Intravenous Lidocaine for Neuropathic Pain: Diagnostic Utility and Therapeutic Efficacy

Transcription

1 Intravenous Lidocaine for Neuropathic Pain: Diagnostic Utility and Therapeutic Efficacy Ian Carroll, MD, MS Corresponding author Ian Carroll, MD, MS Stanford University School of Medicine, 780 Welch Road, Suite 208E, Palo Alto, CA 94034, USA. Current Pain and Headache Reports 2007, 11:20 24 Current Medicine Group LLC ISSN Copyright 2007 by Current Medicine Group LLC Lidocaine is a use-dependent sodium channel blocker that produces analgesia when administered intravenously to patients with neuropathic pain. This article reviews the role and limitations of intravenous lidocaine infusions for neuropathic pain. Lidocaine infusions rarely provide relief that persists significantly beyond the duration of the infusion. Diagnostically, systemic lidocaine may help establish the presence of neuropathic pain and the responsivity to oral sodium channel blockade. However, the data supporting diagnostic infusions remain sparse. Therapeutically, infusions should generally be restricted to patients with neuropathic pain who are unable to take oral medication. Introduction Lidocaine is a local anesthetic that was first introduced in Lidocaine exhibits well-known anti-arrhythmic and local anesthetic properties. Less appreciated by many clinicians is lidocaine s role as a potent antineuropathic agent when administered intravenously. In the absence of patent protection, lidocaine will not be the subject of large, randomized, placebo-controlled studies by a drug company to define its role in the treatment of neuropathic pain. Therefore, virtually all of the information on this uniquely effective agent comes from small investigatorinitiated studies. These studies demonstrate clear efficacy. However, confusion and controversy still exist regarding the role of lidocaine in our armamentarium against neuropathic pain. This article discusses the evidence supporting the use of lidocaine for neuropathic pain and the limitations of its use. Mechanisms of Action Lidocaine is a class IB anti-arrhythmic, use-dependent sodium channel blocker. Sodium channel blockade results in the anti-arrhythmic and local anesthetic properties of lidocaine. How systemic lidocaine induces analgesia in patients with neuropathic pain when delivered systemically remains less well understood at the neurophysiologic level. Lidocaine s antineuropathic analgesic effect has been postulated to work through peripheral, spinal, and supraspinal mechanisms. Peripheral mechanisms It is clear that in regions of injury peripheral nerves aberrantly express high densities of sodium channels that may result in spontaneous ectopic discharge. Systemic lidocaine may have a dissociative effect on nerve conduction and ectopic discharges, blocking the ectopic discharges without blocking nerve conduction [1]. Spinal mechanisms At the spinal level, lidocaine induces a selective depression of C-fiber evoked activity among spinal cord wide dynamic range neurons, as well as hyperexcitability of dorsal horn neurons in neuropathic animals [2,3]. Supraspinal mechanisms A supraspinal mechanism of action for systemic lidocaine is suggested by its effectiveness in patients with hemispheric lesions and post-stroke pain [4]. Furthermore, lidocaine infused for pain management has been reported to result in dramatic behavioral changes [5]. Procaine, another local anesthetic, is known to have profound selective limbic system activation when administered systemically, which correlates with specific regional blood flow changes in the anterior paralimbic area of the brain [6,7]. As demonstrated on positron emission tomography scan, selective activation of an anterior limbic and paralimbic network in the absence of significant cortical activation is achieved by intravenous procaine infusion and induces powerful emotional and visceral experiences in healthy subjects

2 Intravenous Lidocaine for Neuropathic Pain: Diagnostic Utility and Therapeutic Efficacy Carroll 21 [8]. Patients undergoing procaine infusions have reported euphoria, anxiety, depression, and fear, and have also reported phenomena such as derealization and inability to concentrate [8]. Similar emotional changes may account for some of the apparent analgesic actions of lidocaine by altering the processing of the affective dimensions of the pain experience in medial forebrain structures, such as the anterior cingulate cortex and insular cortex. The mechanisms of lidocaine for neuropathic pain have been extensively reviewed elsewhere [9]. Lidocaine Efficacy Tremont-Lukats et al. [10 ] recently published the results of a systematic review and meta-analysis of the effectiveness of local anesthetics for neuropathic pain. In addition to its meta-analysis, this review presents a thorough catalogue of the previous controlled studies of lidocaine for neuropathic pain. The authors noted that clinical trails testing lidocaine have generally enrolled few patients, used varied dose regimens, had different experimental designs, and assessed varied endpoints over varied time periods. In short, they are hard to compare. Nonetheless, they were able to complete a meta-analysis that examined 10 trials comparing lidocaine with placebo for a total of 165 patients taking lidocaine. They concluded that lidocaine had a statistically significant superiority to placebo, but the mean effect was small (approximately one point on a 10-point scale). The authors note that most studies examining the effect of lidocaine on neuropathic pain have examined the role of evoked rather than spontaneous pain. It has been argued that allodynic response is not the appropriate endpoint for investigating the role of systemic lidocaine on neuropathic pain behaviors [9]. This may explain the small effect size measured. Others have concluded that the side effects of these drugs outweigh the incremental analgesia [11 ]. Our experience suggests that the mean effect in this group may be small due to the fact that a proportion of patients has no analgesic response, lowering the measured mean response. However, most patients with an analgesic response describe it as significant. Attal et al. [12] conducted a double-blind, crossover, placebo-controlled study of 22 patients with pain due to peripheral nerve injury. All patients had pain due to postherpetic neuralgia or traumatic nerve injury. Five of 22 patients were pain free with lidocaine, 11 of 22 had 50% reduction of spontaneous pain, and 12 of 22 had 33% reduction of spontaneous pain. Lidocaine reduced both spontaneous neuropathic pain and mechanical allodynia but did not change dynamic mechanical pain thresholds in non-neuropathic areas or thermal allodynia. These results suggest lidocaine exerts a modality-specific effect rather than a general pain-relieving effect. These results also highlight that studies assessing only the patients visual analog scores of pain likely omit important information. This need for detailed assessment of sensory function and modalityspecific pain is highlighted by the factors found to predict responsivity to lidocaine. In these patients, the baseline severity of mechanical allodynia correlated with lidocaine s relief of spontaneous pain (P < 0.01). Conversely, the baseline magnitude of sensory deficits to temperature had an inverse relationship to the effectiveness of lidocaine. Patients with minimal temperature sensory deficits were more likely to respond to lidocaine than were those with major deficits (P < 0.01). Age of patients, etiology of pain, duration of pain, and intensity of pain were not associated with response to intravenous lidocaine. The same group investigated the effect of intravenous lidocaine for central pain in a double-blind, placebocontrolled crossover study. Sixteen patients with either post-stroke pain or spinal cord injury received 5 mg/kg over 30 minutes. Lidocaine significantly reduced spontaneous pain, compared with placebo. This effect remained statistically significant for only 45 minutes. However, two of 16 patients reported more sustained benefit, but none had relief beyond 6 hours. As in their later study of patients with peripheral neuropathic pain [12], in patients with central neuropathic pain, lidocaine reduced mechanical allodynia but did not affect cold-induced allodynia, or pain thresholds [4]. These results appear to contradict earlier uncontrolled reports that lidocaine was not as effective for central pain [13]. Diagnostic Lidocaine Infusions Lidocaine as a test for neuropathic pain We have been using computer-controlled, targeted lidocaine infusions [14] for the past 10 years at the Stanford Pain Management Center, performing approximately 300 infusions per year on outpatients with chronic pain. This experience suggests several important properties of these infusions that are generally supported by the literature. First, diagnostic lidocaine infusions are surprisingly safe. We have not had a single serious adverse event in all of the infusions we have done. This is supported by a recent meta-analysis, which notes that although side effects of lidocaine infusions are common, serious adverse events are rare [10 ]. Indeed, in the initial studies using a computer-controlled infusion pump in this setting, plasma levels more than 15 g/ml were achieved without serious sequelae [14]. In contrast, we currently use a computer-controlled infusion to deliver plasma levels up to but not exceeding 5 g/ml. Side effects of the infusion were common and consisted of somnolence, lightheadedness, and perioral numbness, which were present in 16 of 22 patients in one study [12]. Second, most patients with a clear neuropathic pain disorder (eg, diabetic peripheral neuropathy or postherpetic neuralgia) get some immediate temporary relief with these infusions [4,12,15]. This immediate relief occurs within 1 hour of starting the drug and stands in stark

3 22 Anesthetic Techniques in Pain Management contrast with the relief afforded by oral antineuropathic agents, which may not reach peak effects for weeks. Third, many patients who do not have an obvious neuropathic pain syndrome obtain immediate and profound relief from lidocaine infusions. These patients will often go on to have durable analgesic responses to other sodium channel blockers or even non sodium channel blocking anticonvulsants (eg, gabapentin) or antidepressants (eg, duloxetine). In short, a strong analgesic response to lidocaine seems to suggest the presence of neuropathic pain, even when this was not initially suspected as the principal diagnosis. The literature supporting this use of lidocaine is suggestive but far from definitive. In 1992, Marchettini et al. [16] were the first to propose the use of lidocaine as a diagnostic test for patients with nerve pain. They looked at 10 patients with known peripheral nerve injuries with neuropathic pain. Each patient was given an infusion of lidocaine and placebo. Whereas placebo helped only one patient, all 10 patients experienced a reduction in both spontaneous pain and mechanical hyperalgesia. Therefore, they proposed that lidocaine could be used as a diagnostic aid in patients with complex neural and pain disorders. Other investigators have noted that lidocaine reduces neuropathic pain from such varied causes as thalamic pain, trigeminal neuralgia, and phantom limb pain, but lidocaine does not appear to provide relief from non-neuropathic pain from peripheral nociceptive input, such as a pressure cuff induced ischemia [17]. Similarly, in healthy volunteers, lidocaine appears to selectively suppress secondary hyperalgesia but not acute nociceptive pain [18]. In addition, in patients with peripheral neuropathic pain responsive to systemic lidocaine, pain thresholds to mechanical or thermal stimuli in normal areas are not changed by intravenous lidocaine [12]. Many people with neuropathic pain are not appropriately treated. Indeed, more than 60% of patients with neuropathic pain have never tried appropriate antineuropathic pain medications [19,20]. It appears that a substantial proportion of these patients is not treated appropriately because the neuropathic nature of their pain is not appreciated. Peripheral neuropathy (with its stocking-glove distribution) and postherpetic neuralgia (with its unique presentation and classical radiculopathy) may be easily recognized as neuropathic pain. However, entrapment neuropathies, scar neuromas, and other traumatic neuropathies often are not adequately appreciated as neuropathic conditions on clinical grounds alone. For example, a patient with pelvic pain may be referred for endometriosis and yet have an undiagnosed pudendal nerve neuropathy. A strongly positive analgesic response to intravenous lidocaine in this setting will increase the suspicion of a neuropathic lesion and perhaps prompt the treating physician to look for associated sensory deficits in the pudendal distribution and initiate therapy with a conventional anticonvulsant. In this manner, lidocaine may have some significant utility independent of any long-term efficacy in clarifying that a chronic pain syndrome has a neuropathic underpinning. Lidocaine is uniquely suited to this task because of its rapid onset, the high percentage of patients with neuropathic pain who perceive some benefit with its administration, and its minimal analgesic effect on non-neuropathic pain. In this setting, a positive response to a lidocaine infusion may increase both the physician s and patient s confidence that laborious trials of oral antineuropathic regimens are worthwhile. Diagnostic role of lidocaine for predicting subsequent response to mexiletine Other authors have suggested a more specific diagnostic role for intravenous lidocaine infusions. These authors have suggested that an analgesic response to lidocaine may not just indicate neuropathic pain, but rather that a particular patient s neuropathic pain will respond to treatment with mexiletine. Mexiletine, like lidocaine, is a class IB anti-arrhythmic use-dependent sodium channel blocker. However, unlike lidocaine, which undergoes extensive first pass hepatic metabolism, mexiletine can achieve therapeutic levels when taken orally. Thus, mexiletine is a rational choice as an oral substitute for lidocaine. Indeed, in studies of lidocaine for prophylaxis of ventricular arrhythmia [21], lidocaine has a very high negative predictive value for predicting subsequent response to mexiletine but has a limited positive predictive value. In other words, if a patient s ventricular arrhythmia does not respond to lidocaine intravenously, there is little chance the patient will respond to mexiletine. In 1996, Galer et al. [15] reported a prospective study of nine patients with neuropathic pain who received lidocaine infusions and then were placed on mexiletine. They reported a statistically significant correlation in this small group between the degree of pain relief with lidocaine and the degree of pain relief with mexiletine. Of note, the infusions they used were 45 minutes long, and patients achieved maximum relief at 30 minutes post-infusion. These results are supported by more recent work by Attal et al. [12]. They looked at patients with peripheral neuropathic pain from either postherpetic neuralgia or peripheral nerve injury. Twenty-four patients were randomized to receive either intravenous lidocaine or placebo infusion in a crossover fashion. Two weeks after the infusion, all patients were offered a trial of oral mexiletine. Among 13 patients who received both the lidocaine and mexiletine, a significant correlation was found between the relief of mechanical allodynia with lidocaine and mexiletine (Kendall tau = 0.62, P < 0.01). There was a weaker correlation between the relief of spontaneous pain with mexiletine and lidocaine that did not reach statistical significance (Kendall tau = 0.34, P = 0.058). In this study, the infusions lasted only 30 minutes, and patients reportedly experienced maximal pain relief by the end of the infusion. These are the only studies documenting the value of lidocaine for predicting a response to a subsequent oral regimen for neuropathic pain.

4 Intravenous Lidocaine for Neuropathic Pain: Diagnostic Utility and Therapeutic Efficacy Carroll 23 Physicians treating patients with neuropathic pain face daunting obstacles. To optimize compliance, minimize side effects, and maximize analgesia, each oral antineuropathic medication needs to be started at a low dose and titrated to effect over many weeks in a manner well described as labor intensive [22,23]. Frustratingly, each antineuropathic medication produces pain relief for only some patients with neuropathic pain [24]. Not surprisingly, few physicians have the patience required to persist in a strategy involving months of frustrating side effect laden medication trials. These practical barriers to care undermine decades of research advancing our ability to treat neuropathic pain. In contrast, lidocaine s fast onset of action means that a patient s response to a lidocaine infusion can be characterized in as little as a half hour during an outpatient infusion, instead of weeks. This response to lidocaine may enhance suspicion of an underlying neuropathic pain disorder and predict subsequent response to mexiletine. However, the ability to predict mexiletine response has only been evaluated in 22 patients with peripheral nerve injury. The correlation between the analgesic effect of lidocaine and mexiletine may be a consequence of the pharmacologic similarity of the two drugs, or a consequence of a general degree of responsivity of patients to any pharmacotherapy, or both. The distinction is important because lidocaine infusions may predict responsiveness not just to mexiletine but to better-tolerated medications such as gabapentin. If so, lidocaine could be used as a diagnostic test of responsivity to a broader class of drugs. Therapeutic Lidocaine Infusions The question remains under what circumstances is lidocaine appropriate therapy for neuropathic pain? Lidocaine s intravenous availability and rapid onset make it uniquely useful for hospitalized patients unable to take oral medications. Such patients with neuropathic pain after trauma, surgery, or cancer often experience unique benefits with lidocaine. At my hospital, it is delivered as a continuous infusion starting at 1 mg/kg per hour. Lidocaine levels are checked and possibly adjusted every 8 hours and are kept below 4 g/ml. Lidocaine has an active metabolite with a significantly longer half-life than lidocaine: monoethylglycinexylidide (MEGX). MEGX is not measured with standard lidocaine levels and may contribute substantially to clinical lidocaine analgesia and toxicity after just a couple of days. Consequently, therapy is tailored to the minimal effective dose. Side effects such as tinnitus, perioral numbness, agitation, and dysarthria are carefully sought and used as a basis for reducing the dose. Lidocaine infusions are used with extreme caution in patients with hepatic, cardiac, or renal insufficiency. On rare occasions, we have used lidocaine continuously through an indwelling intravenous catheter for terminally ill patients with neuropathic pain who do not respond to alternative medications. In rats, a single lidocaine infusion may produce prolonged reduction of tactile allodynia for 14 to 21 days far beyond the half-life of the drug [25,26]. Similarly, studies examining the analgesic effects of lidocaine in patients with chronic neuropathic pain report relief sometimes lasting weeks from single infusions [27,28]. In the study by Attal et al. [12] of lidocaine in peripheral neuropathic pain, the analgesic effects of lidocaine were no longer statistically significant beyond 24 hours. However, 22% of patients reported some relief persisting beyond 24 hours, with one patient reporting relief up to 7 days after the infusion. In my experience, after having done thousands of hour-long lidocaine infusions, only rarely does clinically relevant analgesia persist for more than the first few hours after the infusion. We, like others, have observed the unusual patient who appears to have prolonged benefit with each lidocaine infusion. Nonetheless, despite conducting several hundred diagnostic lidocaine infusions per year, we have only one patient who is well managed by intermittent (monthly) infusions. Thus, it would seem clinically relevant prolonged analgesia among the population referred to a tertiary pain clinic is quite low. Conclusions Systemic lidocaine is effective in reducing neuropathic pain in a subset of patients with neuropathic pain. When this effect is averaged over all patients with neuropathic pain, including nonresponders, the effect is still statistically significant, although the magnitude of the effect is modest. For most patients, lidocaine-induced analgesia persists for only a short period after cessation of the intravenous infusion. Thus, for therapeutic purposes, lidocaine infusions are primarily useful for patients with neuropathic pain who have an indwelling catheter and are unable to take oral medication, such as patients typically hospitalized after surgery, trauma, or cancer. Diagnostic infusions are used by some centers to inform the likelihood of a neuropathic pain problem, capture patient confidence, and help select patients for mexiletine treatment. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Devor M, Wall PD, Catalan N: Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. 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5 24 Anesthetic Techniques in Pain Management 4. Attal N, Gaude V, Brasseur L, et al.: Intravenous lidocaine in central pain: a double-blind, placebo-controlled, psychophysical study. Neurology 2000, 54: Leong MS, Solvason HB: Case report: limbic system activation by intravenous lidocaine in a patient with a complex regional pain syndrome and major depression. Pain Med 2000, 1: Benson BE, Carson RE, Kiesewetter DO, et al.: A potential cholinergic mechanism of procaine s limbic activation. Neuropsychopharmacology 2004, 29: Parekh PI, Spencer JW, George MS, et al.: Procaine-induced increases in limbic rcbf correlate positively with increases in occipital and temporal EEG fast activity. Brain Topogr 1995, 7: Servan-Schreiber D, Perlstein WM, Cohen JD, Mintun M: Selective pharmacological activation of limbic structures in human volunteers: a positron emission tomography study. J Neuropsychiatry Clin Neurosci 1998, 10: Mao J, Chen LL: Systemic lidocaine for neuropathic pain relief. Pain 2000, 87: Tremont-Lukats IW, Challapalli V, McNicol ED, et al.: Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis. Anesth Analg 2005, 101: The first large meta-analysis of the effect of local anesthetics on neuropathic pain. The article contains a catalogue of studies on lidocaine and neuropathic pain, for readers interested in looking at specific studies. 11. Rathmell JP, Ballantyne JC: Local anesthetics for the treatment of neuropathic pain: on the limits of meta-analysis. Anesth Analg 2005, 101: This is an important and thoughtful critique of the literature on using local anesthetic medications for neuropathic pain. 12. Attal N, Rouaud J, Brasseur L, et al.: Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology 2004, 62: Galer BS, Miller KV, Rowbotham MC: Response to intravenous lidocaine infusion differs based on clinical diagnosis and site of nervous system injury. Neurology 1993, 43: Schnider T, Gaeta TW, Brose RR, et al.: Derivation and cross-validation of pharmacokinetic parameters for computer-controlled infusion of lidocaine in pain therapy. Anesthesiology 1996, 84: Galer BS, Harle J, Rowbotham MC: Response to intravenous lidocaine infusion predicts subsequent response to oral mexiletine: a prospective study. J Pain Symptom Manage 1996, 12: Marchettini P, Lacerenza M, Marangoni C, et al.: Lidocaine test in neuralgia. Pain 1992, 48: Boas RA, Covino BG, Shahnarian A: Analgesic responses to i.v. lignocaine. Br J Anaesth 1982, 54: Dirks J, Fabricius P, Petersen KL, et al.: The effect of systemic lidocaine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers. Anesth Analg 2000, 91: Gilron I, Bailey J, Weaver DF, Houlden RL: Patients attitudes and prior treatments in neuropathic pain: a pilot study. Pain Res Manag 2002, 7: Berger A, Dukes EM, Oster G: Clinical characteristics and economic costs of patients with painful neuropathic disorders. J Pain 2004, 5: Zehender M, Geibel A, Treese N, et al.: Prediction of efficacy and tolerance of oral mexiletine by intravenous lidocaine application. Clin Pharmacol Ther 1988, 44: Orza F, Boswell MV, Rosenberg SK: Neuropathic pain: review of mechanisms and pharmacologic management. NeuroRehabilitation 2000, 14: Dworkin RH, Backonja M, Rowbotham MC, et al.: Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol 2003, 60: Collins SL, Moore RA, McQuay HJ, Wiffen P: Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. J Pain Symptom Manage 2000, 20: Chaplan SR, Bach FW, Shafer SL, Yaksh TL: Prolonged alleviation of tactile allodynia by intravenous lidocaine in neuropathic rats. Anesthesiology 1995, 83: Sinnott CJ, Garfield JM, Strichartz GR: Differential efficacy of intravenous lidocaine in alleviating ipsilateral versus contralateral neuropathic pain in the rat. Pain 1999, 80: Petersen P, Kastrup J, Zeeberg I, Boysen G: Chronic pain treatment with intravenous lidocaine. Neurol Res 1986, 8: Petersen P, Kastrup J: Dercum s disease (adiposis dolorosa). Treatment of the severe pain with intravenous lidocaine. Pain 1987, 28:77 80.