Baron, R.

Binder, A.

Koroschetz, J.

Serpell, M.G.

Steigerwald, I.

English

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       Baron, R. and Binder, A. and Koroschetz, J. and Serpell, M.G. and Steigerwald, I. (2009) Results from a randomized, controlled trial on efficacy and tolerability of a 5% Lidocaine-Medicated Plaster vs. Pregabalin in patients with Post-Herpetic Neuralgia (PHN) and Painful Diabetic Polyneuropathy (DPN). In: Diabetes UK Annual Professional Conference 2009 , 11-13 March 2009, Glasgow, UK. (Unpublished)  http://eprints.gla.ac.uk/5277/  Deposited on: 06 April 2010   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Diabetes UK Annual Professional Conference 2009 – GlasgowResults from a randomized, controlled trial on efficacy and tolerabilityof a 5% Lidocaine-Medicated Plaster vs. Pregabalin in patients withPost-Herpetic Neuralgia (PHN) and Painful Diabetic Polyneuropathy (DPN)Ralf Baron1, Andreas Binder1, Jana Koroschetz1, Michael G Serpell2, Ilona Steigerwald31Division of Neurological Pain Research and Therapy, University Hospital of Schleswig-Holstein, Kiel, Germany;2University Dept. of Anaesthesia, Gartnavel General Hospital, Glasgow, Scotland;3 Grünenthal GmbH, Medical Affairs, Aachen, Germany.References1 Nicholson B. Am J Manag Care 2006;12 (9 Suppl.):S256-62.2 Rosenstock J, et al. Pain 2004;110:628–38.3 Sabatowski R, et al. Pain 2004;109:26–35.4 Christo PJ, et al. Drugs Aging 2007;24:1–19.5 Hempenstall K, et al. PLoS Med 2005;2:e164.6 Dworkin RH, et al. Pain 2007;132:237–51.7 Galer BS, et al. Pain 1999;80:533–38.8 Meier T, et al. Pain 2003;106:151–8.9 Argoff CE, et al. Curr Med Res Opin 2004;20(Suppl. 2):S21–8.10 Johnson M, et al. Guidelines – summarising clinical guidelinesfor primary care. 34th ed. Berkhamsted: MGP Ltd; February2008. pp 175-17711 Consensus statement. Supplement to Diabetes and primarycare. Vol 10 No 4 200812 Bauer P, Köhne K. Biometrics 1994; 50: 1029-1041.Introductionn Post-herpetic neuralgia (PHN) and diabetic polyneuropathy (DPN) represent common peripheral neuropathicpain syndromes of focal (PHN) and polyneuropathic, or generalised distribution (DPN) type.n Oral pregabalin is an effective treatment for PHN and DPN.2,3 However, as with other systemic treatments,4,5pregabalin is associated with dose-limiting side effects. These include dizziness, somnolence, peripheral oedema,and cognitive and gait impairments.6,3n Topical treatment with 5% lidocaine medicated plaster has been recommended as a first line therapy for themanagement of peripheral neuropathic pain syndromes.10,11 The lidocaine in the hydrogel plaster has asubstantial local effect but undergoes minimal systemic absorption so that side effects are usually limited to mild-to-moderate skin reactions at the site of plaster application.6,7n The analgesic efficacy and good tolerability of lidocaine plaster have been observed in patients with a range ofperipheral neuropathic pain syndromes.8,9n Here we report the results of a randomised, controlled clinical trial that compared the pain relieving efficacy,tolerability, and safety of the locally-acting 5% medicated plaster to that of systemic pregabalin in the treatmentof PHN and painful DPN. This study represents the first head-to-head comparison of these treatments for patientswith peripheral neuropathic pain.Patients and methodsPatients and study designn Male or female patients ≥ 18 years of age with PHN or DPN entered a planned Phase III, open-label, randomized,multicentre trial performed at 53 sites in 14 countries.n PHN was defined as neuropathic pain present for ≥ 3 months after healing of a herpes zoster skin rash.n DPN was defined as painful, distal, symmetrical, sensorymotor polyneuropathy of the lower extremities for≥ 3 months with at least two of the following symptoms present: burning sensation, tingling or prickling,paraesthesias, painful heat or cold sensation in patients with type 1 or type 2 diabetes mellitus.n Screening phase: 14-days drug wash-out period (reduced to ≥ 3 days in patients suffering unbearable pain). Eligiblepatients with a recalled average pain intensity during the previous 3 days of > 4 on an 11-point Numerical Rating Scale(NRS-3) entered the 4-week initial comparative phase (Figure 1) in which they were randomized (1:1 ratio) to receiveone of two treatments:n 5% lidocaine medicated plaster (700 mg lidocaine/plaster; ≤ 3 [PHN] or ≤ 4 [DPN] plasters/day over the areaof maximal pain for ≤ 12 hours/day).n Oral pregabalin (starting dose 75 mg twice daily; titrated to 300 mg/day during the first week in all patients.The dose was increased to 600 mg/day in patients whose response to 300 mg/day was inadequate after oneweek (NRS-3 score > 4).n The trial was planned and conducted using an adaptive design with one planned interim analysis of the datacollected from the first 150 patients. The aim of this trial was to show non-inferiority of 5% lidocaine medicatedplaster in comparison to pregabalin.n The per protocol set (PPS, comprising patients who adhered to the study protocol) was defined as the primaryanalysis set in the study protocol. The full analysis set (FAS) refers to patients analysed on an intent to treatbasis.n This poster presents the final results of the comparative phase (see figure 1) of the trial.Efficacy endpointsn The primary efficacy endpoint was a ≥ 2 point reduction from baseline in NRS-3 or an overall score of ≤ 4 after4 weeks (day 28) of treatment, expressed as a response rate. All drop-outs were classified as non-responders.n Secondary endpoints included the following comparisons between baseline and week 4 data:n Percentage of patients with ≥ 30% and ≥ 50% reductions in baseline NRS-3 scores.n Change in Neuropathic Pain Symptom Inventory (NPSI) score (11-point scale).n Change in allodynia severity rating (‘extremely painful’, ‘painful’, ‘uncomfortable’, ‘no pain’).Safety assessmentn Adverse event (AE) data including relationship to active treatment (drug-related adverse events [DRAEs]) werecollected throughout the trial.Poster Number: P283 (Oral number: A70)AcknowledgementsThis study was supported by Grünenthal GmbH. The authors would like to thank the following study investigators: Prof Dr G Nell, Dr MDe Meulemeester, Dr H Radovan, Dr M Petr, Dr V Stanislav,Dr V Dana, Dr Z Šolle, O Vyšata, Dr B Steinberg, Minnich J, Dr M Sanuri, ProfDr D Ziegler, Dr B Bergtholdt, Laus S, Lehmann R, Dr H-D Stahl, Dr S Mindt-Prüfert, Dr T Meier, Dr V Mayoral, Dr J Ignacio Calvo, Dr R Gálvez,Dr LMiguel Torres, Dr E Catalá, Dr J Guitart, DrMBlagden, Dr B Silvert, Dr D Haworth, Dr S Ratcliffe, Dr PD Rogers, DrMFingler, Dr I Adanic-Mikloska, Dr A Barada, Dr M Persoli, Dr D Spisic, Dr C Power, Dr G Lauria, Dr R Casale, E Motta, K Boczar, M Koziol, A Szczepańska-Szerej,J Pyszkowska, D Szewczyk-Urgacz, Dr M Miguel Rosa, Dr R Duarte, Prof I Demidova, Prof I Gurieva, G Leijon, J E Wirén, G Požlep,A Pražnikar, N Krčevski-Škvarčn The proportion of PHN patients who showed ≥ 30% reduction in NRS-3 was 57.8% in the 5% lidocaine medicatedplaster group and 48.8% in the pregabalin group. A ≥ 50% reduction in NRS-3 was achieved by 35.6% (5%lidocaine medicated plaster) and 20.9% (pregabalin) of PHN patients (Figure 3).n Among DPN patients, ≥ 30%reductions were achieved by 59.6%of lidocaine plaster-treated and 56.4% ofpregabalin-treated patients, and ≥ 50% reductions were achieved by 40.4% of lidocaine plaster-treated and37.2% of pregabalin-treated patients (Figure 3).n After 4 weeks of treatment, there was a significant change from baseline in ‘burning pain’ (11-point scale NPSI)in the lidocaine plaster group (-2.4; p < 0.0001) and in the pregabalin group (-1.8, p = 0.0002) in the combinedpatient population. Significant reductions from baseline scores were also observed in both treatment groups for‘stabbing pain’: (-1.9; p = 0.0003 for lidocaine plaster and -1.9; p < 0.0001 for pregabalin).n For allodynia severity rating, a trend towards greater improvement was observed in patients treated with the5% lidocaine medicated plaster (Figure 4). The proportion of patients reporting ‘no pain or discomfort totouch/uncomfortable but tolerable to touch’ increased from 46.7% to 75.0%in the 5% lidocaine medicatedgroup and from 34.9%to 58.8% in the pregabalin group.Summary and conclusionsn This analysis of a randomized, controlled trial of patients with PHN and DPN indicates that topical treatmentwith 5% lidocaine medicated plaster provides comparable pain relieving efficacy to systemic treatmentwith pregabalin in patients with peripheral neuropathic pain.n Data from the PHN cohort suggest that the 5% lidocaine medicated plaster may be particularly effectiveat producing analgesic responses in these patients, as well as relieving their allodynia, burning and stabbingpain symptoms.n The 5% lidocaine medicated plaster was better tolerated in DPN and PHN patients because treatment wasassociated with fewer DRAEs compared with pregabalin. Fewer patients receiving the 5% lidocainemedicated plaster discontinued therapy due to DRAEs than pregabalin recipients.n These data suggest that, when used in patients with typical peripheral neuropathic pain syndromes like PHNand DPN, 5% lidocaine medicated plaster may possess a pain relieving efficacy comparable to that ofpregabalin combined with an improved safety and tolerability profile (fewer DRAEs and fewerdiscontinuations due to DRAEs).6050403020100PercentageofpatientsThe percentage of patients who experienced adverse events (AEs), drug-related AEs (DRAEs), and DRAEsleading to discontinuation were substantially lower in the lidocaine group than the pregabalin group;* P < 0.0001Figure 5: Proportion of patients experiencing adverse events, drug-related adverse events (DRAEs) and DRAEsleading to discontinuation after treatment with 5% lidocaine medicated plasters or pregabalin.AEs DRAE DRAE disc.*18.746.4*5.841.22.623.5Safetyn In the safety analysis set (comprising 308 patients who received at least one treatment) fewer lidocaine plaster-treated patients than pregabalin-treated patients experienced AEs and DRAEs (p < 0.0001) (Figure 5).n Fewer patients in the 5% lidocaine medicated plaster group experienced DRAEs (9 patients, 5.8%) comparedwith those receiving pregabalin (63 patients, 41.2%) (p < 0.0001) (Figure 5).n Drug-related AEs leading to discontinuation occurred in 36 (23.5%) pregabalin-treated patients (mainly nervoussystem disorders) and in 4 (2.6%) lidocaine plaster-treated patients (mainly application site irritation) (Figure 5).n The majority of treatment emergent AEs experienced by patients receiving either treatment were mild tomoderate in severity. However, patients receiving pregabalin experienced more “severe” events than lidocainerecipients: 20/153 events (13.1%) vs. 7/155 events (4.5%).1009080706050403020100Responserate(%)Response defined as: ≥ 2 point reduction in baseline NRS-3 score or an overall score of ≤ 4 after 4 weeks of treatmentDPN: diabetic polyneuropathyPHN: post-herpetic neuralgiaFigure 2: Response rates in patients with PHN and DPN in the per protocol set.Lidocaine plaster(N = 144)100806040200extremely painfulpainfuluncomfortableno painmissingPatients(%)The graph shows the percentage of patients (per protocol set) with PHN in each treatment group whoreported the severity of allodynia in response to a touch stimulus as ‘no pain’, ‘uncomfortable’, ‘painful’, or‘extremely painful’ at baseline (randomisation) and after 4 weeks of treatment (Day 28). The percentage oflidocaine-treated patients reporting ‘no pain’ or ‘uncomfortable’ to touch was comparable in the two groupsat baseline.Figure 4: Severity of allodynia symptoms reported in patients with PHN treated with 5% lidocaine medicatedplasters or pregabalin.N = 45 N = 40Lidocaine plasterN = 43 N = 34PregabalinOverall PHN DPN65.3N = 94Lidocaine plaster(N = 45)Pregabalin(N = 43)Lidocaine plaster(N = 99)Pregabalin(N = 94)PHNLidocaine plaster Pregabalin(n = 45) (n = 43)26 (57.8) 22 (51.2)65.3 (11.8) 63.5 (12.6)28.2 (4.5) 27.7 (5.4)CharacteristicMale, n (%)Age, mean ± SD(years)BMI, mean ± SD(kg/m2)DPNLidocaine plaster Pregabalin(n = 99) (n = 94)41 (41.4) 43 (45.7)60.9 (10.2) 60.6 (8.9)30.1 (5.2) 30.9 (4.8)OverallLidocaine plaster Pregabalin(n = 144) (n = 137)67 (46.5) 65 (47.4)62.3 (10.9) 61.5 (10.3)29.5 (5.0) 29.9 (5.2)Overall(n = 281)132 (47.0)61.9 (10.6)29.7 (5.1)Table 1: Baseline patient characteristics (Per protocol set).BMI: body mass indexDPN: diabetic polyneuropathyPHN: postherpetic neuralgiaSD: standard deviationEnrolment3 days to 2 weeksIn/ExclusioncriteriaNot includedCreaCl > 60CreaCl<30 30 < CreaCl < 60In/ExclusioncriteriaCombination8 weeksDown titration sub-study4 weeksPregabalin NRS > 4 + Lidocaine plasterPregabalin NRS ≤ 4Lidocaine plaster NRS > 4 + PregabalinTitration to Effect#Lidocaine plaster NRS ≤ 4Lidocaine plasterDrop-outs(side effects)PregabalinTitration to Effect#Comparative4 weeksFigure 1: Phases of the study.Lidocaine plaster (pick-up arm)Responder at 4 weeks (full + partial):NRS reduction of at least 2 or NRS 4 (11-point scale)Pregabalin downtitration + lidocaine plasterPregabalin(N = 137)62.0N = 8562.2N = 2846.5N = 2066.7N = 6669.1N = 651009080706050403020100Responserate(%)Figure 3A: Proportion of patients (per protocol set) experiencing ≥ 30% reductions in baseline pain intensity (NRS-3 scores) after treatment with 5% lidocainemedicated plasters or pregabalin in patients with post-herpetic neuralgia (PHN), diabetic polyneuropathy (DPN) and in both groups ‘overall’.Lidocaine plaster(N = 144)Overall PHN DPN59.0N = 85Lidocaine plaster(N = 45)Pregabalin(N = 43)Lidocaine plaster(N = 99)Pregabalin(N = 94)Pregabalin(N = 137)54.0N = 7457.8N = 2648.8N = 2159.6N = 5956.4N = 531009080706050403020100Responserate(%)Figure 3B: Proportion of patients (per protocol set) experiencing ≥ 50% reductions in baseline pain intensity (NRS-3 scores) after treatment with 5% lidocainemedicated plasters or pregabalin in patients with post-herpetic neuralgia (PHN), diabetic polyneuropathy (DPN) and in both disease groups ‘overall’.Lidocaine plaster(N = 144)Overall PHN DPN38.9Lidocaine plaster(N = 45)Pregabalin(N = 43)Lidocaine plaster(N = 99)Pregabalin(N = 94)Pregabalin(N = 137)32.1 35.620.940.437.2Lidocaine plasterPregabalinResultsPatient disposition and baseline characteristicsn The PPS comprised 281 patients. Of the 88 patients with PHN, 45 received 5% lidocaine medicated plaster and43 received pregabalin. One hundred and ninety three suffered from DPN and 99 were treated with 5%lidocaine medicated plaster while 94 received pregabalin. All patients were Caucasian, 47% were male, meanage was 61.9 ± 10.6 years, and mean duration of pain was 50.9 ± 55.0 months. Median and range time sincehealing of the skin rash (PHN patients) was 18.5 (2-433) months (Table 1).n The lidocaine plaster and pregabalin treatment groups as well as PHN and DPN subgroups were comparableaccording to the baseline characteristics. Baseline characteristics were also similar between the PPS and FAS.n Safety data are available for 308 patients. Ninety eight of these were PHN patients and 210 had DPN.Efficacyn The overall response rate was numerically comparable in patients receiving 5% lidocaine medicated plaster andpatients receiving pregabalin (65.3% vs. 62.0%; p = 0.0066, combined p-value from a two-stage adaptive designaccording to Bauer & Köhne12, testing for non-inferiority, significance level: 0.0038; analysis of the FAS indicatednon-inferiority: p-value 0.0023, further p-values are exploratory).n The same applied to patients with DPN (66.7%for 5% lidocaine medicated plasters and 69.1% for pregabalin).For patients with PHN, there was a trend for greater improvement with 5% lidocaine medicated plaster (62.2%)compared with pregabalin (46.5%) (Figure 2).VST_PO_DUAPC_P283_100x200_lay5:Layout 1  09.03.2009  13:10 Uhr  Seite 1

Guidelines – summarising clinical guidelines for primary care. 34th ed.

Results from a randomized, controlled trial on efficacy and tolerability of a 5% Lidocaine-Medicated Plaster vs. Pregabalin in patients with Post-Herpetic Neuralgia (PHN) and Painful Diabetic Polyneuropathy (DPN) [poster]

Results from a randomized, controlled trial on efficacy and tolerability of a 5% Lidocaine-Medicated Plaster vs. Pregabalin in patients with Post-Herpetic Neuralgia (PHN) and Painful Diabetic Polyneuropathy (DPN) [poster]

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