Original Research Articles Efficacy of a Metered-dose 8% Lidocaine Pump Spray for Patients with Post-herpetic Neuralgiapme_

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1 PAIN MEDICINE Volume 10 Number NEUROPATHIC PAIN SECTION Original Research Articles Efficacy of a Metered-dose 8% Lidocaine Pump Spray for Patients with Post-herpetic Neuralgiapme_ Akifumi Kanai, MD, PhD, Chie Kumaki, MD, Yuriko Niki, MD, Asaha Suzuki, MD, Toshiharu Tazawa, MD, and Hirotsugu Okamoto, MD, PhD Department of Anesthesiology, Kitasato University School of Medicine, Sagamihara, Japan ABSTRACT Objective. Topical lidocaine patch is effective in the treatment of post-herpetic neuralgia (PHN), but not suited for paroxysmal pain because of the long latency of analgesia. Here, we examined the efficacy of 8% lidocaine pump spray (Xylocaine pump spray, XPS) for PHN. Design. Twenty-four patients with PHN were recruited into a randomized, double-blind, placebocontrolled, crossover study (study 1), and 100 patients with PHN were recruited into an openlabeled study (study 2). In study 1, patients were randomized to receive either XPS or saline placebo pump spray (PPS) applied to the painful skin areas. Following a 7-day period, patients were crossed over to receive the alternative treatment. In study 2, XPS was prescribed for patients who were advised to use the spray anytime, with a 2-hour gap between applications, for 2 weeks. The pain was assessed with a visual analogue scale (VAS). Details of use were noted in the diary. Results. In study 1, greater decreases in VAS of persistent pain followed application of XPS (baseline: cm, 15-minute post-spray: cm, mean SD) than with PPS ( cm, cm, [P < 0.01]). The effect persisted for a median of 4.5 hours (range, 2 to 24 hours) after application. In study 2, 13 of 100 patients discontinued the treatment because of mild local side effects or insufficient effect. In the remaining 87 patients, XPS maintained significant pain relief relative to baseline throughout the 2-week period. Satisfaction with the therapy was reported by 79% of patients. Conclusions. In both studies, XPS provided a significant improvement in PHN due to its prompt analgesia, lack of systemic side effects, and convenience of use. Key Words. Post-herpetic Neuralgia; Lidocaine; Topical Spray Background Post-herpetic neuralgia (PHN) is considered the most common and debilitating complication of acute herpes zoster infection and its incidence and duration of symptoms seem to increase Reprint requests to: Akifumi Kanai, MD, Department of Anesthesiology, Kitasato University School of Medicine, Kitasato, Sagamihara , Japan. Tel: ; Fax: ; kanaiakifumi@ aol.com. with age [1]. PHN is typically associated with tactile allodynia, hyperalgesia, and pain paroxysms that greatly impair patients quality of life. The pathophysiology of PHN remains unclear, and there is no ideal therapy. There is evidence to support the use of oral tricyclic antidepressants, anticonvulsants, and potent opioids [2]. However, especially in older patients, the side effects and concomitant diseases often preclude dosage increases and extension of systemic medication to attain a successful control of evoked pain. Ideally, American Academy of Pain Medicine /09/$15.00/ doi: /j x

2 Lidocaine Spray for Post-herpetic Neuralgia 903 the primary goal of therapy would be to prevent the pain; yet, even the most appropriate treatment strategy only reduces the pain to a more tolerable level. Topical application of the local anaesthetic, lidocaine, is effective and well-tolerated for the treatment of PHN [3 5]. Topical lidocaine is applied directly to the painful skin in either a gel or patch vehicle. The patch formulation is approved both in the United States and Europe for pain associated with PHN, whereas the gel is not. The evidence for the patch is greater given this regulatory approval and inclusion in published guidelines. This treatment is reported to produce significant pain relief even with the lack of clinically significant serum levels. The proposed mechanism of action is reduction of both generation and conduction of peripheral pain impulses through sodium channel blockade in dysfunctional or damaged nociceptors situated directly below the application site [6]. Topical lidocaine treatment using a gel or patch preparations may be not suited for breakthrough pain because of the longonset time of analgesia [3 5]. Furthermore, commercially available lidocaine gel and patch are expensive and cannot be used in many countries. On the other hand, the metered-dose lidocaine pump spray, which is always available in most emergency departments for airway anesthesia, has been reported to provide effective postoperative analgesia when applied to surgical wounds [7,8]. Skin with wounds is thought to absorb more lidocaine through the exposed subcutaneous tissue than intact skin in patients with PHN. However, the delivery of a low dose of lidocaine to PHN skin with damaged or dysfunctional nociceptors may produce analgesia that is inadequate for sensory blockade. It is possible that lidocaine spray can produce prompt analgesia without touching the painful site. The purpose of the present study was to examine the effect of lidocaine delivered via a pump spray on pain in patients with PHN. Methods Patients Consecutive outpatients with PHN were enrolled into a randomized, double-blind, placebocontrolled, crossover study 1, and an open-labeled study 2 at Kitasato University Hospital. The study was approved by the Hospital Ethics Committee and informed consent was obtained from all patients. The inclusion criteria for the selection of PHN were age 20 years, pain persisting for 3 months after resolution of the cutaneous lesions, and typical pain intensity of 4 cm according to a 10 cm visual analogue scale (VAS), with 10 cm being the worst pain and 0 cm being no pain. All patients were capable of proper assessment of the severity of pain and condition. Excluded from the study were patients with other neurological diseases, psychological diseases, serious chronic diseases such as ischemic heart disease, pulmonary emphysema, renal failure and interstitial hepatitis, and/or past history of severe drug allergy. Also excluded were other patients being treated with lidocaine and/or other skin drugs, and those in whom oral medications were changed within 1 week before the study. Study Protocol Study 1 Patients were randomized to receive either a metered-dose pump of 8% lidocaine (Xylocaine pump spray, Astra Zeneca) (XPS/PPS group) or saline placebo (PPS/XPS group) on the painful skin. The optimal dose was individually determined to the dose which completely covered all over the painful site as a maximum dose of up to 30 sprays (0.1 ml/single spray, 30 times). Following a 7-day period, the patients were crossed over to receive the optimal dose of the alternative spray. Persistent pain (pain at rest) and tactile allodynia were assessed using the VAS before and 15 minutes after the treatment. Tactile allodynia was evaluated by repetitive gentle movement of a cotton swab over the affected skin. Physical examination, including measurement of blood pressure and pulse rate, was conducted on the pretreatment visit and on completion of or withdrawal from the treatment. Patients were observed for 30 minutes in supine position, and a descriptive scale (markedly better, moderately better, unchanged, or worse) was used to grade outcome. Assessments using four grades of the unwanted effects (1: none, 2: slight, 3: moderate, and 4: severe) were made by the patients themselves. Furthermore, patients were asked to rate pain relapse and time the latency period for recurring pain, and to report the above when they visited our clinic for medical examination at 7 days after therapy. Any medication used previously was discontinued 12 hours prior to randomization to avoid reinforced analgesic effect after the first spray, but treatment was resumed when the pain recurred or failed to relieve the pain. Thereafter, all medication were stopped 12 hours before the second spray. The

3 904 investigators were not informed of the patient background or the content of the spray used for treatment. Study 2 This study is a single-cohort, open-labeled design. A metered-dose 8% XPS (Xylocaine pump spray, Astra Zeneca) was prescribed for the patients and applied by themselves on the painful skin as a maximum single dose of up to 30 sprays (240 mg of lidocaine). Patients were allowed to use the spray anytime for 2 weeks, provided a period of 2 hours separated two successive applications. All medications used previously were continued regularly throughout the study. Patients were asked to keep a diary to assess pain based on VAS. Namely, daily persistent pain was assessed on the first day without XPS and in the following 14 days with XPS. The VAS before and 15 minutes after the spray, and the VAS in the worst, in the average, and in the least pain every 6-hour period (the 24-hour day was divided into four equal periods; 0:00 6:00, 6:00 12:00, 12:00 18:00, 18:00 24:00), and the side effects were noted in the diary. The side effects were evaluated using four grades (1: none, 2: slight, 3: moderate, and 4: severe). At the end of the study 2, a six-item verbal pain relief scale was used (1: complete relief, 2: marked relief, 3: moderate relief, 4: slight relief, 5: no pain relief, 6: worse). Furthermore, satisfaction with therapy was assessed with a 5-point scale (1: very satisfied, 2: satisfied, 3: neither satisfied nor dissatisfied, 4: dissatisfied, 5: very dissatisfied). Blood samples were drawn on the final day of study 2 from those patients who used more than 30 sprays/day, at 60 minutes after the first dosing. The blood concentration of lidocaine was examined using TDX analyzer (Abbott Laboratories, Chicago, IL). Data Analysis In study 1, a difference of at least 3 cm of VAS score between treatments was considered clinically significant. Based on a preliminary examination, we estimated the within-group standard deviation for VAS score of 2.5 cm. For a power of 0.8 and alpha = 0.05, a sample size of 12 patients in each group was calculated to be appropriate. Therefore, we determined that the appropriate sample size was about 24 patients in this study, as these patients were studied in a crossover design. Data are expressed as mean SD. For statistical analysis of the data, differences between the VAS score before and after spray were assessed with a paired Student s t-test. Repeated-measures analysis of variance (anova) with the sequence of spray (lidocaine spray then placebo spray or placebo spray then lidocaine spray) as the independent factor was used to investigate the carryover effect and period effect. Also, anova was used to evaluate the course of VAS score in study 2. If significant differences were detected by anova, individual means were compared by using the Student Newman Keuls test. Categorical variables were compared using the chi-squared test with Yates correction. Differences were assessed with two-sided tests, with an alpha level of Results Kanai et al. Patient Population Twenty-four consecutive outpatients were enrolled in study 1 and 100 consecutive outpatients were enrolled in study 2. Table 1 presents the demographic and baseline clinical characteristics of the patients. Analgesics shown in Table 1 as others were mexiletine, neurotropin, prostaglandin E 1, steroid, and nonsteroidal anti-inflammatory drugs. Three, five, and 44 patients had used more than two analgesics in the XPS/PPS and the PPS/XPS in study 1 and study 2, respectively. The mean VAS score at entry was more than 4 cm in all patients, despite these treatments. We observed no morbidity related to the spray of either XPS or PPS. No patient was lost to follow up during the study period, and all patients provided the required follow-up information. In study 2, 13 (13%) patients discontinued the treatment because of side effects (seven patients) or insufficient effect (six patients). Nonresponders to XPS had no remarkable characteristics. There was no difference in VAS score, doses used, and duration of therapy between nonresponders and responders. Efficacy Measures Study 1 The median (range) single dose was nine (3 15) sprays, resulting in the use of 72 (24 120) mg/application of lidocaine. XPS significantly decreased the VAS score in persistent pain from cm before spray to cm at 15-minute post-spray (P < 0.01). Moreover, PPS significantly decreased the VAS score from cm to (P < 0.05). However, the difference in the change in VAS between XPS and PPS was significant (P < 0.01). Thirteen of 24

4 Lidocaine Spray for Post-herpetic Neuralgia 905 Table 1 Patient characteristics Study 1 XPS/PPS patients suffered from tactile allodynia. Greater decreases in the VAS score followed therapy with XPS (from cm to cm) than with PPS (from cm to cm) (P < 0.01), which had no effect on allodynia. Table 2 details the VAS results for XPS and PPS. The number of patients whose VAS score in persistent pain decreased by more than 2 cm was 0 (0%) after PPS and 19 (79%) after XPS. Nine (38%) patients of the XPS group were pain-free at rest. The results of VAS score in persistent pain in the XPS/PPS and the PPS/XPS groups are shown in Table 3. In this double-blind, crossover study, PPS/XPS Study 2 Number Female : male 7:5 4:8 53:47 Mean (range) age (years) 71 (57 80) 70 (32 91) 72 (32 98) Mean body weight (kg) Median duration of illness (months) No. of patients on analgesics Opioids Antidepressants Anticonvulsants Others Pain location Right : left 6:6 6:6 54:46 Trigeminal Cervical Thoracic Lumbosacral XPS = Xylocaine pump spray; PPS = placebo pump spray. Table 2 VAS in study 1; XPS vs PPS Persistent pain no carry-over effect or period effect was noted. XPS significantly reduced VAS score 15 minutes after administration compared with PPS in the two groups. Table 4 compares the results for both the test drug and the placebo. When the number of patients with unchanged pain control was compared with those with any improvement (permanent or temporary), a significant difference was also found between the two groups (P < 0.01). The effect of lidocaine treatment persisted for a median of 4.5 hours (range, 2 to 24 hours). The improvement in persistent pain in one patient Tactile allodynia VAS score XPS PPS XPS PPS Disappearance of pain (VAS score 0 cm) 9 (38) 0 (0) 3 (13) 0 (0) Reduction by more than 2 cm 10 (42) 0 (0) 8 (33) 1 (4) Reduction within 2 cm scale 3 (13) 9 (38) 1 (4) 3 (13) No change 2 (8) 14 (58) 1 (4) 9 (38) Increased pain 0 (0) 1 (4) 0 (0) 0 (0) Totals 24 (100) 24 (100) 13 (54) 13 (54) P < 0.05, P < 0.01 vs PPS. Values are expressed as number (%). VAS = visual analogue scale; XPS = Xylocaine pump spray; PPS = placebo pump spray. Table 3 VAS in persistent pain in study 1; XPS/PPS vs PPS/XPS (unit: cm) Period 1 Period 2 Group Baseline After 15 minutes Baseline After 15 minutes XPS/PPS (N = 12) , PPS/XPS (N = 12) , P < 0.05, P < 0.01 vs baseline moment; P < 0.01 vs the other group. VAS = visual analogue scale; XPS = Xylocaine pump spray; PPS = placebo pump spray.

5 906 Kanai et al. Table 4 Description of pain control in study 1 Persistent pain Tactile allodynia Pain control XPS PPS XPS PPS Improved 18 (75) 1 (4) 9 (38) 0 (0) Temporary relief only 4 (17) 8 (33) 3 (13) 4 (17) Unchanged 2 (8) 15 (63) 1 (4) 9 (38) Totals 24 (100) 24 (100) 13 (54) 13 (54) P < 0.05, P < 0.01 vs PPS. Includes patients who described their pain as moderately better or markedly better, with relief that lasted the full length of observation. Values are expressed as number (%). XPS = Xylocaine pump spray; PPS = placebo pump spray. Table 5 Comparison of first and second week in study 2 who received placebo disappeared completely within 2 hours. Study 2 The median (range) single dose was eight (3 30) sprays/application, resulting in the use of 64 (24 240) mg/application of lidocaine. The frequency of use was times/day. Twenty-six patients used more than 30 sprays daily. The maximum and minimum daily dosages were 180 and 3 sprays/day, respectively. Figure 1 shows daily VAS rating in 87 patients who treated their pain with XPS for 2 weeks, excluding 13 patients who discontinued the therapy due to adverse or insufficient effects. XPS provided significant pain relief relative to baseline (day 0) throughout the study. There was no statistical difference in VAS between the four assessment periods (0:00 6:00, 6:00 12:00, 12:00 18:00, and 18:00 24:00). Figure 1 shows a gradual reduction in pain rating during the 2 weeks, while Table 5 shows comparison between changes recorded in the first and second weeks. The VAS in the worst pain and the VAS before the spray, which was used as rescue treatment when patients suffered from severe pain, were significantly lower in the second week than first week, despite no significant difference in the spray dosage between the 2 weeks. The pain relief score following lidocaine spray reported by 100 patients at the end of study 2 was as follows; one complete relief, 35 marked relief, Baseline First week Second week VAS in worst pain (cm) , VAS in average pain (cm) , VAS in least pain (cm) VAS before spray (cm) VAS after spray (cm) Frequency of treatment (times/day) P < 0.01 vs baseline, P < 0.01 vs first week. Values are expressed as mean SD. VAS = visual analogue scale. 41 moderate relief, 14 slight relief, seven no pain relief, and two worse. Furthermore, the satisfaction score consisted of 42 very satisfied, 37 satisfied, 11 neither satisfied nor dissatisfied, 10 dissatisfied, and 0 very dissatisfied. Adverse Events In study 1, no substantial changes in blood pressure or pulse rate were found in any subject of the two treatments. In study 2, lidocaine blood concentration was less than 0.1 mg/ml (lower limit of measurement) in all of 26 patients who used more than 30 sprays daily. Serious side effects, such as acute lidocaine intoxication, exces- VAS (cm) DAY Worst pain Average pain Least pain Figure 1 Daily VAS rating in 87 patients treated with XPS for 2 weeks. XPS resulted in significant pain relief relative during week 1 and week 2 compared with baseline (day 0). Data are mean SE. P < 0.05, compared with the respective baseline value. VAS = visual analogue scale; XPS = lidocaine pump spray.

6 Lidocaine Spray for Post-herpetic Neuralgia 907 sive sensory loss, or paresthesia, were not recognized in both study 1 and study 2. Mild side effects were reported in seven patients with XPS in study 2 consisting of local irritation (N = 3), local flare (N = 3), and mild weakness (N = 1). All adverse events were minimal and disappeared without medication within a few hours. Discussion Our results suggest that topical application of 8% lidocaine using a metered-dose pump spray produces prompt analgesia in patients with PHN without serious side effects. The pain relief at 15 minutes was markedly superior to placebo. The fact that the relief is clinically meaningful is shown by the immediate improvement of severe pain aggravated by many factors in daily life. Study 1 implies that XPS provides relatively brief analgesic effect against PHN pain. Thus, it seems difficult for treatment with a few XPS applications/day to provide all-day analgesia. However, as shown in study 2, repetitive usage of XPS can gradually relieve pain associated with PHN. Topical lidocaine on PHN region has been reported to progressively improve the severe pain and quality of life [9]. The progressive analgesia, safety, minimal systemic side effects and drug interactions, and convenience of use may explain the satisfaction with this treatment in approximately 80% of the patients in study 2. Based on results of the present study designed to gauge clinical practice setting, XPS can be considered recommendatory therapy in combination with other agents for PHN. Systemic administration of lidocaine is effective in treatment of several neuropathic pain syndromes [10]. A previous study reported a significant plasma concentration-dependent decrease in pain intensity starting at 1.5 mg/ml [11]. In another study, Sinclair et al. [7] measured plasma lidocaine concentrations in patients following spraying of surgical incisions with 200 mg of lidocaine. The mean maximum lidocaine plasma concentration in their patients was less than 0.2 mg/ml. Although there are no studies that used lidocaine spray over intact skin, the maximum plasma lidocaine concentration has been reported to be approximately 0.2 mg/ml in healthy volunteers treated with application of 5% lidocaine patch at a dose of 2,800 mg of lidocaine on normal skin [12]. In the present study, plasma lidocaine concentration was less than 0.1 mg/ml in all patients who used more than 240 mg of Table 6 Components of Xylocaine pump spray (per ml) Ingredient Purpose Quantity Lidocaine Analgesia 80 mg L-menthol Fragrance 0.5 mg Saccharin Taste 1.5 mg Ethanol Solvent 241 mg Macrogol Auxiliary solvent 300 mg Purified water Volume 377 mg lidocaine, which was calculated considering that one spray of XPS was 0.1 ml (8 mg). Therefore, it is conceivable that the basic mechanism for the rapid effect of XPS in PHN is the local analgesic effect. Increased absorption of lidocaine after topical application is attributed to enhancement of penetration through the skin by the carrier. We believe that the rapid analgesic effect of XPS is due to the composition of the spray solution (Table 6). The XPS contains 24% of ethanol as a solvent. Alcohols such as ethanol, propylene glycol, 1-butanol, and decanol accelerate absorption of transdermal drugs into the skin, thus explaining its addition in pump sprays including XPS for better penetration of the therapeutic agent [13]. Furthermore, the XPS is a saturated solution of lidocaine in water. As water is essential for absorption into the skin, the liquid composition seems to speed the onset of cutaneous topical penetration [14]. In comparison with other lidocaine delivery systems such as lidocaine patch or gel, the XPS has certain advantages. The first advantage is the rapid analgesic effect. Patients with PHN desire prompt pain relief because the pain intensity can change with movement and environment. The second advantage is convenience of use. The XPS container is portable, and provides 800 sprays without the need to touch the painful site, resulting in extensive anaesthesia, availability whenever desired, and utility on allodynic skin.the third advantage is the cost-effectiveness of the treatment. A bottle of XPS is priced at approximately $17. Thus, the cost of 24 sprays of XPS, which was used in one patient as the mean daily dose in this study, is approximately 50 cents. For comparison, the well-known lidocaine patch, LIDODERM (Endo Pharmaceuticals, Inc., Chadds Ford, PA), measuring cm, costs approximately $9. Four patches can be used at a time, and the patch is changed every 12 to 24 hours. In the present study, some patients did not respond to lidocaine spray, and the period of pain

7 908 relief varied widely among patients. These results suggest interindividual variability in local analgesia with lidocaine. Skin is a living tissue whereby many parameters including interindividual variation, cutaneous vasoactivity, skin damage, temperature and hydration can have a major impact on the transdermal uptake of lidocaine [15,16]. It is important to examine the most advantageous skin condition to obtain cutaneous local anaesthesia using the XPS. Furthermore, the skin infiltration of local anaesthetic results in analgesia of varying degree and duration [17]. There are probably several underlying mechanisms for the pain of PHN, and pain with poor response to topical lidocaine may exist. Also, next study is necessary to investigate whether the patch formulation provides effective analgesia for patients whose pain cannot be relieved with the spray formulation. There are several limitations to our study. First, the possibility that our patients distinguished XPS from PPS, as saline did not have the local irritant effect and anesthetic effect of lidocaine. However, none of the patients who used XPS reported local irritation in study 1. Furthermore, the difference in the analgesic effect between XPS and PPS was evident in the first arm of crossover study 1. Second, considering that XPS contains other agents, we cannot exclude the analgesic effect of other chemicals present in the liquid spray. For example, ethanol in the spray increases skin blood flow, which may provide an analgesic effect in PHN [18,19]. Third, treatment only lasted for 2 weeks. It is possible that patients respond differently to the treatment over time. Also, additional side effects may occur following prolonged use of the spray. The safety associated with liberal use of XPS is still unknown. The liberal use may produce the cardiac and central nervous system toxicity. Finally, we should mention the design chosen for study 2 as a limitation for completeness, and that the exclusion of patients who discontinued therapy biases the results of this part of the study. Also, pain during daily life was assessed using a simple protocol. Patients with PHN describe a variety of pain symptoms including allodynia, lancinating or paroxysmal pain, burning pain and deep, boring, aching pain. Future studies should examine the different pattern of response to treatment, using a pain questionnaire that distinguishes these symptoms. Conclusions In conclusion, the present study suggested the efficacy and safety of topical XPS for the treatment Kanai et al. of PHN. The randomized, double-blind, placebocontrolled, crossover study showed that pain relief with topical XPS in PHN patients is significant compared with a vehicle spray when applied directly over the painful region. Topical XPS provides a significant improvement in treatment of PHN pain based on efficacy, lack of systemic side effects, and convenience of use. References 1 Gazewood JD, Meadows S, Halverson L. Clinical inquiries. What is the prognosis of postherpetic neuralgia? J Fam Pract 2003;52: Hempenstall K, Nurmikko TJ, Johnson RW, A Hern RP, Rice AS. Analgesic therapy in postherpetic neuralgia: A quantitative systematic review. PLoS Med 2005;2: Stow PJ, Glynn CJ, Minor B. EMLA cream in the treatment of post-herpetic neuralgia. Efficacy and pharmacokinetic profile. Pain 1989;39: Rowbotham MC, Davies PS, Fields HL. Topical lidocaine gel relieves postherpetic neuralgia. Ann Neurol 1995;37: Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: Double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 1996;65: Wallace MS. Calcium and sodium channel antagonists for the treatment of pain. Clin J Pain 2000; 16:S Sinclair R, Cassuto J, Högström S, et al. Topical anesthesia with lidocaine aerosol in the control of postoperative pain. Anesthesiology 1988;68: Sinclair R, Westlander G, Cassuto J, Hedner T. Postoperative pain relief by topical lidocaine in the surgical wound of hysterectomized patients. Acta Anaesthesiol Scand 1996;40: Katz NP, Gammaitoni AR, Davis MW, Dworkin RH. Lidocaine patch 5% reduces pain intensity and interference with quality of life in patients with postherpetic neuralgia: An effectiveness trial. Pain Med 2002;3: Tremont-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetics to relieve neuropathic pain: A systematic review and meta-analysis. Anesth Analg 2005;101: Wallace MS, Dyck JB, Rossi SS, Yaksh TL. Computer-controlled lidocaine infusion for the evaluation of neuropathic pain after peripheral nerve injury. Pain 1996;66: Gammaitoni AR, Alvarez NA, Galer BS. Pharmacokinetics and safety of continuously applied lidocaine patches 5%. Am J Health Syst Pharm 2002;59: Johnson ME, Mitragotri S, Patel A, Blankschtein D, Langer R. Synergistic effects of chemical enhancers

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