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Ultrasound-guided greater occipital nerve block for patients with occipital h eadache and short term follow up . Korean J Anesthesiol , 61 , 50 \200\2234. Wilkins , K. L. , Mcgrath , P. J. , Finley , G. A. , and Katz , J. ( 1998 ). Phantom limb s ensations and phantom limb pain in child and adolescent amputees . Pain , 78 , 7 \200\2231 2. Shimazaki , M. , Egawa , H. , Motojima , F. , Fujimaki , K. , Hamaguchi , S. , Okuda , Y. , et al . ( 2003 ). [Intrathecal phenol block in a child with cancer pain \200\224a case rep ort] . Masui , 52 , 756 \200\223758. Wolfe , J. , Klar , N. , Grier , H. E. , Duncan , J. , Salem-Schatz , S. , Emanuel , E. J. , and Weeks , J. C. ( 2000 ). Understanding of prognosis among parents of children who died of cancer: impact on treatment goals and integration of palliative care . JAMA , 284 , 246 9 \200\2232475. Simmel , M. L. ( 1962 ). Phantom experiences following amputation in childhood . J Neurol Neurosurg Psychiatry , 25 , 69 \200\22378. Simopoulos , T. T. , Manchikanti , L. , Singh , V. , Gupta , S. , Hameed , H. , Diwan , S. , et al . ( 2012 ). A systematic evaluation of prevalence and diagnostic Yue , W. L. ( 2004 ). Peripheral glycerol injection for the relief of facial neuralgia in children . Int J Pediatr Otorhinolaryngol , 68 , 37 \200\22341. CHAPTER 47 Topical anesthetics and analgesics William T. Zempsky Summary Topical administration of anesthetics and analgesics can allow for the effi cient, painless delivery of medications which may reduce systemic side eff ects associated with th e medication while provid- ing clinical advantages over injected or oral administration for the same clinical situation. Topical anesthetics have become widely used prior to a variet y of painful procedures in children including venous access, laceration repair, and injecti ons. Topical administra- tion of non-steroidal anti-infl ammatory drugs, lidocaine, capsaic in, and other agents also are useful for a range of conditions including acute and chronic musculoskeletal pain, and neuropathic pain. Th ree delivery methods have been utilized to bypass the stratum corneum barrier (Zempsky, 2008 ): \231 Injection of local anesthetics or other medications, usu- ally via a small-gauge hyp odermic syringe, is the oldest of the methodologies. \231 Passive diff usion from creams, gels, or patches comprises the second general class of methodologies. Passive diff usion of topi- cal agents require that they have a molecular weight under 500 Daltons, with a hydrophobic component to allow it to transverse the strat um corneum but also some hydrophilic features to pen- etrate the epidermis (Stamos, 2007 ). \231 Active drug delivery methods which enhance the rate of drug passage through the skin and shorten the time to onset of action. Th ere are a diverse group of technologies which facilitate the drug delivery process. Th ese include heat-enhanced diff usion, iontophoresi s, sonophoresis, laser-assisted transdermal passage, or pressurized gas delivery of powdere d drug particles (Zempsky, 2008 ). Microporation, a newer technology, uses tiny micronee- d les to penetrate the stratum corneum and directly place the drug within the epidermis (Yada v, 2011 ). Background It is important to diff erentiate between topical and transdermal medications. T opical medications target the site of application and ideally produce eff ective drug conce ntrations locally with minimal systemic absorption. Topical anesthetics and analgesics targ et the peripheral nerves and soft tissue at that site (Galer, 2001 ). In con- trast, transd ermal medications do not have to be applied over an involved site and attempt to reach syst emic drug concentrations to achieve therapeutic results (Argoff , 2004 ). Th is chapter wil l focus on topical medications ( Table 47.1 ). Topical as well as transdermal drug delivery is a rapidly expanding fi eld. Most of the dru gs and technologies used for topical anaes- thesia have been well studied in children; howe ver, this is not the case for topical medications used for musculoskeletal and neuro- pathi c pain which will be discussed in this chapter. Th e extrapola- tion of use of the these ag ents in children seem reasonable given several factors: the pharmacodynamic response to mos t medica- tions including local anesthetics, opioids, and non-steroidal anti- infl ammatori es (NSAIDs) are substantially mature by age 2 years, the degree of systemic absorption of t hese topical medications is low, and the local skin eff ects are for the most part minimal and short lived (Berde, 2012 ). Benefi ts of topical drug delivery in general may include the poten- tial for local therape utic drug levels with reduced side eff ects, painless drug delivery, improved patient adher ence (which is especially impor- tant in children) and acceptance, ease of dose termination , avoidance of fi rst-pass metabolism, and direct access to the target site. Th e skin is an eff ective barrier to drug delivery, its primary role being to prevent the ingress or egress of compounds across it ( Tadicherla, 2006 ). Th e stratum corneum, the up permost layer of the skin consists of a thin layer of cornifi ed non-viable kerati- nocytes interconnected by highly ordered lipid bilayers, and has evolved to be a highly eff ective barrier to water-soluble substances, which typically include anesthetics (Houck and Sethna , 2005 ). Topical medications must transverse the stratum corneum to reach their site of ac tion which may be the peripheral transduc- ing terminals of cutaneous sensory fi bres locat ed in the dermis and epidermis (Lumpkin and Caterina, 2007 ), or the local soft tissues inc luding synovial fl uid, synovial tissue and cartilaginous struc- tures (Bandolier extra, 20 05 ) ( Figure 47.1 ). Topical anesthetics for procedural pain Th e ideal topical anesthetic should have good effi cacy, an excellent safety profi le, convenient application, enduring eff ect, and reason- able cost. Specifi c properties important for topical anesthesia prior to a procedure inclu de rapid onset of analgesia to minimize dis- ruption and delay of needed medical procedures , minimal systemic CHAPTER 47 topical anesthetics and analgesics 487 Table 47.1 Common topical anesthetics and analgesics Drug Brand or other names Use Lidocaine prilocaine cream EMLA and others Procedural pain Tetracaine Amethocaine , Ametop Procedural pain LMX 4 , Maxilene Procedural pain Liposomal lidocaine Vapocoolant spray Painease and others Procedural pain 5% lidocaine patch Lidoderm Neuropathic and musculoskeletal pain Topical NSAIDs Flector , Voltaren , Pennsaid , and others Musculoskeletal pain Capsaicin Zostrix , Qutenza , and others Neuropathic pain Menthol and methylsalicylates Many Musculoskeletal pain Ketamine and amitriptyline Compounding pharmacist Neuropathic pain Hair Stratum corneum Granular cell layer Spinous cell layer 1 Basal cell layer Sebaceous gland Erector pill muscle Sweat gland 2 Nerves Hair follicle Collagen and elastin \201bres 3 Artery Vein Figure 47.1 Reproduced from Mark Gardiner et al, Training in Pediatrics: Th e Essential Cur riculum , Figure 9.1, p.194, Oxford University Press, Oxford, UK, Copyright 2009, by per mission of Oxford University Press. Fat (adipose) tissue 1 Epidermis 2 Dermis 3 Subcutaneous tissue absorption, no untoward dermal eff ects, and no adverse eff ect on the success rate of the procedure (Zempsky, 2008 ). No commer- cially available agent is likely to have all of thes e properties. 1:1 ratio, crystals of lidocaine and prilocaine produce a \200\230eutectic mix- ture \200 \231, a mixture that has a lower melting point than either component alone. Within the crea m, the local anesthetics exist as a liquid oil rather than as crystals; this leads to highe r concentration of anaes- thetic within the oil thus an increase in the rate of diff usion into the epidermal and dermal layers. In some countries a eutectic mixture of lidocaine and prilocaine is also available in a patch formulation. Topical anesthetics for procedural pain diff er from one another primarily in their drug de livery mechanisms, rather than in their underlying pharmacological modes of action. Most av ailable agents utilize lidocaine, prilocaine, and/or tetracaine (also known as ame- thocain e) and produce their analgesia through similar mechanisms involving inhibition of sodium io n channels in sensory neurons. A large number of clinical trials in both children and adults have analyzed its effi cacy f or venepuncture pain and intravenous cannulation pain (Ehrenstrom-Reiz, 1983 ; Hallen and U ppfeldt, 1982 ; D. L. Halperin et al., 1989 ; Lander et al., 1996 ; Maunuksela and Korpela, 1986 ; Moller, 1985 ). A meta-analysis of these trials concluded that lidocaine and priloc aine cream provided signifi cant Lidocaine and prilocaine cream , 2.5%/2.5% (EMLA Cream (eutec- tic mixture of local anes thetics), AstraZeneca LP, Wilmington, DE) is the most well studied topical anesthetic and h as been used in clinical practice for approximately 25 years. When mixed in a SECTION 6 pharmacological interventions 488 analgesia for both venepuncture and cannulation procedures, with similar and consistent eff ects across both procedures, with 85% of patients receiving exhibiting signifi cant analge sic benefi t from its application prior to the procedure (Fetzer, 2002 ). Th e analge- sia appears to be independent of age, location of the procedure, and intravenous insertion tech nique (Fetzer, 2002 ). Lidocaine and prilocaine cream also reduces pain associated with vac cination and has not been shown to impact immunogenicity (S. A. Halperin, 2000 ). Tetracaine gel has been demonstrated to provide compara- ble anesthesia to lidocaine and pr ilocaine for venous access and other dermal procedures (Bishai et al., 1999; Lawson et al., 1995 ; R msing et al., 1999 ). For intravenous cannulation a tetracaine gel is preferre d over lidocaine- prilocaine cream (Lander, 2006 ). In neonates, tetracaine is eff ective f or pain of venepuncture and injec- tion but not heel lance (Jain and Ruttner, 2000 ; Jain e t al., 2001 ; Shah et al., 2008 ). Tetracaine gel produces analgesia in 30 to 45 min, and h as a longer duration of anesthesia (4 \200\2236 h) than lido- caine and prilocaine cream (2 h) (Houck and Sethna, 2005 ; Lander, 2006 ). Tetracaine gels \200\231 prolonged duration o f action may be due to a depot eff ect in the stratum corneum and an affi nity of tetracain e for proteins, which may prolong its binding to sodium channels on sensory neurons (Obrien , 2005 ). Th e effi cacy of lidocaine and prilocaine cream is dependent upon dosage and application t ime. A thick layer (2.0 ml) is more eff ective than a thin layer (0.5 ml) in reducing pain (Sims, 1991 ). Th e mini- mum recommended treatment time is 60 min, but longer durations (> 90 min) are known to produce greater pain relief (Houck and Sethna, 2005 ). Protocols (such as application in triage in the emer- gency department) can overcome the practical challen ge of delayed onset of anesthesia for use in clinical settings. No signifi cant systemic adverse events with tetracaine gel have been reported. Transient e rythema followed by oedema and pruritus are the most common side eff ects (Obrien et al., 2 005 ). Tetracaine causes vasodilation which has been theorized to facili- tate vascular acc ess (Houck and Sethna, 2005 ); however, in a com- parative study fi rst attempt success rat es between 4% tetracaine and lidocaine-prilocaine cream were not diff erent (75.8% versus 7 3.9%) (Newbury and Herd, 2009 ). Lidocaine and prilocaine cream is effi cacious and safe for use in neonates and prematures down to 26 weeks for blood draw- ing (Taddio, 1998 ), lumbar puncture (Kaur, 2003 ), suprap ubic aspiration (Nahum, 2007 ) and circumcision (Taddio, 1997 , 1998 ). Effi cacy for heel lancing has not been demonstrated (Taddio, 1998 ). For neonates 0 to 3 months of age or in any child less than 5 kg, maximum total dose of lidocaine and prilocaine cream should be 1 g, the maximum application area should be 10 cm 2 , and the maximum application time should be 1 h (Taddio et al., 1998 ) ( Table 47.2 ). Liposomes are vesicles consisting of concentric lipid bilayers (phospholipids and cholester ol) that enclose an aqueous compart- ment (Kshirsagar, 2005 ). By encapsulating a drug in l iposomes the surrounding bilayer protects it from in vivo degradation enzymes and allows fu sion with other bilayers (Kshirsagar, 2005 ). Liposomal lidocaine 4% is available in the US (LMX 4 , Ferndale Laboratories, Detroit, MI) and Canada (Maxilene , Ferndale Laborat ories, Detroit, MI) and can be used with or without an occlusive dressing. Lidocaine and prilocaine cream causes vasoconstriction, which leads to blanching of the ski n. Allergic and anaphylactoid reac- tions associated with lidocaine or prilocaine can rarel y occur. In young infants who do not have adult levels of methaemoglobin reductase, in pati ents who are on medications which put them at increased risk, or have prolonged application times use of lidocaine and prilocaine cream may be associated with methaemoglobinae- mia. However methaemoglobinaemia was not demonstrated with appropriate use of this agent in neon ates (Taddio, 1998 ). Liposomal lidocaine 4% is effi cacious in children undergoing venous access procedures (Eic henfi eld et al., 2002 ; Koh et al., 2004 ; Taddio et al., 2005 ). Procedural success rate was higher in a liposomal lidocaine 4% group compared to the placebo group in patients unde rgoing venous access (Taddio et al., 2005 ). A sys- tematic review found liposomal lidocain e to be as effi cacious as lidocaine prilocaine cream and tetracaine gel (Eidelman et al., 2005). Tetracaine or amethocaine gel (Ametop Gel \204 , Smith & Nephew, London, UK), currently a vailable in Australia, Canada, New Zealand, and the UK, consists of 4% tetracaine base in a n aqueous gel (Obrien et al., 2005 ). When applied to skin, solid tetracaine par- ticles li quefy to form an oil emulsion that better penetrates the stra- tum corneum (Obrien et al., 2005 ). Like lidocaine and prilocaine cream, tetracaine gel is usually applied with an occl usive dressing. Safety of liposomal lidocaine is similar to other creams and gels. Adverse events are usual ly limited to pallor, redness, and mild itching at the application site (Eichenfi eld et al ., 2005). Liposomal lidocaine 4% has not been investigated in great detail in children youn ger than 2 years of age (Zempsky, 2008 ). Table 47.2 Lidocaine and prilocaine cream maximum recommended dose, application area, and a pplication time by age and weight (EMLA package insert, n.d.) Age and body weight Maximum total dose Maximum application area Maximum application time 0 \200\2233 months or <5 kg 1 g 10 cm 2 1 h 3 \200\22312 months and >5 kg 2 g 20 cm 2 4 h 1 \200\2236 years and >10 kg 10 g 100 cm 2 4 h 7 \200\22312 years and >20 kg 20 g 200 cm 2 4 h Please note: if a patient greater than 3 months old does not meet the minimum weight requir ement, the maximum total dose of lidocaine and prilocaine cream should be restricted to tha t which corresponds to the patient \200\231s weight. Th ese are broad guidelines for avoiding systemic toxicity in applying lidocaine and priloc aine cream to patients with normal intact skin and with normal renal and hepatic function. For more individualized calculation of how much lidocaine and prilocaine may be absorbed, p hysicians can use the following estimates of lidocaine and prilocaine absorption for childr en and adults: the estimated mean ( SD) absorption of lidocaine is 0.045 ( 0.016) mg/ cm 2 /h; the estimated mean ( SD) absorption of prilocaine is 0.077 ( 0.036) mg/cm 2 /h. CHAPTER 47 topical anesthetics and analgesics 489 Unlike the other topical anesthetic options, vapocoolant sprays do not rely on a chemical a nesthetic. Instead, they rapidly cool the skin, which slows initiation and conduction of im pulses in cutane- ous sensory nerves and increases their refractoriness (Burke et al., 1999 ). Composed of volatile liquid refrigerants, vapocoolant sprays are applied to the skin and their rapid evaporation produces a short-lived (<1 min) anesthetic eff ect. Th ese agents can be directly sprayed onto the skin or applied via saturated cotton balls. distribution of delivered drug is dependent on the ion charge, molecular weight, intensity of the electric current, concentration of the drug, contact surface area of the delivery el ectrode, and dura- tion of current (Zempsky and Ashburn, 1998 ). Lidocaine ionto- phoresis provides better anesthesia with a 10 min application than iontophoresis of placebo, and at least equivalent anesthesia to a 60 min application of lidocaine and prilocaine cream, and lidocaine infi ltration (Galinkin et al., 2002 ; Miller 2001 ; Zempsky et al., 1998 , 2004 ). However, tingling, itching, burning sensation, and discom- fort have been documented in trials, and burns, which have been reported to occur at incidences of 1 per 15 000 to 20 00 0 treatments, remain a concern clinical acceptability of this technology for topical anesth esia (Rattenbury and Worthy, 1996; Zempsky et al., 1998 ). Th e Epiture Easytouch \204 Sy stem (Norwood Abbey Ltd, Frankston, Australia), is a single-pulse laser device that can be used before dermal procedures to ablate a patch of stratum corneum 6 mm in diameter which a llows for a topical anesthetic such as liposomal lidocaine to provide anesthesia in about 5 min (Shapiro, 2002 ). Th is system has been shown to be eff ective in reducing pain associ - ated with needle procedures in healthy adults (Baron, 2003 ; Shapiro 2002 ). Mild pain, i tching, and erythema of the skin may be appar- ent at the ablation site following treatment . Patients treated with dermatological lasers are known to experience temporary hyper- pigm entation or hypopigmentation at the treatment site (Zempsky, 2008 ). Studies of vapocoolant sprays for prevention of procedural pain have reported mixed results . In a review of trials for venous access pain four out of eight trials could not demonstra te increased effi - cacy over placebo or no treatment while the other four demon- strated s ignifi cant benefi t (Bandolier extra, n.d.). Studies are also inconsistent for injection pain. A vapocoolant spray provided signifi cant ly more analgesia than cold saline spray in adults (Mawhorter et al., 2004 ) and, when comb ined with dis- traction, provided signifi cantly more pain relief than distraction alone in children and the analgesic eff ect was similar to lidocaine and prilocaine cream plus dist raction (Reis and Holubkuv, 1997 .) However, a meta-analysis of fi ve studies evaluating va pocoolants for immunization did not demonstrate benefi t (Shah, 2009 ). Th e heterogeneous results provided by vapocoolants may be due to the short-lived nature of the anesthesia, small sample sizes of the study, diff erences in the length of anesthesia needed for the procedure, and varied administration technique of the vapocool- ant itself ( Bandolier extra, n.d.). Studies that demonstrated benefi t for immunization pain applied th e vapocoolant using a cotton ball held in place for 10 to 15 sec (Shah, 2009 ). Low-frequency ultrasound produces gaseous cavities in a liquid medium, a process known as a coustic cavitation which can disrupt lipid bilayers in the stratum corneum to accelerate tr ansdermal passage of drugs (Mitragotri and Kost, 2004 ). Th is technology can be used in co njunction with anesthetic creams with shorter appli- cation times. Sonophoresis followed by a 5 min application of lipo- somal lidocaine has been evaluated in both adults and childre n for venous access pain and is superior to no treatment or placebo and equivalent to a 30 min treatment of liposomal lidocaine (Becker et al., 2005 ; Skarbek-Borowska et al., 2006 ; Zempsky et al., 2008 ). Adverse events immediately aft er ultrasound are limited to rednes s and mild discomfort. Use of vapocoolant sprays has been associated with some rare cases of allergic contact derm atitis, and prolonged spraying can cause hypo-pigmentation and atrophic scarring, especiall y in patients with poor circulation. Most vapocoolant sprays contain chemicals that are eye irritants (Bircher, 1994 ). Penetration of local anesthetics through the stratum corneum is accelerated by heat (Hull, 2002 ). Th e lidocaine/tetracaine topi- cal patch (Synera \204 , Nuvo Research Inc. Missi ssauga, Ontario; Rapydan \204 , EUSA, England), has a heating component that gener- ates a mild warming when exposed to air, and an adhesive to fi x the patch to the skin (Sethna e t al., 2005 ). Th e lidocaine/tetracaine patch provided superior analgesia to placebo in a pediatric venous access study of children aged 3 to 17 who received treatment for 20 min pr ior to venous access (Sethna et al., 2005 ). In an adult study the lidocaine/tetracaine pat ch provided superior analgesia for 10-, 20-, and 30-minute application times prior to venou s access than lidocaine/prilocaine cream but at 60 min the two anesthetics were equivalent (Sawyer 2004). Th e lidocaine/tetracaine patch was also equivalent to 4% tetracaine in a st udy of 100 adults requiring venous cannulation for day surgery. Th e warmth has the potenti al to ease venous access by dilating veins but this has not been evalu- ated. Adverse event s with the lidocaine/tetracaine patch are limited to local irritation and erythema. Lidocaine particles can be delivered painlessly into the skin under pressure. Helium gas wh en released accelerates lidocaine particles to velocities that are suffi cient to penetrate the epider- mis and produce local analgesia. Onset of action for venous access procedures is within 1 to 3 min with superiority over placebo in large randomized controlled trials in children. Skin reactions such as erythema, petechiae are short-lived and self-limited (Zem psky, 2008a , 2008b ). Topical anesthetics can also be used to provide either complete or partial anesthesia prior to wound repair (Eidelman et al., 2011 ). Th e most well studied of these solutions are te tracaine adrenaline and cocaine (TAC) and lidocaine, epinephrine (adrenaline), and tetracai ne (LET). Due to the disruption of the epidermis these solu- tions are easily absorbed into the wound with the vasoconstrictor minimizing diff usion. LET has essentially replaced TAC in the US due to the expense of cocaine as well as drug control and safety issues. LET whi ch can be made by the in-hospital drugstore as a liquid or gel preparation, provides excell ent wound anesthesia for facial lacerations in 20 to 30 min (Ernst et al., 1995 ; Schilling et al., 1995 ). TAC and LET are less eff ective for extremity wounds and repair of these l acerations oft en requires supplemental anesthesia (Singer and Stark, 2001 ; Zempsky and Ka rasic, 1997 ). A Cochrane 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.