Th ere are several other active drug delivery technologies which have been demonstrated to be eff ective for speeding lidocaine delivery allowing for more rapid skin anesthesia prior to dermal procedures. Th e following technologies described are not currently in clinical use. Lidocaine iontophoresis is the process where positively charged lidocaine is accelerated in to the skin under the infl uence of a low- voltage direct electrical current ( Figure 47.2 ). Th e quantity and SECTION 6 pharmacological interventions 490 Return Reservoir (saline) Drug Reservoir Battery/ Microcomputer Figure 47.2 Schematic of iontophoretic drug delivery. Reprinted from Advanced Drug Delivery Reviews , Volume 54S, H. E Junginger, Iontophoretic delivery of apomorphine: from in-vitro modeling to the Parkinson patient, pp. S57 \200\22375, Copyright 2002, with permission from Elsevier, http:// www.sciencedirect.com/science/journal/0169409X. Figure includes data from Journal of Controlled Release , Volume 41, Issues 1 \200\2232, Philip G. Green, Ionto phoretic delivery of peptide drugs, pp. 33 \200\22348, Copyright 1996, with permission f rom Elsevier, http://www.sciencedirect.com/science/ journal/01683659. + \200\223 D+ D+ Skin Na+ Cl \200\223 D+ D+ Blood Vessel Drug ions are repelled from the reservoir of similar polarity \200 Drug ions compete for current with extraneous ions \200 Drug \202ux is proportional to applied current review of topical anesthetics for wound repair recommended future trials comparing LET to o ther cocaine-free compounds, as well as further study of in pre-verbal and non-verbal child ren. Application on or near mucous membranes should be avoided with these com- pounds to mi nimize the potential for systemic absorption. treatment is necessary before effi cacy is noted. Side eff ects are usu- ally limited to re dness or other signs of skin irritation. Topical NSAIDS can provide local relief without the risks of an orally or parenterally deli vered NSAID. Th ey have primarily been evaluated for osteoarthritis and acute musculoskelet al injury. Th ese drugs are applied over the injured or painful body part and pen- etrate i nto the subcutaneous tissues, musculature, and tendons where they exert their therapeutic a ction (Esparza et al., 2007 ). Topical medications for the treatment of musculoskeletal and neuropathic pain While indicat ed for the treatment of postherpetic neuralgia in the US, lidocaine 5% topical anesthetic p atch (Lidoderm , Endo Pharmaceuticals, Chadds Ford, PA) has gained usage in a variety of clinical conditions both neuropathic and musculoskeletal. A 5% lidocaine patch is composed of an adhesive material containing that is applied to a non-woven polyester felt backing w hich allows for slow release of lidocaine. Th e patch provides analgesic action, reducing p ain with some decrease in sensory function but without the complete loss of sensation thus it is not eff ective for procedural pain (Krumova et al., 2012 ; Wehrfritz et al., 2011 ). Th e size of the patch is 10 cm \227 14 cm (Galer, 1999 ). Aft er administration of topical NSAIDs peak plasma concentra- tions are 0.2% to 8% of conc entrations achieved with appropriate oral dosing (Heyneman et al., 2000 ). However, levels of NSAID in the meniscus and cartilaginous structures as well as in muscular tissues are fo ur to seven times greater aft er topical administration than oral administration (Bandolier extra, 2005 ; Tegeder et al., 1995). Concentrations in the tendon sheath are several hundr ed times greater than plasma concentration aft er topical administra- tion. Length of time to Cmax is about ten times longer in topically rather than orally administered NSAIDs with Cmax for topical preparations ranging from 2.2 to 23 h (Heyneman et al., 2000 ). Unlike orally administered NSAIDs, topical NSAIDs have not been associated with increased r isk of bleeding, and the risk of any gastrointestinal side eff ects for topical administrat ion is considerably lower (Bandolier extra, 2005 ). Adverse events with topical NSAIDs are predominately local cutaneous reactions. Photosensitivity is a rare adverse reaction to top ical NSAIDs (Bandolier extra, 2005 ). In addition to treatment of postherpetic neuralgia, the 5% lido- caine patch has been used with effi cacy in a variety of neuropathic pain conditions such as post-thoracotomy pain, c omplex regional pain syndrome, and post amputation pain (Devers and Galer, 2000 ). Th e lid ocaine patch is also eff ective for musculoskeletal conditions. Th e 5% lidocaine patch has been shown to be eff ective in adults with osteoarthritis (Galer, 2004a ; Gammaaitoni, 200 4 ) and with lower back pain (Galer et al., 2004b ; Gimbel et al., 2005 ). Th e lack of sig nifi cant side eff ects makes topical 5% lidocaine an appropriate option in adults for any focal neuropathic pain with allodynia or hyperalgesia (Jensen et al., 2009 ). Th e patch mu st be placed at the site of pain in order to be eff ective. Th ere are a variety of preparations of topical NSAIDs includ- ing creams, gels, patches, a nd plasters. NSAIDS delivered topi- cally include diclofenac, ketoprofen, and ibuprofen. Su periority of topical NSAIDs compared with placebo has been demonstrated for both diclofenac and ketoprofen patches for acute musculoskeletal conditions (Haroutiunian et al., 2010 ). Based on a large meta-anal- ysis ketoprofen may be the most eff ective of the topical NSAID s for acute pain (Mason et al., 2004 ). Th ough there are fewer compara- tive trials, in ge neral, topical NSAIDs appear as eff ective and have a better safety profi le in adults than oral NSAIDs, though onset of action is slower (Heyneman et al., 2000 ; Underwood et al., 2 008 ). While it has not been studied specifi cally in children we have used it successfully in man y of the conditions described previously, especially lower back pain and focal neuropathic pains. Lidocaine absorption in adult usage amounts to only 3% to 5% of the total dose avail able in the patch and systemic levels do not increase with daily use, and systemic toxicity in adults is felt not to be a signifi - cant risk (Campbell et al., 2002 ; Lidoderm Packag e Insert, n.d.). For children under 50 kg we limit the treatment to one to two patches for 12 h per day to insure safety. Children over 50 kg can use the adult dose of three patches for 12 h per day. Oft en 7 to 10 days of Unfortunately there are no randomized trials of topical NSAIDs in the pediatric age group. Given the excellent safety profi le and low systemic absorption of topical NSAIDs, utilizat ion of these agents in children and adolescents with acute or chronic muscu- loskeletal pai n is a reasonable option. CHAPTER 47 topical anesthetics and analgesics 491 Capsaicin, the active compound in chili peppers, is a counter irri- tant (a substance appli ed to the skin which, by acting as an irritant on a painful zone, attenuates the sensation of pain) which provides some relief in neuropathic pain conditions. Capsaicin is a TRPV1 ag onist that fi rst activates nociceptive nerve fi bres in the skin and causes the release of substance P which results in neurogenic infl ammation. Th is is followed by reversible def unctionalization of nerve endings resulting in the inhibition of pain transmission (Derry e t al., 2009 ; Irving et al., 2011 ; Knoktova et al., 2008 ). reduced pain in adults with postherpetic neuralgia compared with a lower concentration crea m or placebo and a randomized control- led trial of 10% ketamine reduced allodynia in adult s with complex regional pain syndrome (Finch et al., 2009 ; Lockhart 2004 ). In the second trial no systemic ketamine was detected 1 h aft er applica- tion in ten patients (Fisch et al., 2009). For clinical use these prepa- rations may require the expertise of a compoundin g pharmacist. Dexamethasone, a steroid, can be delivered iontophoretically for a variety of infl ammatory conditions such as medical and lateral epicondylitis, Achilles tendonitis, and plantar fas ciitis (Gudeman, 1997 ; Neeter, 2003 ; Nirschl, 2003 ). In the US this procedure is primari ly performed by physiotherapists. Unlike lidocaine ionto- phoresis described earlier, dexam ethasone is negatively charged so it must be placed on the negatively charged electrode to facilitate drug delivery. Th e data supported the effi cacy of dexamethasone iontophoresis is variable. Th e largest study which evaluated dex- amethasone iontophoresis for epicondyl itis demonstrated reduced pain in the active drug group versus placebo iontophoresis, how- ever the results of several other smaller trials including one for epi- condylitis were mix ed. It is likely that dexamethasone iontophoresis provides short-term benefi ts including p ain relief in acute muscu- loskeletal injuries (Torro, 2011 ). Low-concentration (0.025% and 0.075%) capsaicin creams have shown mild effi cacy in a varie ty of neuropathic conditions includ- ing postherpetic neuralgia, diabetic neuropathy, polyn europathy, and postsurgical neuropathic pain. Th ese creams must be applied several times a day and can take several weeks of application to have eff ect (Knotkova et al., 2008). Mor e recently an 8% capsaicin patch has been developed for one-time use and shown effi cacy in post- herpetic neuralgia and HIV neuropathic pain (Irving et al., 2011 ). Oral capsaicin h as shown some effi cacy in reducing mucositis pain in adult cancer patients (Berger et al., 1995 ). Local skin irritation with capsaicin cream use is common with burning and erythema and itch ing are predominant side eff ects. Th ese eff ects usually diminish aft er 1 to 2 weeks of use. Pretreatment of the skin with topical anesthetic is necessary prior to use of the caps aicin 8% patch to improve tolerability. One pediatric study of dexamethasone iontophoresis demon- strated effi cacy in a case serie s of 28 patients with juvenile idio- pathic arthritis treated for temporomandibular joint i nvolvement (Mina, 2011 ). Side eff ects in this study and others are similar to those menti oned previously with iontophoresis. Use of capsaicin in pediatrics is limited to case reports. Th is includes the use of a comp ounded form of 10% capsaicin in a 9-year-old with erythromelalgia (McElhiney, 2011 ). Given the rare incidence of systemic side eff ects, use of capsaicin for neuropathic pain in chi ldren and adolescents could be considered and will be limited by tolerance to the applicati on. Conclusion Th ere are a variety of eff ective topical medications for both pro- cedural pai n as well as musculoskeletal and neuropathic pain. For procedural pain these medications ha ve been well studied in chil- dren and their use should be encouraged. Th ere is limited da ta to support the effi cacy of topical medications in the pediatric popula- tion for muscul oskeletal and neuropathic pain conditions. However, given the excellent safety profi le inc luding lack of systemic absorp- tion and minimal local side eff ects the use of these medic ations in the pediatric age group should be considered. Other counter irritants such as methyl salicylates and menthol have also been used for musc uloskeletal pain. Methyl salicylate may have direct analgesic eff ects but also provides ti ssue warming by its vasodilatory eff ects (Higashi et al., 2010). Menthol \200\231s mode of action is likely the cooling eff ect it has on the skin. Th ere is limited evi- dence for the effi cacy of these compounds however a recent study of a 10% methyl salicylate 3% menth ol patch demonstrated greater pain relief than placebo in 208 adults with muscle strains (H igashi et al., 2010). Th e identifi cation of peripheral opioid receptors and the adverse systemic eff ects of op ioids have led to the use of topical opio- ids primarily in the palliative care setting for ulcers and mucosi- tis (Coggeshell and Carlton, 1997 ; Lebon et al., 2009 ). Morphine is t he most common opioid reported in the literature although diamorphine, methadone, oxycodone , and meperidine have also been studied. A review of 19 studies (six randomized controlled trials and 13 case reports) found support for effi cacy but recom- mended further larger tr ials (Lebon et al., 2009 ). Morphine is used either mixed with intrasite gel to apply to ul cers, or swished and spit as a 1% or 2% mouthwash for mucositis (Cerchietti et al., 2003 ; Zeppetella et al., 2003 ). A case report on the use of topical mor- phine gel in two adoles cents with epidermolysis bullosa reported good effi cacy with no side eff ects despite prol onged use for 4 weeks and 5 months (Watterson et al., 2004 ). Case example A 15-year-old girl presents to the chronic pain clinic with a 4-month history of back pain. Her pain is usually a 4 to 6 out of 10 at rest but increases to an 8 to 9 out of 10 with a ctivity. She continues to attend school, has no trouble sleeping, and her mood as reported by her both herself and her mother is good. She does say it is hard to concentrate at schoo l because she has to shift positions multiple times during class to stay comfortable. She i s frustrated because she has not been able to participate in dance since her pain started. She has had an extensive workup that includes orthopedic evaluation, plain fi lms and a mag netic resonance imaging scan of the lumbosacral spine. Th e radiologi- cal studies were nor mal. She took ibuprofen for several weeks aft er the onset of pain; however, this was not h elpful. She has had eight sessions of physiotherapy focused on core strengthening. She says the physiotherapy has not reduced her pain but that the Ketamine and amitriptyline either alone or in various combi- nations have been used to prov ide pain relief in neuropathic pain conditions. Th e evidence supporting their use is mixed although negative studies may refl ect lower concentrations of the agents used. A study of 4% amitriptyline and 2% ketamine demonstrated SECTION 6 pharmacological interventions 492 patients with post-herpetic neuralgia, and patients with acute herpes zoster . J Pharm Sci , 91 , 1343 \200\2231350. electrical stimulation they do during therapy does reduce her pain temporarily. On physical exam she is a comfortable appearing, pleasant, non- obese female. Notable fi ndings on her exam include paraspinal muscular tenderness and tightening in the lumbar region. She has i ncreased pain with forwards and especially backwards fl ex- ion. She has no evidence of hyp ermobility and her neurological exam is normal. Recommendations: you recommend a lidocaine 5% patch. She should apply it for 12 h daily (usually at night). She should cut the patch i n half and place the halves over the areas of maximal tenderness. Th e patches should be pl aced in the same location every night. You tell her to give it at least 2 weeks of regular use to expect results (the manufacturer recommends 7 to 10 days for pain reduction from pos therpetic neuralgia but our experience for back pain is that it takes a longer period of ti me). You also recommend that she obtain a TENS (transcutaneous electric nerve stimulation) unit from her physiotherapist. She can wear this at times during the day when her pain beco mes severe. It is also helpful during school classes to help reduce pain and enable her to concentrate. Follow-up : she returns to the clinic 6 weeks later with her pain essentially resolved. She experienced no local irritation or other side eff ects from the patch. She co ntinues to use the lidocaine patches and has now transitioned from physiotherapy and is doi ng some low-intensity dancing. You tell her to use the patches for another 2 weeks and retu rn to see you again if her pain returns. Cerchietti , L. C. , Navigante , A. H. , Korte , M. W. , Cohen , A. M. , Quiroga , P. N. , Villaamil , E. C. , et al . ( 2003 ). Potential utility of the peripheral analgesic propert ies of morphine in stomatitis related pain: a pilot study . Pain , 105 , 265 \200\223273. Coggeshell , R. E. , and Carlton , S. M. ( 1997 ). Receptor localization in mammalian dorsa l horn d primary aff erent neurons . Brain Res Rev , 24 , 28 \200\22366. Derry , S. , Lloyd , R. , Moore , R. A. , and McQuay , H. J. ( 2009 ). Topical capsaicin fo r chronic neuropathic pain in adults . Cochrane Database Syst Rev , 7 (4), CD007393 . Devers , A. and Galer , B. S. ( 2000 ). Topical lidocaine patch relieves a variety of neuro pathic pain conditions: an open label study . 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T. , Sullivan , J. , Paulson , D. M. , and Hoath , S. B. ( 2004 ). Evaluation of a low-dose lidocaine iontophoresis system for topical anesthesia in adults and children: a randomized, controlled trial . Clin Th er , 26 (7), 1110 \200\2231119. CHAPTER 48 Drugs for neuropathic pain Sachin Rastogi and Fiona Campbell Summary Neuropathic pain is defi ned as \200\230pain arising as a direct consequence of a lesion or disease aff ecting the somatosensory system \200\231. It is oft en contrasted wit h nociceptive pain which is associated with tissue injury or infl ammation. Neuropathic pai n exhibits certain clinical features that diff erentiate it from nociceptive pain. Neuropat hic pain conditions in children are diff erent from those in adults and include complex reg ional pain syndrome (CRPS), phantom limb pain, postoperative and post-traumatic neuropathic pain, and autoimmune and degenerative neuropathies, e.g. Guillain \200\223Barr syndrome , Charcot \200\223Marie \200\223Tooth disease. However, a lack of rand- omized controlled t rials in children means that evidence from adult studies guides pharmacological management of neuropathic pain in children, which is problematic as the aetiologies and mechanisms are diff erent. partially understood phenomenon with characteristic clinical fea- tures, which have predomi nantly been described in adults. For the purposes of this chapter the term \200\230childre n \200\231 will refer to all chil- dren and adolescents unless indicated otherwise. Th ough it is well known that children suff er from neuropathic pain, there have been few pediatri c studies. Moreover, it is likely that given the diff er- ences in nervous system anatomy a nd physiology between adults and children, as well as diff erent aetiologies of neuropathic pain, there are signifi cant diff erences in mechanisms and prognoses.