Systemic lidocaine for neuropathic pain relief : PAIN (original) (raw)
1. Introduction
The clinical use of systemic lidocaine (an amide local anesthetic and anti-arrhythmic agent) for pain treatment was first introduced in 1961 by two anesthesiologists who reported the effective post-operative pain relief with intravenous (i.v.) lidocaine infusion (Bartlett and Hutaserani, 1961). Intravenous lidocaine was not generally regarded as a useful therapeutic tool for pain relief for the next 2 decades largely due to its broad spectrum side-effects on both cardiac and central nervous systems. Boas et al. (1982) reported the reduction of deafferentation pain and central pain with i.v. lidocaine (lignocaine), indicating a possible therapeutic value of i.v. lidocaine for managing intractable neuropathic pain syndromes. Since then, systemic lidocaine has been increasingly used in the management of chronic pain syndromes such as diabetic neuropathic pain (Kastrup et al., 1987; Bath et al., 1990). Over the last decade, the clinical use of lidocaine for neuropathic pain management has gained much attention for two major reasons. First, studies on animal models of neuropathic pain have suggested a link between spontaneous ectopic discharges of the injured nerve and peripheral mechanisms of neuropathic pain, and such spontaneous discharges can be suppressed by i.v. lidocaine in a clinically relevant dose range. Second, the use of oral lidocaine congeners such as mexiletine has made it possible to provide a convenient, long-term treatment route for lidocaine therapy. Intravenous lidocaine has also been used as a diagnostic tool for selecting candidates for oral treatment with lidocaine congeners.
While systemic lidocaine and its oral congeners have been considered a treatment modality for neuropathic pain management, a number of issues remain to be addressed with regard to both the scientific basis recommending the use of lidocaine therapy and details of clinical trials with systemic lidocaine and its oral congeners. This article will first review the laboratory data concerning peripheral mechanisms of neuropathic pain. Focuses will be put on (1) electrophysiological evidence indicating lidocaine-induced suppression of ectopic discharges after peripheral nerve injury, and (2) behavioral data concerning changes in signs of experimental neuropathic pain after systemic lidocaine. The current status of lidocaine therapy for neuropathic pain treatment will then be examined. Clinical issues regarding the lidocaine dosage, plasma concentration, administration route, treatment duration, and the influence of these parameters on clinical outcomes will be considered. Finally, recent development in our understanding of different classes of sodium channels will be discussed, with an emphasis on their link to certain neuropathic pain symptoms and on the potential therapeutic role of subtype-specific sodium channel blockers in neuropathic pain treatment.
2. Laboratory studies
Neuropathic pain is an extremely complex entity of chronic pain syndromes. Symptoms and signs manifesting neuropathic pain may include spontaneous pain, hyperalgesia, allodynia, pain summation, and radiation of pain beyond the dermatome distribution (Thomas, 1984). The complexity of neuropathic pain also is reflected by multi-factorial contributions to both the development and maintenance of neuropathic pain (Mao et al., 1995). Much of the current knowledge concerning possible mechanisms of neuropathic pain comes from studies using animal models such as those involving neuroma formation after deafferentation (Wall and Gutnick, 1974) and peripheral neuropathy following nerve injury (Bennett and Xie, 1988; Kim and Chung, 1992). In particular, animal models of peripheral nerve injury produce symptoms and signs closely resembling the clinical entity of neuropathic pain and provide opportunities for in-depth research of both peripheral and central mechanisms. The discussion of central mechanisms of neuropathic pain is beyond the scope of this article. The following sections will focus on peripheral mechanisms of neuropathic pain, with a particular emphasis on mechanisms of generation and suppression of spontaneous ectopic discharges following nerve injury.
2.1. Electrophysiological evidence
Injury to the peripheral nerve can result in both anatomic and physiological changes. Physiologically, primary afferent input that encodes nociceptive information from peripheral to the spinal cord can only be generated following the stimulation of peripheral receptors by chemical, heat, and/or mechanical stimuli. This physiological property of primary afferent neurons could be altered when a peripheral nerve is injured, such that primary afferent input could be generated spontaneously without activation of peripheral receptors. Such input is often referred to as spontaneous ectopic discharges (Devor, 1991). Electrophysiological studies in animal models of peripheral nerve injury have provided valuable information regarding the loci and nature of such ectopic discharges: (1) ectopic discharges can be initiated along the injured nerve, DRG, and peripheral neuromata (Wall and Gutnick, 1974; Chabal et al., 1989; Kajander et al., 1992; Abdi et al., 1998; Stebbing et al., 1999); (2) types of peripheral nerve injury leading to ectopic discharges may include complete deafferentation (Wall and Gutnick, 1974), loose nerve ligation (Bennett and Xie, 1988; Kajander et al., 1992), and ligation of an individual nerve root (Kim and Chung, 1992; Abdi et al., 1998); (3) the onset of ectopic discharges ranges from a few hours to a few days after nerve injury (Wall and Gutnick, 1974; Chabal et al., 1989; Kajander et al., 1992; Abdi et al., 1998; Stebbing et al., 1999); (4) the time course of ongoing ectopic discharges can be as long as 40 days after the initial nerve injury (Wall and Gutnick, 1974); and (5) ectopic discharges from neuromata often manifest as high frequency, rhythmic, spontaneous discharges, while those from DRG neurons are likely to be slow, irregular activities in the absence of input from either central (spinal cord) or peripheral (nociceptor) regions (Devor et al., 1992).
Since ectopic discharges are aberrant action potentials along the injured nerve, which are known to be conducted via the activation of sodium channels, it is logical to postulate that local anesthetics (a class of agents blocking sodium channel performance) would also suppress ectopic discharges. Indeed, a number of studies clearly indicate that lidocaine given systemically can silence ectopic discharges in several animal preparations (Chabal et al., 1989; Devor et al., 1992; Sotgiu et al., 1994; Omana-Zapata et al., 1997; Abdi et al., 1998). Details of these studies are summarized in Table 1 including the route and dosage of lidocaine administration. Two important points concerning these studies are worthwhile mentioning. (1) Systemic lidocaine has been shown to have dissociative effects on nerve conduction and ectopic discharges, i.e. suppression of ectopic discharges without blocking nerve conduction (Devor et al., 1992). The data indicate that sodium channels generating ectopic discharges are likely to be different from those mediating normal action potential conduction along a peripheral nerve. (2) Mexiletine, a congener of lidocaine, also suppresses spontaneous ectopic discharges when given intravenously (Chabal et al., 1989). These findings have significant bearings on the behavioral studies discussed later in this article.
Effect of lidocaine on ectopic dischargea
Two studies examined spontaneous discharges associated with the development of neuromata in human subjects (Nystrom and Hagbarth, 1981; Nordin et al., 1984). Spontaneous nerve activities were recorded from peripheral nerve fibers with neuromata following limb amputation, and such spontaneous activities were not changed after local infiltration of neuromata with 1% lidocaine (Nystrom and Hagbarth, 1981), indicating a source of generators independent of neuromata. In contrast, local lidocaine did block burst activities induced by tapping neuromata (Nystrom and Hagbarth, 1981). It is of importance to note that the preparations for recording spontaneous activities are different between human and animal studies. In human studies, spontaneous activities were recorded from a nerve bundle, whereas in animals activities were recorded from a single filament dissected from a severed nerve bundle. In addition, a true pattern of spontaneous discharges and the source of such discharges (large versus small fibers, sensory versus motor fibers) are difficult to evaluate from a nerve bundle with connections to peripheral sites. Future studies with improved experimental conditions and designs should provide more information pertaining to patterns of spontaneous discharges in pain patients.
2.2. Behavioral evidence
Data derived from the electrophysiological studies indicate that (1) ectopic discharges develop after peripheral never injury and (2) systemic lidocaine can indeed silence such ectopic discharges. These electrophysiological findings led to the hypothesis that spontaneous pain and other neuropathic pain symptoms may be related to spontaneous ectopic discharges after nerve injury. Thus, if the generation of ectopic discharges is somehow attributable to the development and maintenance of certain symptoms of neuropathic pain, it would be expected that systemic lidocaine will also reduce behavioral manifestations of neuropathic pain. Several animal studies have indeed indicated that systemic lidocaine could reduce neuropathic pain (Chaplan et al., 1995; Abdi et al., 1998; Jasmin et al., 1998; Sinnott et al., 1999). These studies are summarized in Table 2.
Effect of lidocaine on experimental neuropathic paina
Several important observations have been made in these behavioral studies. First, only certain types of neuropathic pain behaviors are responsive to systemic lidocaine administration. Neuropathic pain behaviors responding to systemic lidocaine include hyperalgesia and allodynia (Chaplan et al., 1995; Abdi et al., 1998; Jasmin et al., 1998; Sinnott et al., 1999). There are significant variations with regard to the reduction of allodynia even using the same animal model and the same dosage, ranging from complete recovery from allodynia on the side of injury to no response to lidocaine treatment (Sinnott et al., 1999). Second, dosages effective for the reduction of neuropathic pain behaviors range from 1.5 to 5.0 mg/kg, and the measured lidocaine plasma level is between 1.2 and 2.1 μg/ml in these studies (see Table 2). Lidocaine administered intrathecally or locally onto the injured nerve did not attenuate neuropathic pain behaviors (Chaplan et al., 1995). Third, it has been shown that an i.v. lidocaine infusion as compared to a lidocaine bolus produces similar effects on neuropathic pain behaviors. In the event that i.v. lidocaine infusion is used, the rate of i.v. infusion appears to be a determinant factor of the outcomes (Chaplan et al., 1995). Fourth, mexiletine (10–100 mg/kg given subcutaneously (s.c.)) attenuated hyperalgesia and mechanical allodynia in neuropathic rats with selective nerve root ligation (Jett et al., 1997), and lamotrigine (10–100 mg/kg, s.c., an oral anti-epileptic agent) reversed cold allodynia in a rat model of constrictive nerve injury as well (Hunter et al., 1997). Finally, a single lidocaine infusion has been shown to produce prolonged reduction of tactile allodynia (at least 14–21 days) far beyond the pharmacological half-time of lidocaine (Chaplan et al., 1995; Sinnott et al., 1999). Although a similar phenomenon of prolonged reduction of hyperalgesia after local bupivacaine injection has been reported in the animal model of sciatic nerve ligation (Mao et al., 1992), mechanisms of this lidocaine action remain to be determined (Strichartz, 1995). Taken together, these observations support the hypothesis that systemic lidocaine could reduce neuropathic pain behaviors, and such actions are likely to be mediated through the suppression of spontaneous ectopic discharges.
2.3. Caveats and considerations
While the above-mentioned electrophysiological and behavioral studies provide evidence supporting (1) a link between injury-induced ectopic discharges and neuropathic pain behaviors, and (2) a role of systemic lidocaine in attenuating both ectopic discharges and neuropathic pain behaviors, a number of issues remain to be addressed. Since this body of evidence forms much of the scientific basis for the current clinical use of lidocaine therapy, we attempt to examine these studies and offer our thoughts in several important issues.
2.3.1. Ectopic discharges
Initially, ectopic discharges were demonstrated in an animal model of neuromata after deafferentation (Wall and Gutnick, 1974). The generation of ectopic discharges was then observed in other forms of nerve injury including constrictive nerve injury (Kajander et al., 1992) and selective nerve root ligation (Abdi et al., 1998). A common technical procedure used to record ectopic discharges involves dissecting an injured nerve fiber to a single filament that displays ectopic discharges under either in vivo or in vitro conditions (Wall and Gutnick, 1974; Chabal et al., 1989; Devor and Wall, 1990; Kajander et al., 1992; Abdi et al., 1998; Stebbing et al., 1999). The injured nerve was severed at the time of recording at either distal or proximal site relative to the locus of injury (Kajander et al., 1992; Abdi et al., 1998; Stebbing et al., 1999). This process itself raises some concerns. The experimental procedure of dissecting and severing an injured nerve is an acute insult to the nerve itself. It is well known that acute nerve injury can result in injury discharges (Seltzer et al., 1991). In a rabbit model, sustained discharges of Aδ and C-fiber single units lasted for over 10 h after acute nerve injury (in the absence of previous nerve injury) and such discharges are also suppressed by lidocaine with a concentration comparable to the plasma level of lidocaine used in other studies (Tanelian and MacIver, 1991). Therefore, it remains to be seen whether there is a distinction between patterns of ectopic discharges resulting from acute nerve section (injury discharges) and from chronic nerve injury. It would be of particular interest to ask if a similar pattern of ectopic discharges could be demonstrated in human subjects with neuropathic pain.
2.3.2. Mechanisms of ectopic discharges
Mechanisms of ectopic discharges have been mainly related to an abnormal activation of sodium channels of the injured nerve, because systemic lidocaine, a sodium channel blocker, suppresses ectopic discharges in animal preparations (Chabal et al., 1989; Devor et al., 1992; Sotgiu et al., 1994; Omana-Zapata et al., 1997). However, other mechanisms also have been proposed (Woolf and Wiesenfeld-Hallin, 1985; Sotgiu et al., 1994; Zhang et al., 1997; Lee et al., 1999). It has been shown that the sensitivity of α-adrenergic receptors is increased after peripheral nerve injury (Zhang et al., 1997; Lee et al., 1999), and antagonism of α-adrenergic receptors can effectively suppress ectopic discharges (Zhang et al., 1997; Lee et al., 1999). These studies indicate that increased sensitivity of α-adrenergic receptors alone is sufficient, if not necessary, to generate ectopic discharges. Are there two types of ectopic discharges – those mediated by abnormally acting sodium channels versus those mediated by sensitized α-adrenergic receptors with normal sodium channels? If this is the case, a combination of lidocaine and an α-adrenergic receptor antagonist may be employed in treating neuropathic pain patients with symptoms such as spontaneous pain that is likely to be mediated by ectopic discharges. On the other hand, systemic lidocaine has been shown to produce suppression of neuronal activity (Woolf and Wiesenfeld-Hallin, 1985; Sotgiu et al., 1994), including C-afferent fiber-evoked activity in the spinal cord (Woolf and Wiesenfeld-Hallin, 1985). Interestingly, spinal administration of mexiletine (10–100 μg) also has been shown to reduce spontaneous and peripherally-evoked neuronal activity in the rat's spinal cord following selective nerve root ligation (Chapman et al., 1998). Thus, mechanisms of systemic lidocaine and its congeners on pain relief are multi-fold and likely to be complicated.
2.3.3. Discrepancies between electrophysiological and behavioral data
An essential characteristic of ectopic discharges is that such electrophysiological activities occur spontaneously in the absence of peripheral stimulation. Experimental preparations investigating spontaneous ectopic discharges were indeed isolated from the peripheral site (Wall and Gutnick, 1974; Chabal et al., 1989; Kajander et al., 1992; Abdi et al., 1998; Stebbing et al., 1999). However, most behavioral studies examining the effect of lidocaine on neuropathic pain behaviors have used allodynia as a test endpoint (Table 2). In fact, none of these studies have used spontaneous pain behavior scores as an independent measure. By definition, an innocuous peripheral stimulation (tactile or temperature) has to be applied in order to elicit allodynic responses. Thus, one might argue that allodynic responses are not the appropriate behavioral endpoint for investigating the role of systemic lidocaine on neuropathic pain behaviors, because systemic lidocaine has been shown to suppress only spontaneous ectopic discharges without blocking nerve conduction. It is thus difficult to envision how systemic lidocaine could block stimulation-evoked allodynic responses.
Even though in clinical settings it is possible that patients may report paresthesia in the absence of peripheral stimulation, this type of sensation is distinctively different from allodynic responses. This is not just a semantic argument; both clinical manifestations and mechanisms are likely to be distinguishable between allodynia and paresthesia. One possible explanation for these discrepancies is that systemic lidocaine may exert its anti-allodynic effects via central mechanisms (Woolf and Wiesenfeld-Hallin, 1985; Sotgiu et al., 1994) independent of the suppression of ectopic discharges. Alternatively, it may be proposed that sodium channels located on Aβ-large fibers are sensitized after nerve injury and allodynic responses are exaggerated in the presence of ectopic discharges. Therefore, suppression of ectopic activities with systemic lidocaine makes it difficult to elicit allodynia. In this regard, a model of neuropathic pain has been proposed in which ongoing nociceptive afferent input from a peripheral locus is thought to maintain the dynamically-altered central process underlying allodynia, because local infiltration of the affected region with lidocaine temporarily blocks allodynia within the time course of a local block (Gracely et al., 1992). These possibilities may be examined in future studies to provide a better understanding of peripheral mechanisms of neuropathic pain.
3. Clinical studies
Although a role of systemic lidocaine in pain relief was first discovered in acute post-operative pain management (Bartlett and Hutaserani, 1961; Cassuto et al., 1985), systemic lidocaine has not been widely used for acute pain management mainly for two reasons: (1) significant cardiac and central nerve system side-effects associated with high doses of lidocaine required for acute pain relief preclude a routine use of lidocaine therapy in this setting; and (2) other therapies such as epidural administration of a local anesthetic and/or a narcotic provide effective acute pain management with minimal side-effects. Thus, the following sections will focus on the current status of lidocaine therapy for neuropathic pain management.
3.1. Effect of systemic lidocaine on neuropathic pain
Intravenous lidocaine (3 mg/kg over 3 min followed by a continuous infusion of 4 mg/kg for 60 min) was first shown to be effective in reducing neuropathic/central pain, including thalamic pain, trigeminal neuralgia, and phantom limb pain (Boas et al., 1982). In this same study, the authors found that the same dose of lidocaine did not provide any beneficial effect on pain of peripheral (nociceptive) origin such as pressure cuff-induced ischemic pain. Similar results of reduced pain from nerve injury with systemic lidocaine were reported in a review of 211 cases of chronic pain management (Edwards et al., 1985). These studies used a bolus dose of lidocaine with or without subsequent continuous infusion. In another study, however, i.v. lidocaine (500 mg) was given at a rate of 8.35 mg/min for 60 min in order to determine a dose–response and plasma concentration–response relationship (Ferrante et al., 1996). It was found that lidocaine infusion resulted in complete pain relief in 10 out of 13 patients, as measured by VAS scores and scores from the short form of the McGill Pain Questionnaire and the Multidimensional Pain Inventory (Ferrante et al., 1996). Both dose–response and plasma concentration–response relationships are steep as shown in the study, suggesting that a small change in the lidocaine dose or plasma concentration gives rise to a significant break in pain scores once the plasma lidocaine concentration reaches a certain level (0.62 μg/ml). Comparisons of lidocaine doses, plasma concentrations, and types of neuropathic pain are given in Table 3. These findings thus provide evidence for an alternative treatment method in neuropathic pain management.
Effect of lidocaine on clinical neuropathic pain
Systemic lidocaine also has been shown to be effective in treating pain associated with other neuropathic conditions (Table 3) (Kastrup et al., 1987; Bath et al., 1990; Brose and Cousins, 1991; Rowbotham et al., 1991; Tanelian and Brose, 1991; Marchettini et al., 1992; Devulder et al., 1993; Edmondson et al., 1993; Calissi and Jaber, 1995; Ferrante et al., 1996; Galer et al., 1996). In a randomized, double-blind, cross-over study (Bath et al., 1990), i.v. lidocaine (5 mg/kg over 30 min) but not saline reduced diabetic neuropathic pain symptoms for 3–21 days as measured by a clinical scale including pain, dysesthesia, paresthesia, nightly pain exacerbation, and sleep disturbances. The treatment for the pain of postherpetic neuralgia (PHN) is often unsatisfactory. In a well-designed study (Rowbotham et al., 1991), i.v. lidocaine infusion with a target dose of 5 mg/kg (maximal 450 mg) significantly decreased PHN pain (VAS scores) as compared to saline controls. Interestingly, the authors also found that allodynia disappeared in the majority of subjects who reported definite pain relief and the pain relief resulting from lidocaine infusion was not different from that of morphine infusion.
Although an intravenous route of lidocaine administration has been used in the majority of lidocaine studies, subcutaneous 10% lidocaine also has been shown to be effective in treating neuropathic cancer pain patients who failed to respond to systemic and spinal opioids (Devulder et al., 1993). Importantly, the plasma concentration (2–5 μg/ml) of subcutaneous lidocaine associated with substantial pain relief is comparable to that of i.v. lidocaine infusion (Devulder et al., 1993). Evidently, it is the plasma level of lidocaine rather than the route of administration that determines the effectiveness of systemic lidocaine. This concept is, at least in part, supported by a study in which topical 5% lidocaine gel, with a maximal plasma concentration of 0.6 μg/ml, reduced PHN pain by a local but not a systemic action because the plasma level of lidocaine from this topic treatment is too low to have a meaningful systemic effect (Rowbotham et al., 1995).
Several points may be made with regard to the effect of systemic lidocaine on neuropathic pain. First, the effective dose range of systemic lidocaine (1.5–5.0 mg/kg) is comparable among different neuropathic pain conditions. This range of lidocaine doses has been shown to suppress ectopic discharges without blocking nerve conduction. Second, the range of the lidocaine plasma level is from 0.62 to 5.0 μg/ml. Third, the effect of systemic lidocaine on neuropathic pain may differ depending on the source of pain generation. It has been reported that systemic lidocaine may be more efficacious in relieving neuropathic pain from peripheral nerve injury as compared to that from damage to the CNS or with unknown etiologies (Galer et al., 1993). Fourth, while the validity of computer-controlled lidocaine infusion has been investigated (Schnider et al., 1996; Wallace et al., 1996, 1997), little information is available regarding the duration of pain relief after an i.v. bolus versus continuous infusion of lidocaine. The onset and peak action of systemic lidocaine vary notably in the literature. For instance, the onset of lidocaine effect on pain relief ranges from 1 to 45 min after lidocaine administration. Conceivably, both the onset and peak effect of lidocaine will differ based on the type of administration (bolus versus slow infusion). To date, there is no consensus about the appropriate duration of observation after either lidocaine bolus or infusion to evaluate the outcomes. Finally, there are significant side-effects associated with high doses of systemic lidocaine (Rowbotham et al., 1991; Ferrante et al., 1996; Wallace et al., 1996). The presence of intolerable side-effects such as significant lightheadedness is one important factor that may be attributable to the discontinuation of lidocaine therapy.
3.2. Intravenous lidocaine test
Although systemic lidocaine has been shown to relieve several types of neuropathic pain, its long-term use is limited by the requirement of either an i.v. or subcutaneous delivery system. Oral congeners of lidocaine have thus been introduced in order to provide a long-term, convenient method of lidocaine therapy. The idea is that if a positive response to i.v. lidocaine is obtained, the patient is likely to benefit from the oral therapy with lidocaine congeners as well. Therefore, the i.v. lidocaine test is employed to select patients who might be good candidates for oral therapy with a lidocaine congener. Unfortunately, data about the lidocaine test are scarce and the current use of the lidocaine test is rather empirical and anecdotal. In a case report (Tanelian and Brose, 1991), the i.v. lidocaine test (5 mg/kg) showed significant pain relief (7/10 to 1/10 on VAS scores) in a patient with lower extremity neuropathic pain. The patient was started on oral mexiletine up to 900 mg/day and his pain was reportedly resolved.
In a prospective study (the only study of this type) (Galer et al., 1996), both 2 and 5 mg/kg i.v. lidocaine given in two separate sessions during a 45 min period resulted in significant pain relief (VAS scores) in nine patients with peripheral neuropathic pain. The authors reported that the subsequent response to oral mexiletine treatment was correlated with the average response to the lidocaine test. This study thus suggests that a positive lidocaine test may be used to predict a positive oral therapy with a congener of lidocaine. While these reports are informative, no consensus has been reached concerning dosage, observation duration, the endpoint of a positive lidocaine test, and the predictive value of a positive lidocaine test for oral therapy with lidocaine congeners. These issues will be further discussed later in this article.
3.3. Effect of lidocaine congeners on neuropathic pain
As discussed earlier, the use of oral congeners of lidocaine could extend the use of i.v. lidocaine therapy and provide a long-term, alternative method for treating neuropathic pain. Mexiletine is a local anesthetic, which is a class Ib anti-arrhythmic agent and a structure analogue of lidocaine. Mexiletine is administered orally with about 90% oral bioavailability. The peak effect takes place in 1.5–4 h after administration and the drug is mainly metabolized in the liver (over 90%) with an elimination half-life of about 6–17 h. Although the impairment of liver functions will significantly alter the metabolism of mexiletine and thus increase its elimination half-life, renal dysfunctions (even in dialysis) do not significantly decrease the dose requirement. Because of its cardiac effects, mexiletine is contraindicated for patients with significant (second and third) heart blocks and is not recommended in patients with uncompensated congestive heart failure (Jarvis and Coukell, 1998; see this review for more information on mexiletine).
Mexiletine has been used in the treatment of a variety of neuropathic pain syndromes including peripheral neuropathy after nerve injury (Tanelian and Brose, 1991; Chabal et al., 1992; Galer et al., 1996), diabetic neuropathic pain (Dejgard et al., 1988; Galer et al., 1996; Jarvis and Coukell, 1998), central pain (Awerbuch and Sandyk, 1990; Edmondson et al., 1993; Chouu-Tan et al., 1996), cancer-related neuropathic pain (Ferrante et al., 1996; Chong et al., 1997), and phantom limb pain (Tanelian and Brose, 1991; Davis, 1993). Several important points from these studies should be noted. First, the doses of mexiletine range from 400 to 1200 mg/day. The mean plasma level is 0.76 μg/ml when patients take a daily dose of 400–1200 mg of mexiletine. This dose range and plasma level of mexiletine is reported to be effective in treating peripheral neuropathic pain. Second, outcomes vary among these clinical trials with both positive and negative results. Only in few mexiletine trials was an i.v. lidocaine test reportedly used before the initiation of oral mexiletine therapy. Third, it is not clear from these studies whether mexiletine was administered alone or with other medications including tricyclic anti-depressants (TCAs), non-steroidal anti-inflammatory drugs (NSAIDs), and/or narcotics. Fourth, although mexiletine is generally regarded as a safe agent with few side-effects, significant side-effects do develop, which include gastrointestinal (GI) intolerance, dry mouth, and CNS symptoms such as sleep disturbances, headaches, and drowsiness. The GI intolerance is the most common side-effect and a major factor limiting the mexiletine therapy.
3.4. Caveats and considerations
The introduction of lidocaine therapy has provided an alternative method in the management of neuropathic pain syndromes. Because of the complexity of neuropathic pain and the relative ineffectiveness of conventional agents (NSAIDs and narcotics) in treating neuropathic pain, any alternative means to tackling this intractable pain is encouraging. Both systemic lidocaine and its oral congeners have indeed brought new hope for patients with debilitating neuropathic pain syndromes. It should be pointed out, however, that much of the information about these treatments comes from empirical and anecdotal experiences (case reports). The lack of well-controlled clinical trials leaves clinicians with a true trial-and-error practice.
3.4.1. Lidocaine therapy
Since systemic lidocaine is thought to relieve pain associated with abnormal activation of sodium channels under neuropathic conditions, one would expect that clinical symptoms relieved from systemic lidocaine will probably involve a subset of symptoms such as spontaneous pain that is more likely to be mediated by spontaneous ectopic discharges. However, the vast majority of studies using the lidocaine therapy have employed general VAS scores as the outcome measurement. Thus far, little effort has been made to individualize symptoms (spontaneous pain, hyperalgesia, allodynia, etc.) and to analyze the effect of lidocaine on each of these symptoms. This deficiency raises at least two concerns. First, in the absence of data examining the effect of systemic lidocaine on individual neuropathic pain symptoms, it would be difficult to determine whether a positive response to systemic lidocaine is due to a generalized change in pain perception or due to a specific reduction of certain pain symptoms. Such determinations would be even more challenging when a negative response is encountered after systemic lidocaine, because lidocaine may have reduced pain from one source such as spontaneous pain but not the pain from other sources. In this latter clinical scenario, the rating for a generalized VAS score may not be different before and after systemic lidocaine leading to a false negative result. Second, the use of individual symptoms as independent variables, rather than a general VAS score, will help identify a subgroup of patients who may be particularly susceptible to systemic lidocaine. This approach will provide a rational guideline, rather than a trial-and-error practice, towards formulating a refined treatment plan for diversified neuropathic pain symptoms.
3.4.2. Lidocaine test
Three important issues remain to be addressed concerning the lidocaine test. First, the dose range of systemic lidocaine used in the test varies extensively among pain centers, from a fixed 100 mg/patient to 5 mg/kg of a patient's body weight (Tanelian and Brose, 1991; Galer et al., 1996). The rate of administration also varies from an i.v. push to a slow infusion over 30–60 min. These inconsistencies obviously create variations in lidocaine test results. Second, outcome measures of the lidocaine test also differ among pain centers. As discussed above, a meaningful measure of the test results is critical to guide the next step of a treatment plan. Thus far, there is a lack of standards as to (1) what to measure to determine a positive test result, (2) how much change to be expected (such as percent changes of pain scores) to indicate a positive result, and (3) when to measure after the lidocaine test (from 5 to 45 min in the literature) to determine the test results. Third, although double-blind studies have been carried out, the actual ‘blindness’ of these studies is questionable in the absence of active placebo controls. This argument is based on the fact that systemic lidocaine can indeed produce side-effects such as lightheadedness in the range of plasma concentrations (0.95–1.5 μg/ml) used in these tests (Rowbotham et al., 1991; Ferrante et al., 1996; Wallace et al., 1996). It is practically impossible for a patient not to notice CNS side-effects (even a minor one) after systemic lidocaine administration.
The predicative value of the lidocaine test for a positive oral trial of lidocaine congeners remains to be determined. There is only one study that has attempted to answer this question (Galer et al., 1996). However, the study was compromised by the fact that the pain relief measured by both the VAS score (about 10–20% changes) and the pain relief scale score (equivalent to a mild to moderate pain relief) were minimal after the lidocaine test itself. The study also did not include an active placebo control group and no information was given as to whether patients taking oral mexiletine also had other pain medications during the trial. In regards to the pitfalls of these studies, one may ask that if a positive lidocaine test predicates a positive oral trial, would a negative lidocaine test predict a negative oral trial? Needless to say, more studies are warranted to further address these issues.
3.4.3. Oral therapy with mexiletine
The efficacy of mexiletine in neuropathic pain treatment remains to be evaluated. Although mexiletine is regarded as safe with few side-effects, long-term use of this drug could lead to clinically significant side-effects (Chabal et al., 1992; Jarvis and Coukell, 1998). Several practical issues should be addressed before placing patients with neuropathic pain on a long-term treatment with a lidocaine congener. For example, the efficacy of mexiletine alone on neuropathic pain should be well documented, since patients with neuropathic pain commonly take several medications including TCAs and sometimes narcotics. In particular, if a combination of medications is needed in a treatment regimen, an indication for mexiletine should be sought. In addition, side-effects associated with long-term use of mexiletine alone or in combination with other pain medications such as TCAs and narcotics should be addressed. In this regard, well-controlled, large-scale clinical trials would be invaluable not only to address technical details (dosage, duration, etc.) but also to identify pain symptoms that are likely to be responsive to such a treatment.
4. New sodium channels and neuropathic pain
Recent studies have shown that there exist more than 10 sodium channels encoded by different genes, which produce inward membrane currents necessary for the generation and conduction of action potentials (Nystrom and Hagbarth, 1981; Waxman et al., 1999a,b). At least six sodium channel currents have been identified in DRG neurons and may be attributable to both physiological (nociceptive) and pathophysiological (neuropathic) pain conditions (Waxman et al., 1999a,b). It is the abnormal sodium channel activity and changes in sodium channel expression under neuropathic conditions that have drawn much attention over the last several years. Three crucial questions are asked. (1) What type of sodium channel currents are particularly linked to neuropathic pain after peripheral nerve injury? (2) Can the suppression of abnormal activity of a selective sodium channel subtype lead to an improvement of neuropathic pain? (3) What agent(s), if not lidocaine, would provide channel-specific blockade in human neuropathic conditions? Comprehensive reviews concerning some of these issues have been given (Waxman et al., 1999a,b). The following sections will highlight recent findings and examine the clinical relevance of these findings in neuropathic pain management.
(1) Although multiple sodium channel currents have been demonstrated in isolated DRG neurons, two types of sodium channels are of particular interest (Waxman et al., 1999a,b). They are tetrodotoxin-sensitive (TTX-S) and TTX-resistant (TTX-R) sodium channels. While TTX-S sodium channels are preferentially expressed in large and medium DRG neurons, TTX-R sodium channels, including two subgroups (PN3/SNS and NaN/SNS2), are expressed preferentially in small diameter DRG neurons including C-afferent neurons (Quashoff et al., 1995; Akopian et al., 1996).
(2) TTX-R sodium channels may have a specific function in pain and pain modulation. Mutant mice with no expression of the SNS isoform of TTX-R sodium channels showed analgesia to noxious mechanical stimuli, decreased response to noxious heat stimuli, and delayed development of inflammatory hyperalgesia to carrageenan injection. In contrast, there were no differences in responses to tactile stimuli elicited by Von Frey filaments between mutant and wide-type mice (Akopian et al., 1999), indicating a selective involvement of TTX-R sodium channels in pain modulation.
(3) Heterogeneity of TTX-R sodium channels exists in terms of their role in chronic pain (Porreca et al., 1999). Selective knock-down of the PN3/SNS isoform of TTX-R sodium channels in DRG neurons with anti-sense oligodeoxynucleotides prevented thermal hyperalgesia and tactile allodynia after either selective spinal nerve ligation or chronic inflammation induced by complete Freund's adjuvant (CFA). In contrast, both hyperalgesia and allodynia were not influenced by knock-down of the other isoform (NaN/SNS2) of TTX-R sodium channels (Porreca et al., 1999).
(4) Both TTX-S and TTX-R sodium channel expressions are altered after peripheral nerve injury and axotomy (Cummins and Waxman, 1997). In particular, there was down-regulation of TTX-R sodium currents and up-regulation of a rapidly repriming TTX-S sodium current after nerve injury (Cummins and Waxman, 1997). These changes give rise to abnormal, high frequency, spontaneous firings of isolated DRG neurons, mimicking spontaneous ectopic discharges demonstrated in previous electrophysiological studies (Wall and Gutnick, 1974; Chabal et al., 1989; Kajander et al., 1992; Abdi et al., 1998; Stebbing et al., 1999). These findings appear to be contradictory to the data suggesting the importance of TTX-R sodium channels in hyperalgesia and allodynia (Porreca et al., 1999). One possible explanation is that alterations of TTX-S and TTX-R sodium channels seen in this study may be attributable to spontaneous pain behavior which was not examined in previous studies (Porreca et al., 1999).
(5) The effect of lidocaine on TTX-S and TTX-R sodium channels is likely to be different. TTX-R sodium channels are about four times less sensitive to lidocaine than TTX-S sodium channels in uninjured DRG neurons (Roy and Narahashi, 1992). Similar results have been seen in DRG neurons after axotomy (Cummins and Waxman, 1997). Behavioral studies also appear to support a relatively high sensitivity of TTX-S sodium channels to lidocaine (Akopian et al., 1999).
These new findings of diversified sodium channel subtypes provide evidence for a link between specific sodium channel subtypes and peripheral mechanisms of neuropathic pain. The exact role of sodium channel subtypes in pain in general and neuropathic pain in particular is yet to be investigated. It is likely that both TTX-S and TTX-R sodium channels are involved in mechanisms of neuropathic pain. The imbalance between the expression of these two types of sodium channels after nerve injury may be more crucial than the absolute quantity of each channel subtype in mechanisms of neuropathic pain. In addition, a causal relationship between alterations of sodium channel subtypes after nerve injury and the development and/or maintenance of specific symptoms of neuropathic pain needs to be established. This requires, in part, the use of subtype-specific sodium channel blockers in both in vivo and in vitro studies. The effect of lidocaine on activities of an individual sodium channel subtype remains inconclusive. To our knowledge, there are no subtype-selective sodium channel blockers available at the present time. The knock-down technique with anti-sense oligodeoxynucleotides provides a useful means in determining the contribution of a certain sodium channel subtype to mechanisms of neuropathic pain. However, a therapeutic value of this technique in pain patients appears to be remote. Nevertheless, the progress on studies of subtype-specific sodium channels may lead to the development of refined methods for treating neuropathic pain with reduced side-effects.
5. Summary
The clinical use of systemic lidocaine therapy has added a new modality to the treatment regimen for intractable neuropathic pain. Both anecdotal reports and prospective clinical studies have supported the use of systemic lidocaine and its oral congeners for neuropathic pain treatment. As reviewed in this article, however, a number of issues need to be addressed in order to have a rational application, rather than an empirical, trial-and-error practice, of this treatment modality in the management of neuropathic pain. Well-designed clinical trials, including the use of active placebos, should be carried out to validate the clinical outcome of using both systemic lidocaine and oral congeners of lidocaine. Importantly, individual neuropathic pain symptoms should be sorted and the effect of systemic lidocaine and its oral congeners on these individual symptoms should be well documented. The clinical validity of using the lidocaine test as a selecting process for oral therapy with lidocaine congeners needs to be further examined. Some of these issues and their considerations are given in Fig. 1.
Clinical issues of lidocaine therapy.
Laboratory studies have provided evidence supporting the clinical use of lidocaine therapy. However, mechanisms of systemic lidocaine on neuropathic pain are yet to be understood. While the effect of systemic lidocaine on suppressing spontaneous ectopic discharges is likely to be an important mechanism in reducing neuropathic pain, the possible central effect of systemic lidocaine remains to be explored. Importantly, evidence summarized in this article indicates that (1) not all spontaneous ectopic discharges are mediated by abnormal sodium channel activities, and α-adrenergic receptor sensitization plays a significant and sufficient role in generating spontaneous ectopic discharges as well, and (2) not all neuropathic pain symptoms are underlined by spontaneous ectopic discharges. It is thus extremely important that symptoms of neuropathic pain should be treated individually to seek the maximal benefit of systemic lidocaine and its oral congeners.
New findings of different sodium channel subtypes and their link to certain neuropathic pain symptoms are encouraging. This line of research may significantly advance our understanding of pain physiology in general and peripheral mechanisms of neuropathic pain in particular. Such knowledge may also lead to the development of new agents targeting sodium channel subtypes. The clinical application of subtype-specific sodium channel blockers may provide better treatment for a subset of neuropathic pain symptoms with reduced side-effects. Until then, the thoughtful use of systemic lidocaine and its oral congeners remains a valuable adjunct in neuropathic pain management.
Acknowledgements
Portions of this work were supported by the US PHS grant DA08835 (J.M.).
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Keywords:
Lidocaine; Ectopic discharge; Neuropathic pain; Sodium channel; Mexiletine
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