that described above in that we now administer phentolamine (35 mg in 1 ml saline) as a continuous infusion over a 2-minute period. Though there are no absolute contraindications to this diagnostic test, caution is advised, particularly in patients with cardiac disease.

5 FOCUS/Campbell, Meyer, Raja 7 Table 1. Protocol for phentolamine diagnostic test Patient preparation 9 Patient in supine position 9 Monitor ECG, blood pressure 9 Establish IV line (screened off from patient) 9 Establish baseline pain level via sensory testing* Saline pretreatment ml bolus lactated Ringer's solution, followed by 2 ml/ kg/hr IV, throughout test 9 Sensory testing* every 5 min for at least 3 rain or until a stable pain rating is achieved. If pain level decreases substantially, do not administer phentolamine (patient may be a placebo responder). Phentolamine administration 9 Propranolol (2 mg IV) 9 Infusion of phentolamine (35 mg in 1 ml saline) over 2-min period (patient should have no cue when this is started) 9 Repeat sensory testing every 5 min during infusion Postphentolamine testing 9 Sensory testing for 15-3 min 9 Continue to monitor ECG, HR for ->3 min *Suggested sensory tests: Stimulus-independent (ongoing) pain 9 1 cm visual analog scale (VAS) from "no pain" to "most intense pain" Stimulus-evoked pain 9-1 verbal scale or VAS 9 Mechanical test (e.g., soft hairbrush, blunt pressure, tuning fork) 9 Cold test (e.g., small drop of acetone or ethyl chloride spray if acetone insufficient) THE ALPHA-1 ADRENORECEPTOR IS THE CULPRIT IN SMP There are two principal subgroups of alpha-adrenoreceptors: alpha-1 and alpha-2. The alpha-1 receptor is associated with blood vessels and mediates vasoconstriction induced by norepinephrine release. Alpha-2 receptors are located on the terminals of sympathetic fibers. When this autoreceptor is activated, norepinephrine release from the sympathetic terminals is inhibited. Which of these two alpha receptors is involved in SMP? Since alpha-1 and alpha-2 antagonists are not readily available in a topical preparation, we first explored topical application of clonidine, an alpha-2 agonist, to the painful area in patients with and without SMP. 8 If the alpha-2 receptor is the culprit, clonidine would be expected to exacerbate the pain. However, if the alpha-1 receptor is involved in SMP, application of the alpha-2 agonist might relieve pain via the local suppression of norepinephrine release. Six pa.tients were studied, four with SMP and two with SIP. Clonidine is supplied as a patch for cutaneous application (Catapres-TTS, Boehringer). Postjunctional alpha-2 adrenoreceptors have been reported in peripheral vasculature. The 1.5-cm 2 patch delivers systemically about.3 mg of clonidine per day. All four patients with SMP had complete relief of their hyperalgesia to touch in the local area treated with the clonidine patch. Ongoing pain was not affected, as the area of relief from the hyperalgesia was small compared to the entire affected region. In contrast, no pain relief was obtained for the two patients with SIP. Two obstacles interfere with use of clonidine as a chronic treatment: dermatitis from repeated use of the patch, and failure of the clonidine patch to confer pain relief outside the small area covered by the patch. The relief of hyperalgesia from clonidinewvas not due to a local anesthetic effect since touch detection thresholds were unaffected by the clonidine patch. The skin was never rendered analgesic, rather, stimulus-evoked pain thresholds were normalized in the SMP patients. These experiments suggest that activation of the alpha-1 adrenoreceptor leads to pain in patients with SMP. To verify this hypothesis, we injected the area rendered free of hyperalgesia by clonidine with norepinephrine or the alpha-1 agonist phenylephrine. Injection of norepinephrine into the skin of normal subjects caused little pain and did not produce hyperalgesia to mechanical stimuli. In contrast, norepinephrine evoked substantial pain when injected into the clonidine-treated area of patients with SMP (Fig. 3). Within 15 minutes of this injection, hype~algesia to mechanical and cooling stimuli developed at the patch site. Similar results were obtained f1- lowing injection of phenylephrine. HOW DOES ALPHA-1 ADRENERGIC STIMULATION EVOKE PAIN? We know that activation of nociceptors is associated with the sensation of pain. 4 Our hypothesis to account for SMP is: As a result of injury, peripheral tissues express alpha-1 adrenoreceptors. When these alpha-1 receptors are activated by the release of norepinephrine from the sympathetic terminals, the nociceptor is activated and pain develops. How does sympathetic blockade also lead to relief of the hyperalgesia to mechanical stimuli (in particular, touch-evoked pain), a common manifestation of SMP? This hyperalgesia could develop through peripheral and/or central mechanisms. Although primary afferent nociceptor sensitization accounts for certain aspects of hyperalgesia in tissue injury, 4 the touch-evoked pain commonly seen in SMP and other neuropathic pain states appears to be due to a "central sensitization." Central neurons, activity in which

6 8 FOCUS/Campbell, Meyer, Raja A case 1: patch site,9 9 9 case 1: contr, site o o normal subjects (n=4) c- 4- #-, :oooo. o oooo !! 5p.g NE ,3 4 Time (min) B 5- c- ~ n 4-9 " case 1: patch site 9 case 1: adjacent site 9 -~ 3- UJ I 2- c-- t I -5!-III ---- "-- I I I I 1 I /ig! NE Time (min) Figure 3. Rekindling of pain and hyperalgesia by intradermal injection of norepinephrine. Topical application of clonidine via transdermal patch resulted in reduction in pain to light touch at the site of the patch for this patient. (A) When norepinephrine was injected into the area of the patch, it produced intense pain that lasted for several minutes (closed squares). In contrast, similar injections into normal subjects produced little pain (open circles). (B) Fifteen minutes after the norepinephrine injection, pain to light touch reappeared at the clonidine treatment site. From Davis et al. 6 With permission. leads to the sensation of pain (central pain signalling neurons), develop an enhanced response to non-nociceptive inputs, viz., from low-threshold mechanoreceptors. The concept that activity in the non-nociceptive low-threshold mechanoreceptors can evoke pain stems from several lines of evidence. Touch-evoked pain disappears when activity in low-threshold mechanoreceptors is selectively blocked with an ischemic pressure block# The latency for recognition of pain evoked by touch is short, and requires that the primary afferent signal be conducted in A-beta fibers In patients with SMP, electrical stimulation of the involved peripheral nerve at low intensities evoked pain and a tingle sensation. 24 Under conditions of a sympathetic block, the same electrical stimulation evoked sensations of tingling only. Similarly, tactile stimuli applied during the block do not pro duce pain. 36 Thus, whether stimulation of lowthreshold mechanoreceptive fibers evoked pain depended on whether the patient was under the influence of a sympathetic block. How might we account for the relief of hyperalgesia following a sympathetic block? The sympathetic block clearly reverses the central sensitization, such that low-threshold mechanoreceptor input no longer induces activity in the central pain-signalling neurons. The most likely explanation of this highly plastic central sensitization/desensitization cycle emerges from consideration of the experimental work on mechanisms of secondary hyperalgesia due to cutaneous injury23 This work has shown that tonic nociceptor input to the central nervous system that occurs, for example, with injection of capsaicin into the skin, induces the same form of central sensitization. if the nociceptor input is reduced or eliminated

7 FOCUS/Campbell, Meyer, Raja 9 (e.g., by anesthetizing the area of capsaicin injection), the touch-evoked pain in the region of secondary hyperalgesia is eliminated. TM In a similar manner, the sympathetic block eliminates touch-evoked pain, because the sympathetically mediated tonic discharge of the nociceptive fibers is eliminated. Our model, then, is as follows. An injury results in a barrage of activity in nociceptors. This barrage leads to sensitization of the central pain-signalling neurons such that input from low-threshold mechanoreceptors now has the capacity to evoke pain. Sympathetic efferent fibers activate nociceptive fibers directly or indirectly via agonist action at the alpha-1 adrenoreceptor. In addition to evoking pain, the nociceptor activation maintains the central painsignalling neurons in a sensitized state. The injury that originally activated the nociceptive neurons gets better, but the sympathetically mediated mechanism by which nociceptors may also be activated persists via the action of norepinephrine (released from the sympathetic terminals) on the nociceptor-related alpha-1 receptors. At this point in the disease a sympathetic block is performed, and the sympathetically mediated activation of nociceptors is eliminated. With elimination of the tonic nociceptor input to the central nervous system, the sensitization of central pain-signalling neurons is eliminated, and touching the skin no longer induces pain. ARE ALPHA-1 RECEPTORS EXPRESSED ON NOClCEPTORS? Our model is not yet complete, because we have to account for how nociceptors are activated by alpha- 1 agonists. Animal models provide evidence that nociceptors develop an alpha-adrenergic sensitivity following injury. In normal skin, nociceptors do not respond to sympathetic efferent activity. 32 However, follow!n~g;a cutaneous burn injury, A-fiber nociceptors in ca.ts became responsive to sympathetic stimulation..2:~ Ir~ addition, C-fiber nociceptors in the rat became responsive to sympathetic stimulation after injection of their receptive field with a mixture of inflammatory mediators. 3~ A peripheral alpha-adrenergic sensitivity has also been shown to develop in regener.ated nerve sprouts. 11 In contrast to our clinical observations that activation O'f the alpha-1 r.eceptor is the culprit in SMP, two studie~=in~animals suggest that the alpha-2 receptor may ~e" ifnportanl Sato and Per131 recently demonstratedthat, following a partial nerve injury in cats, some C-fiber nociceptors were activated by sympathetic stimulation and/or norepinephrine administration. This sympathetically mediated activation was attenuated by yohimbine, an alpha-2 antagonist. From behavioral studies in rats, Levine et al. TM suggested that under pathological conditions, norepinephrine released from sympathetic terminals can activate alpha-2 adrenoreceptors on the sympathetic terminals to stimulate release of prostaglandins. Thus, the hyperalgesic effect of norepinephrine was mediated by prostaglandins. This work in injury models in animals is not borne out by experimental work in patients with SMP. Topical administration of the alpha-2 adrenergic agonist clonidine not only did not induce pain but rather reduced hyperalgesia locally. Recent evidence indicates that activation of alpha-2 receptors blocks neurogenic inflammation (Moskowitz, personal communication), which raises the possibility that alpha-2 inhibitory receptors are located on nociceptors. Loh and Nathan 21 demonstrated that regional guanethidine delivered distal to the area of nerve injury still produced pain relief. Thus, even in cases of nerve injury, the interaction with the alpha-1 receptor is likely to be in the tissues innervated by the injured nerve. Is the interaction with the nociceptor itself, or is the activation of the nociceptor indirect? In patients with SMP, alpha-1 receptors could develop on cellular elements (e.g., platelets or mast cells) such that norepinephrine released by the sympathetic terminals induces release of inflammatory mediators from these cells, leading to nociceptor activation. Evidence against this explanation comes from psychophysical studies in humans. Intradermal injection of inflammatory mediators such as prostaglandins and bradykinin produces hypei'algesia to heat stimuli? 2 Though hyperalgesia to mechanical and cooling stimuli are consistent features of SMP, 8.4~ hyperalgesia to heat is frequently not an attribute of SMP. 24 In addition, an indirect effect due to changes in blood flow is unlikely, since pain relief from phentolamine did not correlate with changes in cutaneous blood flow or temperature. 37 We conclude that alpha-1 mediated pain does not result from actions on nonneural cells. The hypothesis that we currently favor is that alpha-1 adrenoreceptors are expressed on the peripheral terminals of nociceptors themselves. One possible scenario is as follows. A barrage of activity in nociceptive fibers produces a phenotypic change, such that the production of alpha-1 receptors in the cell body is up-regulated. The alpha-1 receptors are transported to the periphery and incorporated into the nociceptor terminals. Now the elements necessary for a vicious circle are in place. Norepinephrine released by the sympathetic efferent fibers activates the nociceptors. Nociceptive inputs to the spinal cord trigger sympathetic efferent activity normally. The sympathetic discharge augments nociceptor ac-

8 1 FOCUS/Campbell, Meyer, Raja tivity. This provokes further alpha-1 receptor synthesis in the nociceptors, and the vicious loop continues. How does a series of sympathetic blocks lead to sustained pain relief? The sympathetically mediated activation of the nociceptive fibers is eliminated by the sympathetic blocks. This leads to a down-regulation of the production of alpha-1 receptors. That sustained pain relief can be obtained even from one sympathetic block suggests another possible mechanism: Alpha-1 receptors are in place in the terminals of the nociceptors, but in an inactive form. Neural activity in the nociceptors invokes expression of these receptors. Loss of neural activity in the terminals of the nociceptors down-regulates expression of the alpha-1 receptors and leads to sustained pain relief. In some cases down-regulation might not occur, in which case a more permanent form of sympatholysis may be necessary. THE FUTURE This is an exciting time in the field of sympathetically maintained pain. We are converging, after decades of speculation, on the molecular mechanism by which pain and activity in the sympathetic nervous system gain an association. Implications for patient care will be many. Clinicians may at the outset make two types of errors with regard to SMP: overdiagnosis and underdiagnosis. SMP should be considered in.any patient with serious pain for which no other mechanism is evident. This is particularly true if the pain is in an area with abundant sympathetic innervation, such as the hand or foot. Though underdiagnosis may be a problem, overdiagnosis may also be a problem. The work discussed here suggests rigorous criteria for establishment of the diagnosis of SMP. The phentolamine diagnostic test described above appears to be a safe, well-tolerated means of testing for the presence of SMP. Perhaps even more important, however, the phentolamine test lends itself to placebo controls, a crucial adjunct to evaluation of pain relief. Patients in whom phentolamine relieves pain can also be tested in other ways. Clonidine can be applied to the painful area via a patch to determine whether hyperalgesia is locally attenuated. If hyperalgesia is locally relieved bythe clonidine, alpha-1 agonists (e.g., 1 I~g phenylephrine) and suitable controls can be injected into the affected skin to determine whether hyperalgesia is rekindled. If the zone of pain is small, the patient may even find local treatment with clonidine to be a satisfactory longterm treatment. Other yet-to-be-developed topical sympatholytic therapies may be even more effective. Many aspects of the mechanism of SMP need yet to be resolved. Do nociceptive dorsal root ganglion cells synthesize alpha-1 receptors? If so, does injury modulate this production? There are alpha-1 receptor subtypes. Which one is involved in SMP? Are there situations where alpha-2 receptors or even beta receptors become involved in SMP? Why does it take several minutes for intracutaneous norepinephrine and phenylephrine to rekindle hyperalgesia in SMP? How prevalent is SMP? Can SMP be demonstrated in tissues other than skin? Why is hyperalgesia to cooling stimuli such a prominent part of SMP? The next few years should see much productive work directed at resolution of these issues. Acknowledgments The authors thank Drs. Rolf-Detlef Treede and Karen D. Davis for many helpful discussions. This research was supported by NIH Grants NS and NS " References 1. Abram SE, Lightfoot RW: Treatment of long-standing causalgia with prazosin. Reg Anesth 6:79-81, Arner S: Intravenous phentolamine test: diagnostic and prognostic use in reflex sympathetic dystrophy. Pain 46:17-22, Bonica J J: Causalgia and other reflex sympathetic dystrophies. Adv Pain Res Ther 3: , Campbell JN, Raja SN, Cohen BH et al: Peripheral neural mechanisms of nociception, pp In Wall PD, Melzack R (eds): Textbook of pain. Churchill Livingstone, London, Campbell JN, Raja SN, Meyer RA, Mackinnon SE: Myelinated afferents signal the hyperalgesia associated with nerve injury. Pain 32:69-94, Davis KD, Treede RD, Raja SN eta I: Topical application of clonidine relieves hyperalgesia in patients with sympathetically-maintained pain. Pain 47:39-317, 1991 (in press) 7. Flothow PG: Relief of pain from a neurologic viewpoint. Northwest Med 29:69-76, Frost SA, Raja SN, Campbell JN et al: Does hyperalgesia to cooling stimuli characterize patients with sympathetically maintained pain (reflex sympathetic dystrophy)? pp In Dubner R, Gebhart GF, Bond MR (eds): Proc. Vth World Congress on Pain, Elsevier, Amsterdam Ghostine SY, Comair YG, Turner DM et al: Phenoxybenzamine in the treatment of causalgia. J Neurosurg 6: , Gomez B, Borbujo J, Garcia-Villalon AL et al: Alpha1 and Alpha2-adrenergic response in human isolated skin arteries during cooling. Gen Pharmacol 22: , 1991

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