7 th November % of patients had lidocaine plasters prescribed for the licensed indication of post herpatic neuralgia

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1 Directorate of Integrated Care Health and Social Care Board Linenhall Street Belfast BT2 8BS Tel : Fax : Web Site: 7 th November 2013 Dear colleague Lidocaine Plaster (Versatis ) Recommendations for Primary and Secondary Care in Non- Specialist settings. Dear Colleague, A regional expert group has been established to inform and facilitate the delivery of HSC Board defined Pharmaceutical Clinical Effectiveness (PCE) objectives relating to product selection, procurement, and prescribing guidance within the area of pain management. To inform the work of the expert group, an audit of lidocaine prescribing was undertaken in 17 practices (288 patients) in primary care. This demonstrated that: 74% of patients had lidocaine plasters initiated by their GP 4% of patients had lidocaine plasters prescribed for the licensed indication of post herpatic neuralgia 58% of patients had been reviewed within the last 6 months 29% of patients audited were recommended to stop treatment following the review Following this audit and a review of current guidance the HSCB in conjunction with the regional expert group on pain management have agreed the following recommendations relating to the use of lidocaine Plasters (Versatis ) for primary and secondary care.

2 Recommendation Lidocaine plasters should only be considered as 3 rd line treatment where satisfactory pain reduction is not achieved with 2 nd line oral treatment: to treat post herpetic neuralgia to treat localised allodynia (unlicensed use) e.g. painful scarring Note: Lidocaine Plasters should NOT normally be used for treatment of back pain Good Prescribing Practice: Patients should be reviewed 2-4 weeks after initiation. If no benefit has been seen after 2-4 weeks, treatment should be stopped If worthwhile benefit* is seen, other pain medications should be down-titrated with the aim of reducing to stop If patients are receiving long term therapy- after 6 months, attempt to reduce dosage with a view to stopping treatment altogether or maintaining the lowest effective dose * Worthwhile benefit would be considered to be an improvement in pain or decrease in sleep disturbance For further information see Appendix 1 Yours sincerely Joe Brogan Assistant Director of Integrated Care Pharmacy & Medicines Management

3 Appendix 1 Further Information on Lidocaine Plasters (Versatis ) Summary Versatis is a 5% lidocaine medicated plaster, for local treatment of pain associated with postherpetic neuralgia (PHN). A maximum of three plasters (total area 420cm 2 ) can be applied to the affected area, for no more than 12 hours/day. Efficacy in PHN has been assessed in four trials, only two of which have been published in full. Statistically significant improvements in pain relief and pain intensity scores were shown compared to placebo, but the clinical significance of these results is difficult to interpret. An open-label study has investigated the use of lidocaine medicated plaster for up to one year, but data are limited. No comparative studies with existing systemic or topical therapies for PHN are available. There are also no specific data on use as adjunctive therapy. Long-term safety data are limited but application site reactions such as skin redness or rash were the most frequently reported adverse events. The place of lidocaine medicated plaster in the treatment of PHN is difficult to determine. In view of the limited evidence of efficacy, lack of comparative data and higher drug costs, use would be expected to be in individuals in whom existing treatments have failed or are not tolerated, or where compliance issues with oral medication precludes treatment. The Scottish Medicines Consortium has now approved lidocaine patches (Versatis ) for use in Scotland. The SMC stated There are only limited comparative data available for lidocaine plasters, the comparative clinical effectiveness remains unclear. It is restricted to use in patients who are intolerant of first-line systemic therapies for post-herpetic neuralgia or where these therapies have been ineffective. Lidocaine patches may be considered as third line option in treating localised pain in patients unable to take oral medication (NICE CG96) Versatis is a lidocaine medicated plaster (LP) with a local analgesic effect at the site of application. It is the first treatment of its type in the UK. Each plaster consists of an aqueous adhesive base containing 700mg (5% w/w) lidocaine, and covers an area of 10cm x 14cm (140cm2). It is licensed for the treatment of postherpetic neuralgia (PHN), which is pain associated with previous herpes zoster infection.² Clinical Evidence Four studies have specifically investigated the use of LP in PHN. These studies are summarised below. Rowbatham et al (1996) The first study was a 4-way, single dose, crossover design involving LP, vehicle patch (VP) and observation only. 3 Pain intensity was measured using a 100 mm visual analogue scale (VAS) and pain relief using a 6-point scale. Subjects were allowed to continue oral PHN medicines, but were not allowed to start new ones. LP showed a statistically significant improvement in pain intensity and pain relief compared to both VP and observation at 12 hours, however results were only presented graphically making them difficult to interpret. The maximum effect on pain intensity was seen at 4 hours after application. There was then a lessening of effect from 4 to 12 hours, at which point available data suggest the mean decrease in VAS from baseline was approximately 9 mm. What constitutes a clinically significant change in VAS has not yet been clearly defined, although one study in acute pain has suggested a minimal clinically significant

4 difference of 12 mm (95%CI 9-15 mm). 4 No data were provided beyond 12 hours when the patch was removed (as per the licensed indication). VP alone also showed a statistically significant improvement in pain relief at 12 hours and pain intensity at 6 hours vs. observation alone. Key Message: The outcome of a 9mm reduction in a 100mm visual scale does not meet the suggested requirement of 12mm for a clinically significant difference. Rowbatham et al (2)(1996) Efficacy results from a second trial have only been presented as a conference abstract. 5 More detail on this trial is available on the FDA website.6 Patients with moderately severe PHN and allodynia applied either LP or VP for 12 hours each day for 4 weeks (n=150). Endpoints included VAS pain scores and a 6-item pain relief scale, but the primary endpoint is not clearly defined. Despite a substantial reduction in VAS pain scores in both groups, no significant difference was seen between LP and VP at the end of the study (40.8 vs. 37.7, p=0.3708). This demonstrated a large placebo effect in the control group. However patients from the LP group reported a greater increase in VAS pain scores during the washout phase. Neuropathic Pain Scale (NPS) data from the previous study have been published separately, although this measure does not appear to have been a pre-planned end point. 7 Of the 150 patients in the original trial, 96 were eligible for this analysis on the basis of NPS inclusion criteria. NPS scores were measured at baseline and three weeks. The NPS measures 8 specific qualities of neuropathic pain e.g. sharp, hot, as well as pain intensity and unpleasantness, using a 0-10 rating scale for each quality. LP resulted in a statistically significant reduction in four composite NPS scores compared to VP, although the primary endpoint was not clearly defined. It should be noted that the NPS does not include items such as paroxysmal pain or numbness, and there has been some concern that it has not yet been fully validated in neuropathic pain. 8 There is also no indication as to what constitutes a clinically significant response with this scale, making interpretation of the results difficult. Key Message: there was no significant difference in pain scores seen between LP and placebo. Galer et al (2002) The third published trial recruited patients who had already been using, and deriving pain relief from the LP. 9 Patients (n=33) with PHN were randomised to receive either LP or VP for up to 14 days followed by crossover to the other arm for 14 days. The primary endpoint was time to exit, defined as a decrease of 2 categories on the verbal pain relief rating for 2 consecutive days compared to pre-study values. Patients receiving active treatment remained in the trial for longer (mean >14 days) than those receiving placebo (mean 3.8 days), suggesting that in a population known to respond to LP, withdrawal of treatment results in a loss of pain relief. Key Message: Interpretation of the results and clinical applicability is difficult to assess due to the choice of primary end point. Baron et al (2000) In an unpublished 8 week, open label, uncontrolled study (n=265) ~50% of patients had a response to LP classed as a 2 point reduction on a 6 point pain scale. Of 71 then randomised to LP or VP for 2-14 days, 9/36 (LP) and 16/35 (VP) withdrew due to lack of benefit. 1 Data from a long-term study is available as a conference abstract. 10 In this open label study, 249 patients (152 treated with LP for up to 10 weeks in a previous study) received LP for 12 hours/day for up to 1 year. Only 143 patients completed 12 months of treatment, although no reasons are provided for the large number of dropouts. Mean pain intensity scores decreased in both treatment naive patients as well as those already previously exposed to LP. Scores decreased from 5.6 to 3.4 after 18 weeks for the treatment naive group, and from 3.9 to 3.4 after 12 weeks for pretreated patients, then remained constant for the remainder of the 52 weeks in both groups. However, it is important to note that efficacy data were only reported for the per protocol set 2 (n=138), defined as those patients who completed 12 months treatment and had at least one safety assessment. Overall QoL measurements for both subgroups were reported as showing improvement at 52 weeks compared to baseline scores, although absolute figures are not presented. Key Message: Interpretation of the results is difficult due to limited absolute data, the high drop out rate, the per protocol analysis, the absence of a comparator group, and the open label design of the study.

5 Scottish Medicines Consortium Decision ADVICE: following a resubmission Lidocaine 5% medicated plaster (Versatis ) is accepted for restricted use within NHS Scotland for the treatment of neuropathic pain associated with previous herpes zoster infection (post-herpetic neuralgia). There are only limited comparative data available for lidocaine plasters, the comparative clinical effectiveness remains unclear. It is restricted to use in patients who are intolerant of first-line systemic therapies for post-herpetic neuralgia or where these therapies have been ineffective. NICE Clinical Guideline 96 (March 2010) Neuropathic Pain Appraisal ADVICE: Third-line treatment If satisfactory pain reduction is not achieved with second-line treatment: refer the person to a specialist pain service and/or a condition-specific service and while waiting for referral: consider topical lidocaine for treatment of localised pain for people who are unable to take oral medication because of medical conditions and/or disability. Safety In trials LP was reported to be well tolerated, with a similar incidence of adverse effects seen in the active and vehicle groups. Long-term safety data are limited but suggest after 52-weeks of treatment only 12.4% of patients reported an adverse effect, of whom 4.4% discontinued due to an adverse event (mainly application site events). 9 It should be noted that there is no scope for site rotation of the patch. These figures must be viewed with caution as the study included patients who had already completed a trial with LP and therefore may not reflect the general population. Also a full explanation is not given for the high drop out rate in this trial. Based on available data systemic effects are thought to be unlikely and have not been seen in trials to date. Place in Therapy The exact place in therapy of LP in the treatment of PHN is difficult to determine due to the limitations of the available data. Additionally, there are no comparative data vs. existing treatment options, no specific data for use as adjunct therapy, and the optimal length of treatment with LP has yet to be defined. In multidose studies it is not clear when pain scores were evaluated in relation to patch application time. This has implications as single dose studies have shown that there was a trend to decreased pain relief from 4 hours after application to LP removal, at 12 hours. 2 Long-term safety data are also limited. Finally, drug costs are potentially higher than existing treatments. Until further data are available Versatis may have a place in patients who cannot tolerate, have compliance issues with, or have failed on, systemic or other topical treatment options. Risk Management Issues: Patients must be aware of the need to remove LP after 12 hours.

6 Cost Comparisons Estimated Annual costs NI Drug Tariff July Lidocaine plaster (Versatis) 880 Pregabalin 600mg (caps) 840 Gabapentin 1200mg (caps) 50 Amitriptyline 75mg (tabs) ,000 References: 1. NICE Clinical Guideline for consultation. Neuropathic Pain. NICE Versatis. Summary of Product Characteristics. Available at URL: 3. Rowbotham MC, Davies PS, Verkempinck C et al. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain 1996;65: Kelly AM. The minimum clinically significant difference in visual analogue pain score does not differ with severity of pain. Emerg Med J 2001;18: Rowbotham MC, Davies PS, Galer BS. Multicenter, double-blind, vehicle-controlled trial of long term use of lidocaine patches for postherpetic neuralgia [abstract 184]. In: Abstracts of the 8th World Congress of the International Association for the Study of Pain, Vancouver. 1996: US Food & Drug Administration: Lidoderm Review. 7. Galer BS, Jensen MP, Ma T et al. The Lidocaine patch 5% effectively treats all neuropathic pain qualities: results of a randomized, double-blind, vehicle controlled, 3-week efficacy study with use of the neuropathic pain scale. Clin J Pain 2002;18: Cruccu G, Anand P, Attal N et al. EFNS guidelines on neuropathic pain assessment. European Journal of neurology 2004;11: Galer BS, Rowbotham MC, Perander J et al. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: results of an enriched enrolment study. Pain 1999;80: Baron R, Binder A, Boesl I et al. Long-term efficacy, safety and quality of life with lidocaine 5% medicated plaster in post herpetic neuralgia. Poster presented at EFIC annual meeting, Istanbul 2000