An Open-Label Study of the Lidocaine Patch 5% in Painful Idiopathic Sensory Polyneuropathy

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1 Blackwell Science, LtdOxford, UKPMEPain Medicine American Academy of Pain MedicineSeptember/October Original ArticleLidocaine Patch 5%Herrmann et al. PAIN MEDICINE Volume 6 Number An Open-Label Study of the Lidocaine Patch 5% in Painful Idiopathic Sensory Polyneuropathy David N. Herrmann, MBBCh,* Richard L. Barbano, MD, PhD,* Stephanie Hart-Gouleau, MD, Janet Pennella-Vaughan, MS, NP, and Robert H. Dworkin, PhD* Departments of *Neurology, Pathology, Anesthesiology, Oncology, and Psychiatry, University of Rochester, Rochester, New York, USA ABSTRACT Abstract Objective. Painful idiopathic distal sensory polyneuropathy is common, but has been largely ignored as a model for the evaluation of neuropathic pain therapies. We have therefore conducted a safety, tolerability, and effectiveness study of the lidocaine patch 5% in painful idiopathic distal sensory polyneuropathy. Design. A prospective open-label, flexible dosing, 3-week study period with a 5-week extension. Setting. Peripheral Neuropathy clinics and Anesthesiology Clinical Research Center at a tertiary care facility. Patients. Twenty subjects with a diagnosis of idiopathic distal sensory polyneuropathy (with or without associated impaired glucose tolerance), with a baseline mean pain daily rating of 4 on a visual analog scale. Intervention. Lidocaine patch 5%, maximum of four patches daily for 18 hours. Main Outcome Measure. Change from baseline week to week 3 mean daily diary pain ratings. Secondary endpoints included assessments of safety and tolerability as well as quality of life measures. Results. Subjects with idiopathic distal sensory polyneuropathy, both with and without impaired glucose tolerance, showed significant improvements in pain and quality of life outcome measures over a 3-week treatment period. These improvements were maintained in a subgroup of patients treated for an additional 5 weeks and permitted a taper of concomitant analgesics in 25% of subjects. The lidocaine patch 5% was well tolerated. Conclusions. The lidocaine patch 5% appeared well tolerated and potentially effective in the management of painful idiopathic distal sensory polyneuropathy. Idiopathic distal sensory polyneuropathy is an appropriate patient population for the conduct of clinical trials of neuropathic pain therapies. Key Words. Lidocaine Patch 5%; Neuropathic Pain; Idiopathic Sensory Polyneuropathy; Impaired Glucose Tolerance; Quality of Life Reprint requests to: David N. Herrmann, MBBCh, Department of Neurology, University of Rochester, SMH 601 Elmwood Ave, Box 673, Rochester, NY 14642, USA. Tel: ; Fax: ; David_Herrmann@urmc. rochester.edu. American Academy of Pain Medicine /05/$15.00/

2 380 Herrmann et al. I diopathic distal sensory polyneuropathy (ISP) accounts for about 20% of patients in a tertiary peripheral neuropathy clinic setting [1]. Its cardinal symptom, burning feet, is often disabling and resistant to therapy [2]. Recent epidemiological studies suggest that about 35% of cases are associated with impaired glucose tolerance (IGT) as defined by a 2-hour glucose tolerance test [3]. There have been no prospective clinical trials of treatments for patients with this chronic neuropathic pain syndrome, and agents in clinical use are selected primarily based on their efficacy in diabetic neuropathy. We recently conducted a prospective, openlabel study of a more flexible dosing regimen of the lidocaine patch 5% in 56 subjects with painful diabetic neuropathy (up to four patches/24 hours, 18 hours on, 6 hours off ), and found it to be safe, well tolerated, without systemic side-effects, and effective [4]. As ISP often presents with pain restricted to the feet, topical therapies for neuropathic pain have potential advantages over systemic therapies, which are typically associated with such side-effects as excessive sedation. We therefore conducted a prospective open-label study of this more flexible dosing regimen of lidocaine patch 5% in 20 patients with ISP to assess the effectiveness and safety of this treatment and the feasibility of conducting clinical trials in ISP. of clinical or laboratory evidence of another neuromuscular syndrome, systemic disorder, or neurotoxin exposure known to predispose to sensory neuropathy; and 4) a history of familial peripheral neuropathy. The inclusion and exclusion criteria for ISP with IGT were identical to those for ISP without IGT, except that patients with IGT had an abnormal 2-hour 75 g glucose tolerance test, with a 2-hour blood glucose value in the IGT range ( mg/dl) [7]. Study Design Treatment consisted of the daily application to the area of maximal ISP pain of up to four lidocaine patches (18 hours on, 6 hours off per day) for 3 weeks, followed by an additional 5 weeks during which taper of concomitant analgesics was permitted [4]. An attempt was made at each dosing period to cover the entire painful region with lidocaine patches. Patients completed the BPI average pain rating in a daily diary. Assessments were also conducted weekly of Short-Form McGill Pain Questionnaire (SF-MPQ) pain intensity and quality [8], BPI pain relief [6], sleep quality, BPI interference of pain on daily activities [6], Beck Depression Inventory (BDI) [9], and Profile of Mood States (POMS) [10]. Plasma lidocaine levels were drawn approximately hours after the last patch application at the end of treatment weeks 1 and 3 [4]. Methods Patients The study protocol was approved by the University of Rochester Institutional Review Board (IRB) and all patients provided informed consent. The inclusion criteria included: 1) presence of signs and symptoms of painful distal polyneuropathy greater than 3 months in duration, supported by the finding of a distal sensory or sensorimotor axonal polyneuropathy on nerve conduction studies, or if normal, by abnormal epidermal innervation on punch skin biopsies taken from the distal leg and proximal thigh [2,5]; 2) an average daily pain rating for the baseline week of 4 on the Brief Pain Inventory (BPI) [6] 0 10 rating scale of average pain; and 3) a stable analgesic drug regimen for at least 1 week prior to the baseline visit. Exclusion criteria included: 1) any other pain more severe than the painful ISP; 2) any history of known diabetes mellitus or screening evidence thereof from a fasting blood glucose, HgA1c, or 2-hour, 75 g glucose tolerance test; 3) the presence Statistical Analysis The primary outcome variable was the change from baseline week to week 3 mean daily diary pain ratings. Secondary outcome measures of change from baseline to week 3 included additional pain and quality of life measures as well as assessments of safety and tolerability. Analysis was performed on data from all patients for whom baseline and any post baseline data were available. Final assessments were performed at the time of discontinuation for all patients who discontinued study medication prematurely for any reason. All patients were included in the safety analyses. A two-way repeated-measures anova with terms for visit (baseline vs week 3 or baseline vs week 8) and patient group (IGT vs no IGT) was used to compare within- and between-group changes in outcome variables. McNemar s test was used for within-group comparisons of sleep quality. Analysis of adverse events was descriptive. P 0.05 two-tailed was considered significant.

3 Lidocaine Patch 5% 381 Results Twenty patients with painful ISP were enrolled. Patients with (N = 8) and without IGT (N = 12) did not differ with respect to age, sex, weight, height, or baseline daily diary pain intensity. Significant improvement was found in the primary endpoint of change in baseline week to week 3 mean daily diary pain ratings as well as in SF- MPQ total, sensory, affective, and visual analog scale pain scores and BPI pain relief scores in the total sample of patients (Table 1). From baseline to week 3, 40% of patients demonstrated a 30% reduction in weekly mean daily diary pain ratings and 30% of patients demonstrated a 50% reduction; from baseline to week 8, 65% of patients demonstrated a 30% reduction and 55% of patients demonstrated a 50% reduction. Treatment was accompanied by significant improvements from baseline to week 3 in general activity, normal work, sleep, and overall pain interference as assessed by the BPI (Table 2). Significant improvement was also seen in BDI depression scores and in all of the POMS mood scales except for anger-hostility and vigor-activity (Table 2). With one exception, the interactions between visit and patient group were not significant, indicating that subjects with and without IGT did not differ in the extent to which they improved with treatment; the one significant interaction indicated that patients without IGT had a greater response to treatment than patients with IGT on the daily diary pain ratings. Five patients were able to successfully discontinue or taper prior stabilized analgesics between treatment weeks 3 and 8 when taper of concomitant analgesics was permitted. Two patients had complete discontinuation (one gabapentin, one tramadol), and three patients maintained reduced dosages of gabapentin (11% and 25% reduction) and tramadol (50% reduction). No patients required increase in concomitant analgesics. Improvements in pain and quality of life were maintained for all of the outcome measures at 8 weeks that demonstrated significant benefits at 3 weeks except for SF-MPQ affective pain and POMS fatigue-inertia and confusion-bewilderment scores. However, improvement in sleep quality and the BPI mood and relations with other people items became significant after the additional 5 weeks of treatment. Of the 20 patients enrolled, only one withdrew secondary to a treatment-related adverse event (application site burning) during the initial 3-week study period, and five were withdrawn (none due to adverse events) after week 3 but before the end of the study at week 8 (three patient choice, two patients had conflicting travel arrangements, one lack of efficacy, and one at the sponsor s request due to the subject missing the primary endpoint study visit). Five patients reported at least one treatment-related adverse event, none of which were serious (application site burning, application site pain, erythema, dry mouth, and taste disturbance). The mean ± SD trough plasma lidocaine levels did not differ significantly between the end of treatment weeks 1 (24.9 ± 22.9 ng/ml), 3 (35.2 ± 37.2 ng/ml), and 8 (28.3 ± 31.3 ng/ml). These levels are well below lidocaine serum levels associated with antiarrhythmic effects (1,500 ng/ ml) and toxicity (5,000 ng/ml). Discussion In this open-label trial, lidocaine patch 5% significantly improved pain and quality of life in patients with painful ISP with and without IGT. Although Table 1 Pain intensity and relief outcome measures Measure* ISP with IGT (Patients N = 8) Week 3 (N = 7) ISP Without IGT (Patients N = 12) Total Sample (N = 20) Week 3 (N = 12) Week 3 P Value BPI daily diary mean pain rating 5.6 (1.5) 5.1 (1.2) 6.7 (1.8) 4.0 (2.1) 6.3 (1.7) 4.4 (1.9) SF-MPQ Sensory score 13.0 (5.7) 10.0 (6.8) 16.8 (9.0) 11.8 (9.0) 15.3 (7.9) 11.1 (8.1) Affective score 2.1 (2.4) 1.3 (2.1) 3.4 (3.5) 2.0 (2.6) 2.9 (3.1) 1.7 (2.4) 0.01 Total score 15.1 (7.3) 11.3 (8.6) 20.3 (11.9) 13.8 (11.2) 18.2 (10.4) 12.8 (10.1) Visual analog scale 65.5 (11.5) 51.8 (17.7) 72.0 (16.9) 43.6 (19.6) 69.4 (15.0) 46.9 (18.8) <0.001 BPI pain relief score 41.3 (31.8) 51.3 (16.4) 36.7 (20.6) 54.2 (20.7) 38.5 (25.0) 53.0 (18.7) 0.03 * BPI = Brief Pain Inventory; SF-MPQ = Short-Form McGill Pain Questionnaire. The BPI average pain daily diary mean scores range from 0 to 10; the MPQ sensory, affective, total, and visual analog scale scores range from 0 to 33, 0 to 12, 0 to 45, and 0 to 100 mm; the BPI pain relief score ranges from 0 to 100 (percent pain relief). P values are from a two-factor repeated measures ANOVA model for continuous variables and from McNemar s test for the categorical variable Sleep Quality.

4 382 Herrmann et al. Table 2 Quality of life outcome measures ISP with IGT (Patients N = 8) ISP Without IGT (Patients N = 12) Total Sample (N = 20) Measure* Week 3 (N = 7) Week 3 (N = 12) Week 3 P Value Sleep quality Satisfactory/wake up refreshed (%) Brief Pain Inventory General activity 6.4 (3.2) 4.0 (3.3) 5.8 (2.8) 3.8 (3.3) 6.1 (2.9) 3.9 (3.2) Mood 5.3 (3.8) 3.8 (3.1) 3.8 (2.5) 3.0 (2.8) 4.4 (3.1) 3.3 (2.8) 0.12 Walking ability 5.6 (3.5) 5.5 (3.6) 6.1 (3.0) 5.0 (3.4) 5.9 (3.1) 5.2 (3.4) 0.21 Normal work 6.6 (3.2) 5.3 (2.9) 5.0 (3.0) 4.0 (3.5) 5.7 (3.1) 4.5 (3.3) 0.03 Relations with other people 3.8 (3.5) 2.3 (3.3) 1.8 (2.2) 1.8 (2.5) 2.6 (2.9) 2.0 (2.8) 0.36 Sleep 5.5 (2.8) 5.5 (2.3) 6.9 (3.1) 4.8 (3.3) 6.4 (3.0) 5.1 (2.9) 0.05 Enjoyment of life 4.4 (3.4) 5.5 (3.7) 4.8 (3.1) 3.3 (2.3) 4.6 (3.2) 4.2 (3.1) 0.57 Summary score 37.5 (18.9) 31.8 (18.3) 34.2 (14.9) 25.6 (17.7) 35.5 (16.2) 28.1 (17.7) 0.02 Beck Depression Inventory 14.6 (11.3) 11.4 (10.0) 10.4 (5.3) 6.3 (5.0) 12.2 (8.4) 8.3 (7.6) <0.001 Profile of Mood States Tension-anxiety 9.6 (9.8) 7.3 (9.4) 7.8 (6.0) 4.7 (5.0) 8.5 (7.5) 5.7 (7.0) Depression-dejection 17.1 (15.3) 11.8 (12.8) 9.3 (7.1) 6.4 (8.0) 12.4 (11.5) 8.6 (10.2) Anger-hostility 11.6 (11.3) 8.6 (10.2) 7.6 (7.6) 5.5 (6.2) 9.2 (9.2) 6.8 (7.9) 0.08 Vigor-activity 13.9 (6.5) 15.4 (5.8) 15.5 (5.9) 16.2 (5.7) 14.9 (6.0) 15.9 (5.6) 0.48 Fatigue-inertia 14.1 (7.8) 12.1 (8.1) 12.3 (6.5) 8.9 (7.8) 13.1 (6.9) 10.2 (7.8) 0.01 Confusion-bewilderment 5.4 (7.8) 4.1 (7.6) 2.7 (4.6) 0.1 (3.0) 3.8 (6.1) 1.7 (5.5) 0.02 Total mood disturbance 71.8 (43.8) 62.4 (41.9) 55.1 (24.8) 43.3 (23.9) 61.8 (33.7) 51.0 (32.7) * The Brief Pain Inventory average pain daily diary mean scores range from 0 to 10; the McGill Pain Questionnaire sensory, affective, total, and visual analog scale scores range from 0 to 33, 0 to 12, 0 to 45, and 0 to 100 mm; the BPI pain relief score ranges from 0 to 100 (percent pain relief). P values are from a two-factor repeated measures ANOVA model for continuous variables and from McNemar s test for the categorical variable Sleep Quality.

5 Lidocaine Patch 5% 383 a placebo effect cannot be excluded, the beneficial response was consistent across measures, was maintained out to 8 weeks of treatment, and permitted tapering of one or more concomitant oral analgesics in some patients. Pharmacokinetic studies did not show any significant systemic accumulation of lidocaine, and thus the mechanism of action is likely mediated via a local effect on sodium channels of cutaneous sensory afferents. Our data, however, do not address the mechanism of action of the lidocaine patch 5%, and whether it is the same or different in patients with different diagnoses. The higher dosing regimen of lidocaine patch 5% used in this study demonstrated good tolerability with withdrawal of only one subject during the study period due to a local adverse event (application site pain); this is an important advantage in a syndrome that affects older individuals and those in the work force, in whom sedation, falls, and other adverse effects of oral analgesics are of concern. One potential limitation of the lidocaine patch 5% is the difficulty of wearing and securing the patches with ambulation. In this study of 20 subjects we did not encounter this as a limitation. In our clinical experience (outside of this study), a minority of patients have expressed such difficulty; in some cases, cutting of the patches to better contour them to the area of maximal pain, and the use of hypoallergenic tape to secure them has been helpful. A further objective of this study was to assess the feasibility of conducting clinical trials in patients with ISP. Although common, ISP has been neglected as a target in clinical trials of new treatments for chronic neuropathic pain. In a number of respects ISP offers a population of patients that has distinct advantages for clinical trials. First, the natural history of ISP is predictable, with chronic rather than remitting pain in most instances [1], and there are fewer confounding factors than in diabetic neuropathy, where fluctuations in hypoglycemic therapy and glycemic control may complicate evaluations of the effects of investigational agents. Second, the increasing number of clinical trials in postherpetic neuralgia and painful diabetic neuropathy is making recruitment of patients increasingly difficult. ISP provides an additional patient group for clinical trials of neuropathic pain treatments. Third, ISP presents a spectrum of sensory fiber type dysfunction ranging from pure small fiber dysfunction to mixed large and small fiber loss. Relatively precise classification of ISP according to sensory fiber class involvement is now possible using recently developed measures of large (medial plantar nerve, vibrometry) and small (skin biopsy with assessment of epidermal nerve fibers) sensory fibers [2,3,5,11]. These measures permit evaluation of different patterns of treatment response in ISP patients with different profiles of sensory dysfunction. In this study, analyses of treatment response according to sensory fiber class involvement were uninformative because of the sample size; however, future larger studies of neuropathic pain therapies in ISP could incorporate such analyses. In conclusion, a randomized, vehicle-controlled trial is required to confirm our observations that the lidocaine patch 5% was an effective and welltolerated treatment for painful ISP with and without IGT. The ISP population is an attractive one for randomized clinical trials of treatments for neuropathic pain. Acknowledgments This study was supported by Endo Pharmaceuticals, Chadds Ford, Pennsylvania. R.H.D. received a research grant from Endo Pharmaceuticals. R.L.B. has received research grants or consulting fees from Allergan, Astra- Zeneca, and Ortho-McNeil Pharmaceutical, and R.H.D. has received research support, consulting fees, or speakers bureau honoraria in the past year from Abbott Laboratories, Allergan, AstraZeneca, Bristol Myers-Squibb, Elan Pharmaceuticals, Eli Lilly & Co., Endo Pharmaceuticals, EpiCept Corporation, GlaxoSmithKline, Johnson & Johnson, Merck KGaA, NeurogesX, Novartis Pharmaceuticals, Ortho-McNeil Pharmaceutical, Pfizer, Purdue Pharma, Reliant Pharmaceuticals, and UCB Pharma. References 1 Wolfe GI, Baker NS, Amato AA, et al. Chronic cryptogenic sensory polyneuropathy: Clinical and laboratory characteristics. Arch Neurol 1999; 56: Holland NR, Crawford TO, Hauer P, et al. Small fiber sensory neuropathies: Clinical course and neuropathology of idiopathic cases. Ann Neurol 1998;44: Sumner CJ, Sheth S, Griffin JW, Cornblath DR, Polydefkis M. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology 2003;60: Barbano RL, Herrmann DN, Hart-Gouleau S, Pennella-Vaughan J, Dworkin RH. Effectiveness, tolerability, and impact on quality of life of lidocaine patch 5% in diabetic polyneuropathy. Arch Neurol 2004;61:914 8.

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