|Year : 2021 | Volume
| Issue : 2 | Page : 135-140
Clinician's perspective on neuropathic pain and use of Lidocaine 5% patch with hydrogel technology in postherpetic neuralgia
Kailash Kothari1, Shirazahmed A Munshi2, Manish Raj3, Prakash Rajendra Deshmukh4, Manjiri Neelesh Ranade5, Venkatesh Nevagi6
1 Pain Clinic of India, Mumbai, India
2 CHEERS Interventional Pain Management and Spine Endoscopy Center, Ahmedabad, Gujarat, India
3 Department of Pain Management, Yatharth Superspeciality Hospital, Noida, Uttar Pradesh, India
4 Pain Clinic of India, Kalyan, India
5 Pain Clinic of India, Thane, Maharashtra, India
6 Pain Clinic of India, Goa, India
|Date of Submission||16-Feb-2021|
|Date of Decision||08-May-2021|
|Date of Acceptance||17-May-2021|
|Date of Web Publication||31-Aug-2021|
Dr. Kailash Kothari
Pain Clinic of India, Apollo Spectra Hospital, Chembur, Mumbai - 400 071, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Neuropathic pain (NP) is a condition that affects the quality of life (QoL) of many patients. It is often difficult to treat effectively due to the complexity of this disorder. This study was aimed to assess clinician's perspectives on NP, particularly for postherpetic neuralgia (PHN), posttraumatic neuralgia (PTN), and painful diabetic neuropathy (PDN). Further, the study aimed to evaluate the safety and efficacy of lidocaine 5% patch with hydrogel technology in PHN. Materials and Methods: These two aspects were assessed through two prospective survey-based questionnaire studies that were conducted from January 2018 to December 2018 with clinicians from relevant specialties across India. Data were collected from clinicians' inputs based on their clinical practice and statistically analyzed. Results: More than half of the clinicians reported prolonged duration of NP in PHN, PTN, and PDN conditions. After applying lidocaine 5% patch with hydrogel technology, around 83.58% of clinicians opined that patients experienced a cooling and soothing effect due to the presence of a hydrogel layer in the patch. A significant reduction in pain score was reported by 76.11% of clinicians and 79.1% of them agreed that there was pain relief during the intermittent patch-free period also. The majority of the doctors (74.6%) reported an absence of any side effects. Conclusion: Study findings revealed that topical application of lidocaine 5% patch with hydrogel technology is safe and effective in PHN.
Keywords: Neuropathic pain, painful diabetic neuropathy, posttraumatic neuralgia, postherpetic neuralgia
|How to cite this article:|
Kothari K, Munshi SA, Raj M, Deshmukh PR, Ranade MN, Nevagi V. Clinician's perspective on neuropathic pain and use of Lidocaine 5% patch with hydrogel technology in postherpetic neuralgia. Indian J Pain 2021;35:135-40
|How to cite this URL:|
Kothari K, Munshi SA, Raj M, Deshmukh PR, Ranade MN, Nevagi V. Clinician's perspective on neuropathic pain and use of Lidocaine 5% patch with hydrogel technology in postherpetic neuralgia. Indian J Pain [serial online] 2021 [cited 2021 Nov 30];35:135-40. Available from: https://www.indianjpain.org/text.asp?2021/35/2/135/325199
| Introduction|| |
Neuropathic pain (NP) is a severely debilitating form of pain. The International Association for the Study of Pain defines NP as pain caused by a lesion or disease of the somatosensory nervous system. A systematic review of 21 studies conducted around the world reported that the general prevalence of NP ranges from 6.9% to 10.0%. NP syndromes are highly complex and potentially have multiple underlying mechanisms. They include a different set of syndromes, They include different syndromes, such as postherpetic neuralgia (PHN) which is a common complication of acute herpes zoster infection or posttraumatic neuralgia (PTN) which is a painful condition due to post-trauma neuropathy or painful diabetic neuropathy (PDN) which is a late complication of diabetes mellitus.
PHN is the most resistant chronic pain problem and an important cause of debilitating NP. PHN occurs in 9%–19% of patients with herpes zoster. Its occurrence depends on age: the risk of PHN is low in patients under 50 years of age (2%), ~20% in patients over 50 years of age, and ~ 35% in patients over 80 years of age. Pain persisting for 3 months or more indicates transition from acute herpes zoster infection to PHN. PHN pain may be spontaneous or stimulus induced, constant or intermittent, of characteristic nature such as burning, throbbing, pain, shooting, or stabbing. Allodynia is most prevalent and often considered the most distressing and debilitating component of the disease. Pain from PHN has a potentially high impact on the quality of life (QoL) and is frequently underdiagnosed and undertreated. Efforts to develop a more rational therapeutic approach for the management of NP, especially PHN, remain challenging and are normally highly resistant to traditional analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs). The primary reason for this lacuna is complex mechanisms involved in the pathogenesis of NP. With this background, this study was conducted to assess the clinician's perspective on NP, particularly for PHN, PTN, and PDN. Further, this study also evaluates the safety and efficacy of lidocaine 5% patch with hydrogel technology in PHN.
| Materials and Methods|| |
Two prospective survey-based questionnaire studies were conducted from January 2018 to December 2018. The first survey questionnaire consisted of three questions to assess the clinician's perspective on NP, particularly for PHN, PTN, and PDN. A total of 1514 clinicians from relevant specialties were enrolled in this survey from different states across India. Based on the response from the first survey, the second survey in PHN indication was conducted with clinicians who were treating PHN patients with lidocaine 5% patch with hydrogel technology. The second survey questionnaire consisted of five questions relating to the safety and efficacy of lidocaine 5% patch with hydrogel technology in PHN. All clinicians were well informed regarding the academic purpose of both the questionnaire surveys.
The analysis of the survey data was processed using Microsoft Excel Office 365. The data obtained from the multiple-choice questions were analyzed quantitatively and were presented in the form of a percentage of participants opting for each of the individual responses.
| Results|| |
A total of 1514 clinicians from relevant specialties participated in the first survey. Among the 911 clinicians who reported treating PHN patients, 82.9% were treating up to 8 patients/month, 13.39% were treating 9–20 patients/month, and 3.62% were treating >20 patients/month. Similarly, 1161 clinicians reported treating PTN patients, 53.66% were treating up to 8 patients/month, 36% were treating 9–20 patients/month, and 10.33% were treating >20 patients/month. For PDN, 1102 clinicians reported treating this condition, out of which 47.73% were treating up to 8 patients/month, 35.39% were treating 9–20 patients/month, and 16.87% were treating >20 patients/month [Figure 1].
More than half of the clinicians reported a prolonged duration of NP extending beyond 3 weeks in all three conditions, i.e. 57.86% in PHN, 53.4% in PTN, and 77.86% in PDN out of 800, 936, and 859 clinicians, respectively, from among those who responded [Figure 2].
Regarding the treatment modalities used, 328 clinicians reported using topical treatments for PHN such as gabapentin (30.18%), local anesthetics (24.69%), capsaicin (10.06%), calamine (9.14%), NSAIDs (6.09%), and others/combinations (28.04%). For the treatment of PTN, 375 clinicians preferred topical medications such as gabapentin (35.73%), local anesthetics (16.26%), capsaicin (4.53%), NSAIDs (18.66%), and others/combinations (24.8%). For the treatment of PDN, 299 clinicians used topical treatments such as gabapentin (43.47%), local anesthetics (15.38%), capsaicin (5.68%), NSAIDs (8.02%), and others/combinations (27.42%) [Figure 3].
From among 67 clinicians who participated in the second survey, 83.58% opined that patients experienced the cooling and soothing effect of the hydrogel layer after applying lidocaine 5% patch. The majority of clinicians (76.11%) reported a significant reduction in pain score after applying lidocaine 5% patch with hydrogel technology [Figure 4]. Further, 79.1% of clinicians also reported significant pain relief during the intermittent patch-free period [Figure 5].
|Figure 4: Reduction in pain score after application of lidocaine 5% patch with hydrogel technology|
Click here to view
The majority of the clinicians (74.6%) did not report any local/generalized side effects after applying lidocaine 5% patch with hydrogel technology [Figure 6]. Only 25.3% of doctors reported local side effects such as rashes, redness, itching, and irritation which were of mild-to-moderate intensity. Further, all clinicians opined that there were no generalized side effects from lidocaine 5% patch with hydrogel technology.
| Discussion|| |
Despite significant advances in treatment options for NP, this condition remains extremely difficult to treat. NP remains a clinical challenge for several reasons, primarily due to the specific pathophysiological features underlying a painful neuropathic syndrome. A growing body of evidence suggests the existence of specific and multifactorial changes during NP syndromes at different levels of the nervous system.,,,,
In the last decade, care for NP has undergone several major improvements. Painful neuropathies were initially treated like any other syndrome of pain, merely by traditional analgesics and then came the more specialized antineuropathic treatment options, such as calcium channel blockers (gabapentin and pregabalin) and NMDA receptor antagonists (memantine and ketamine), that led to the emergence of (inter) national guidelines proposing a multimodal and balanced NP treatment (combining analgesics and adjuvants or different classes of adjuvant drugs). This shift in the therapeutic approach to NP has been followed by an increasing trend toward a more mechanism-based treatment. Rather than simply treating the debilitating symptomatology of etiologies, such as diabetes and herpes zoster infections, doctors increasingly integrated underlying pathophysiological mechanisms into the choice of treatment options. The advent of lidocaine 5% patch with hydrogel technology should mean an additional and important step toward transgression from the traditional etiology-based approach to a much more clinically sound pathophysiology-based approach for the treatment of painful neuropathies.
Lidocaine 5% patch with hydrogel technology
Lidocaine 5% patch with hydrogel technology is approved internationally and registered in approximately fifty countries worldwide for the treatment of PHN pain. This patch is recommended by international guidelines as a first-line treatment for localized peripheral NP such as PHN.
Excited nociceptors are considered a crucial part of NP syndromes pathophysiology.,,, Lidocaine functions in dermal nociceptors by blocking abnormally functioning (sensitized) Nav 1.7 and Nav 1.8 Na+ channels, thus reducing ectopic discharge., Lidocaine has also been shown to regulate T-cell activity and inhibit the production of nitric oxide, thereby reducing inflammatory processes in the deep tissue, such as injured muscles, joints, or constricted nerves., This pharmacological action of lidocaine is complemented by the mechanical cooling and soothing effect of the hydrogel layer in the patch while also providing a barrier effect to the hypersensitive skin in PHN. Thus, dual pharmacological and mechanical mechanisms constitute the innovative hydrogel technology of this patch. The hydrogel layer is formed from a hydrophilic gel matrix with a high capacity to hold water. This water-holding capacity is sufficient enough to provide adequate adhesiveness while avoiding excess vaporization.
The cross-linked porous network structure of the hydrogel matrix offers a high degree of biocompatibility resembling that of natural skin tissue. It permits controlled release of the drug lidocaine at a rate which is dependent on the diffusion coefficient gradient across the skin. This maintains a highly targeted local concentration of lidocaine over the affected area for a prolonged time. Further, the highly viscous gel matrix promotes hydration and swelling of the stratum corneum or keratinized layer of skin, thus improving lidocaine permeability., These features of the hydrogel patch offer a definite advantage over conventional topical formulations which are not able to penetrate the natural barrier of intact skin and hence find no recommendation or approval for treatment of localized NP such as PHN.
Safety and efficacy
A multicenter study was conducted in 265 PHN patients in 12 European countries with an initial 8-week open-label, active run-in phase using lidocaine 5% patch with hydrogel technology, followed by a 2-week double-blind, placebo plaster-controlled phase. Most of the patients reported a significant analgesic effect which was maintained during the study's active 8-week pretreatment period. There were also considerable improvements in secondary endpoints measuring levels of pain intensity, severity of allodynia, QoL as well as sleep during the run-in phase. In the double-blind phase of the study, secondary efficacy endpoints suggested a better efficacy for lidocaine 5% patch with hydrogel technology over placebo.
An open-label effectiveness study of lidocaine 5% patch with hydrogel technology in 332 PHN patients for 28 days demonstrated significant reductions in all mean pain intensity scores and pain interference with QoL. Most patients reported improvements in outcome metrics, regardless of the timeframe after the onset of the shingles rash. This study confirmed that in a clinical practice setting, lidocaine 5% patch with hydrogel technology should be considered first-line therapy, alone or in combination with other agents. It was concluded that although this patch was extremely effective in long-term PHN, it would seem wise to start therapy as soon as possible during PHN.
In another study, an elderly cohort of eight PHN patients who were taking several medications to treat comorbidities and with a high chance of drug–drug interactions were treated using lidocaine 5% patch with hydrogel technology. Good pain relief was observed during a follow-up period of 3 months, which was associated with a 46% reduction in the size of painful area after 1 month and a 66% reduction after 3 months. Therefore, this treatment might have another significant clinical effect: the reduction of the allodynic area.
In an open-label trial in PHN and PDN patients at 51 European centers, lidocaine 5% patch with hydrogel technology was compared with pregabalin in a two-stage, randomized, open-label, multicenter study. When the study findings were evaluated by sign, more patients in the PHN group responded to the lidocaine 5% patch with hydrogel technology than to pregabalin treatment (63.3% vs. 46.8%). Among the secondary endpoints, a decrease in Numerical Rating Scale (NRS)-3 scores by ≥30% (57.8% vs. 48.8%) and ≥50% (35.6% vs. 20.9%) were higher with this patch than with pregabalin in patients with PHN.
The benefits of lidocaine 5% patch with hydrogel technology in combination with pregabalin were assessed in patients of PHN and PDN. Patients treated with combination therapy for 4 weeks attained mean decreases in NRS-3 scores, above those experienced during the initial 4 weeks of monotherapy with either treatment.
In our study, the majority of the clinicians (76.11%) opined that there was a significant reduction in pain score with lidocaine 5% patch with hydrogel technology. Further, 79.1% of them also reported significant pain relief during the intermittent patch-free period. Around 83.58% of clinicians testified the cooling and soothing effect of the hydrogel layer in the patch.
Many clinical trials report that lidocaine 5% patch with hydrogel technology is tolerated well for the treatment of PHN pain with low systemic uptake and minimal drug–drug interactions.,, An analysis of research based on safety and tolerability of this patch found favorable tolerability in both short and long terms with a low risk of systemic adverse drug reactions. A recent review has documented good safety profile in study participants who were treated for PHN for a period of up to 7 years.
The most common adverse events with this patch are application site reactions which are usually mild and transient.,,, In our study also, few clinicians (25.3%) reported that patients experienced local skin reactions of mild-to-moderate intensity, but none of them reported any generalized adverse reaction with this patch.
| Conclusion|| |
Lidocaine 5% patch with hydrogel technology establishes a breakthrough advance in the treatment of localized peripheral NP conditions and is a first-line recommended treatment for symptomatic relief of PHN pain. Based on extensive clinical trial data, lidocaine 5% patch with hydrogel technology is documented to be a safe and effective treatment for NP associated with PHN both in short-term and long-term management. This patch is particularly suited for long-term use in patients vulnerable to side effects of systemic analgesic agents because of the low risk for systemic side effects and lack of association with concurrent medication. Hydrogel technology provides a cooling and soothing effect with additional barrier action on the hypersensitive skin of PHN patients. Hence, lidocaine 5% patch with hydrogel technology can be considered as a first therapeutic alternative available with a direct effect on the injured or sensitized cutaneous nociceptors in PHN condition.
Financial support and sponsorship
Conflicts of interest
The corresponding contributor participated in this study survey which was conducted, funded, and supported by Modi-Mundipharma Pvt. Ltd. The samples of lidocaine 5% patch with hydrogel technology (Lidovalor®) were also provided by Modi-Mundipharma Pvt. Ltd.
| References|| |
Merskey H, Bogduk N. Task Force on Taxonomy of the International Association for the Study of Pain. Classification of Chronic Pain Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 2nd
ed. Seattle: IASP Press; 2002. p. 212.
van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: A systematic review of epidemiological studies. Pain 2014;155:654-62.
Opstelten W, Mauritz JW, de Wit NJ, van Wijck AJ, Stalman WA, van Essen GA. Herpes zoster and postherpetic neuralgia: Incidence and risk indicators using a general practice research database. Fam Pract 2002;19:471-5.
Navez ML, Monella C, Bösl I, Sommer D, Delorme C. 5% lidocaine medicated plaster for the treatment of postherpetic neuralgia: A review of the clinical safety and tolerability. Pain Ther 2015;4:1-15.
Backonja M, Woolf CJ. Future directions in neuropathic pain therapy: Closing the translational loop. Oncologist 2010;15 Suppl 2:24-9.
Attal N, Cruccu G, Haanpää M, Hansson P, Jensen TS, Nurmikko T, et al.
EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol 2006;13:1153-69.
Todorovic SM, Jevtovic-Todorovic V. Regulation of T-type calcium channels in the peripheral pain pathway. Channels (Austin) 2007;1:238-45.
Romero-Sandoval EA, Horvath RJ, DeLeo JA. Neuroimmune interactions and pain: Focus on glial-modulating targets. Curr Opin Investig Drugs 2008;9:726-34.
Aurilio C, Pota V, Pace MC, Passavanti MB, Barbarisi M. Ionic channels and neuropathic pain: Physiopathology and applications. J Cell Physiol 2008;215:8-14.
Hans G, Deseure K, Adriaensen H. Endothelin-1-induced pain and hyperalgesia: A review of pathophysiology, clinical manifestations and future therapeutic options. Neuropeptides 2008;42:119-32.
White FA, Jung H, Miller RJ. Chemokines and the pathophysiology of neuropathic pain. Proc Natl Acad Sci U S A 2007;104:20151-8.
Dina OA, Khasar SG, Alessandri-Haber N, Bogen O, Chen X, Green PG, et al.
Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy. Eur J Neurosci 2008;28:1180-90.
Djouhri L, Koutsikou S, Fang X, McMullan S, Lawson SN. Spontaneous pain, both neuropathic and inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J Neurosci 2006;26:1281-92.
Bostock H, Campero M, Serra J, Ochoa JL. Temperature-dependent double spikes in C-nociceptors of neuropathic pain patients. Brain 2005;128:2154-63.
Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: Irritable nociceptors and deafferentation. Neurobiol Dis 1998;5:209-27.
Chevrier P, Vijayaragavan K, Chahine M. Differential modulation of Nav 1.7 and Nav 1.8 peripheral nerve sodium channels by the local anesthetic lidocaine. Br J Pharmacol 2004;142:576-84.
Persaud N, Strichartz GR. Micromolar lidocaine selectively blocks propagating ectopic impulses at a distance from their site of origin. Pain 2002;99:333-40.
Shiga M, Nishina K, Mikawa K, Obara H. The effects of lidocaine on nitric oxide production from an activated murine macrophage cell line. Anesth Analg 2001;92:128-33.
Tanaka A, Minoguchi K, Oda N, Yokoe T, Matsuo H, Okada S, et al.
Inhibitory effect of lidocaine on T cells from patients with allergic asthma. J Allergy Clin Immunol 2002;109:485-90.
Kubo J, Tsuru S, Tsurushima K, Yamasoto S; Inventors. Lidocaine-Containing Hydrogel Patch. United States Patent US 8,920,831: Hisamitsu Pharmaceutical Co Inc, Assignee; 2014.
Sarvaiya JI, Kapse GK, Tank CJ, Upadhyay JS. Formulation and evaluation of topical hydrogel patch containing amide type local anaesthetic agent. Int J Pharm Res Scholars 2012;1:164-9.
Silna EA, Krishnakumar K, Nair SK, Narayanan AV, Dineshkumar B. Hydrogels in topical drug delivery – A review. Int J Innov Drug Discov 2016;6:87-93.
Binder A, Bruxelle J, Rogers P, Hans G, Bösl I, Baron R. Topical 5% lidocaine (lignocaine) medicated plaster treatment for post-herpetic neuralgia: Results of a double-blind, placebo-controlled, multinational efficacy and safety trial. Clin Drug Investig 2009;29:393-408.
Katz NP, Gammaitoni AR, Davis MW, Dworkin RH; Lidoderm Patch Study Group. Lidocaine patch 5% reduces pain intensity and interference with quality of life in patients with postherpetic neuralgia: an effectiveness trial. Pain Med 2002;3:324-32.
Casale R, Di Matteo M, Minella CE, Fanelli G, Allegri M. Reduction of painful area as new possible therapeutic target in post-herpetic neuropathic pain treated with 5% lidocaine medicated plaster: A case series. J Pain Res 2014;7:353-7.
de León-Casasola OA, Mayoral V. The topical 5% lidocaine medicated plaster in localized neuropathic pain: A reappraisal of the clinical evidence. J Pain Res 2016;9:67-79.
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;65:39-44.
Rowbotham MC, Davies PS, Fields HL. Topical lidocaine gel relieves postherpetic neuralgia. Ann Neurol 1995;37:246-53.
Galer BS, Rowbotham MC, Perander J, Friedman E. Topical lidocaine patch relieves postherpetic neuralgia more effectively than a vehicle topical patch: Results of an enriched enrollment study. Pain 1999;80:533-8.
Nalamachu S, Gould EM, Gannaitoni AR. Use of the lidocaine patch 5% in the treatment of neuropathic pain. J Neuropathic Pain Symptom Palliation 2006;2:3-13.
LIDODERM® Patch Prescribing Information. Malvern, PA: Endo Pharmaceuticals Inc.; January 2015. Available at: www.lidoderm.com.
Scilex Pharmaceuticals. Ztlido™ Prescribing Information. San Diego, CA: Scilex Pharmaceuticals Inc.; November 2018. Available at www.ztlido.com.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]