Schilling , C. G. , Bank , D. E. , Borchert , B. A. , Klatzko , M. D. , and Uden , D. L. ( 1995 ). Tetracaine, epinephrine and cocaine (TAC) versus lidocaine, SECTION 6 pharmacological interventions 494 Torro , J. , Bruneti , L. , and Patel , M. ( 2011 ). Ionotphoretic administration of dexame thasone for musculoskeletal pain . J Musculoskel Med , 28 , 410 \200\223421. epinephrine, and tetracaine (LET) for anesthesia of lacerations in children . Ann Emerg Med , 25 , 203 \200\223220. Sethna , N. F. , Verghese , S. T. , Hannallah , R. S. , Solodiuk , J. C. , Zurakowski , D. , and Berde , C. B. ( 2005 ). A randomized controlled trial to evaluate S-Caine patch for r educing pain associated with vascular access in children . Anesthesiology , 102 (2), 403 \200\223408. Underwood , M. , Ashby , D. , Carnes , D. , Castelnuovo , E. , Cross , P. , Harding , G. , et al . ( 2008 ). Topical or oral iburpofen for chronic knee pain in older people. Th e TOI B study . Health Technol Assess , 12 , ix \200\223155. Watterson , G. , Howard , R. , and Goldman , A. ( 2004 ). Peripheral opioids in Shah , V. S. , Taddio , A. , Hancock , R. , Shah , P. , and Ohlsson , A. ( 2008 ). Topical amethocaine gel 4% for intramuscular injection in term neonates: a double-blind, placebo-co ntrolled, randomized trial . Clin Th er , 30 (1), 166 \200\223174. infl ammatory pain . Arch Dis Child , 89 , 679 \200\223681. Wehrfritz , A. , Namer , B. , Ihmsen , H. , Mueller , C. , Filitz , J. , Koppert , W. , et al . ( 2011 ). Diff erential eff ects on sensory functions and measures of epidermal nerve fi ber density aft er application of a lidocaine patch (5%) on healthy human skin . Eur J P ain , 15 (9), 907 \200\223912. Shah , V. , Taddio , A. , Rieder , M. J. ; HELPinKIDS Team . ( 2009 ). Eff ectiveness and t olerability of pharmacologic and combined interventions for reducing injection pain during routine childhood immunizations: systematic review and meta-analyzes . Clin Ther , 31 (Supp l 2), S104 \200\223151. Yadav , J. D. , Vaidya , K. A. , Kulkarni , P. R. , and Raut , R. A. ( 2011 ). Microneedles : promising technique for transdermal drug delivery . Int J Pharma Biosciences , 2 , 684 \200\223708. Shapiro , H. , Harris , L. , Hetzel , F.W. , and Bar-Or , D. ( 2002 ). Laser assisted deliv ery of topical anesthesia for intramuscular needle insertion in adults . Lasers Surg Med , 31 (4), 252 \200\223256. Zempsky , W. T. ( 2008 a). Pharmacologic approaches for reducing venous access pain . Pediatrics , 122 , S140 \200\223153. Zempsky , W. T. , Anand , K. J. , Sullivan , K. M. , Fraser , D. , and Cucina , K. ( 1998 ) . Lidocaine iontophoresis for topical anesthesia before intravenous line placement in child ren . J Pediatr , 132 (6), 1061 \200\2231063. Sims , C. ( 1991 ). Th ickly and thinly applied lignocaine-prilocaine cream prior to venepu ncture in children . Anaesth Intensive Care , 19 (3), 343 \200\223345. Singer , A. J. , an d Stark , M. J. ( 2001 ). LET versus EMLA for pretreating Zempsky , W. T. , and Ashburn , M. A. ( 1998 ). Iontophoresis: noninvasive drug lacerations: a randomized trial . Acad Emerg Med , 8 , 223 \200\223230. delivery . Am J Anesthesiol. , 25 (4), 158 \200\223162. Skarbek-Borowska , S. , Becker , B. M. , Lovgren , K. , Bates , A. , and Minugh , P.A. ( 20 06 ). Brief focal ultrasound with topical anesthetic decreases the pain of intravenous plac ement in children . Pediatr Emerg Care , 22 (5), 339 \200\223345. Zempsky , W. T. , Bean-Lejewski , J. , Kaufman , R. E. , Koh , J. L. , Malviya , S. V. , Ro se , J. B. , et al . ( 2008 c). Needle free powder lidocaine delivery system provides rapid and eff ective analgesia for venipuncture or cannulation pain in children: Th e randomized double-blind COMFORT-003 trial . Pediatrics , 121 , 979 \200\223987. Stamos , S. P. ( 2007 ). Topical agents for the management of musculoskeletal pain . J Pain Symptom Manage , 33 , 342 \200\223355. Zempsky , W. T. , and Karasic , R. B. ( 1997 ). EMLA versus TAC for topical anesthesia of e xtremity wounds in children . Ann Emerg Med , 30 , 163 \200\223166. Taddio , A. , Ohlsson , A. , Einarson , T.R. , Stevens , B. , and Koren , G. ( 1998 ). A sy stematic review of lidocaine-prilocaine cream (EMLA) in the treatment of acute pain in neon ates . Pediatrics , 101 (2), E1 . Zeppetella , G. , Paul , J. , and Ribeiro , M. D. ( 2003 ). Analgesic effi cacy of morphine applied topically to painful ulcers . J Pain Symptom Manage , 25 , 555 \200\223558. Taddio , A. , Soin , H.K. , Schuh , S. , Koren , G. , and Scolnik , D. ( 2005 ). Liposomal lidocaine to improve procedural success rates and reduce procedural pain among children: a randomized controlled trial . CMAJ , 172 (13), 1691 \200\2231695. Zempsky , W. T. , Robbins . B. , and McKay , L. ( 2008 b). Reduction of topical anesthetic onset time using ultrasound: A randomized controlled trial prior to venipuncture in young c hildren . Pain Med , 9 , 795 \200\223802. Taddio , A. , Stevens , B. , Craig , K. , Rastogi , P. , Ben-David , S. , Shennan , A. , et al . ( 1997 ). Effi cacy and safety of lidocaine prilocaine cream for pain during circumci sion . N Engl J Med , 336 , 1197 \200\2231201. Zempsky , W. T. , Robbins , B. , Richards , P. T. , Leong , M. S. , and Schechter , N. L. ( 2008 d). A study evaluating venipuncture pain in children receiving a novel needlefree pow der lidocaine delivery system for rapid local analgesia . J Pediatr , 152 , 405 \200\22341 1. Tadicherla , S. and Berman , B. ( 2006 ). Percutaneous dermal drug delivery for local pain control . Th er Clin Risk Manage , 2 , 99 \200\223113. Tegeder , I. , Muth-Selbach , U. , Lotsch , J. , R sing , G. , Oelkers , R. , Brune , K. , et al . ( 1999 ). Application of microdialysis for the determination of muscle and subcu taneous tissue concentrations aft er oral and topical ibupfofen administration . Clin Pharm acol Th er , 65 , 357 \200\223368. Zempsky , W. 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. Th ough basic mechanisms underlying pain transmission are reasonably well understood, neuro pathic pain is a complex, inter- dependent dynamic state, which is likely infl uenced by mu ltiple factors including etiology, previous pain experience, and genetic factors. Interindi vidual variability in chronic pain expression and response to analgesics are known to have a genetic basis, which may guide future treatments (Sorge et al., 2012 ), including those f or neuropathic pain. Translation of these mechanisms into drug therapy has not been simple, further complicated by the fact that underlying mechanisms in children are diff erent from those in adults. Examples include the increased plasticity of the develop- ing nervous sys tem and altered response to injury, and the reduced spinal microglial response to nerve inj ury during earlier stages of development (Moss et al., 2007 ; Vega-Avelaira et al., 2007 ; see also Vega-Avelaira and Beggs, Chapter 7, this volume). One could pos- tulate that these diff erences might improve the prognosis of neuro- pathic pain in children. In this chapter we propose an algorithm for drug therapy for neuropathic pain in children b ased on best available evidence, our clinical experience, and the safety of these drugs in pediatric prac- tice. We suggest a step-wise approach incorporating fi rst-, second-, third -, and fourth-line therapies that should be tried methodically according to eff ectiveness and side eff ects. Neuropathic pain in children, if identifi ed and treated in a timely man ner as part of an interdisciplinary framework, using multimodal strategies can be managed e ff ectively. Introduction Neuropathic pain Th e International Association for the Study of Pain (IASP) d efi nes pain as \200\230an unpleasant sensory and emotional experience associated with act ual or potential tissue damage, or described in terms of such damage \200\231 (Merskey and Bogduk, 1994 , p. 210). Pain can be catego- rized in various ways; by (1) its temporal prof i le (i.e. acute, chronic, recurrent), (2) disease type (e.g. sickle cell pain, cancer pain ), or (3) pain mechanism (nociceptive, neuropathic). Neuropathic pain has recently been def i ned as \200\230pain arising as a direct consequence of a lesion or disease aff ecting th e somatosensory system \200\231 (Treede et al., 2008 ). Traditionally, pain type is broadly classifi ed into nociceptive and neuropathic. Nociceptive pain is initiated by normal acti vation of pain pathways by noxious stimuli, whereas neuropathic pain is associated with abn ormal activation of pain pathways involving both the peripheral and central nervous system. It is a complex, Clinical features Neuropathic pain is characterized by positive symptoms and nega- tive sym ptoms (sensory loss, numbness). Positive symptoms are either spontaneous pains that can be (1) continuous (e.g. burn- ing, throbbing) or intermittent (e.g. shooting, stabbing) or (2) evoked (e.g. hyperalgesia and allodynia). Hyperalgesia is defi ned as \200\230increased p ain from a stimulus that usually provokes pain \200\231 and allodynia as \200\230pain due to a stimulus that does not normally pro- voke pain \200\231 (Merskey and Bogduk, 1994 ). P ositive symptoms may be understood in terms of pathological changes in the peripheral nerve s, as a way in which the nervous system attempts to compen- sate for sensory loss. A high i ndex of suspicion is required to make a diagnosis of neuropathic pain, and an early clue is the poor response to simple analgesics such as acetaminophen and non-steroidal anti- infl ammatory drugs. Diagnosis is presently based upon the history comprising qualitative pain d escriptors and basic neurological SECTION 6 pharmacological interventions 496 Table 48.1 Causes of neuropathic pain in children examination. Common pain descriptors include burning, throb- bing, electrical, stabbing, sh ooting, pricking, and pins and needles. In addition to positive and negative symptoms, auto nomic dys- function can sometimes be seen (e.g. vasomotor, sudomotor, and trophic changes), particularly in the context of complex regional pain syndrome (CRPS) (see Clinch, Chapter 24; Vega-Avelaira and Beggs, Chapter 21; Walker, Chapter 7, this volume). Causes of neuropathic pain in children Speci \201 c examples Peripheral causes Postsurgical pain Pain after amputation Postoperative neuropathic pain Complex regional pain syndrome Type 1 (without nerve injury) Neuropathic pain: children versus adult Neuropathic pain in adults aff ects up to 8% of the population with sig- nifi cant impact on quality of life (Torrance et al., 2006 ); no epid emio- logical data exists regarding prevalence in children (Walker, 2008 ). Th is might in part be due to a lack of an agreed defi nition and diag- nostic criteria for pediatric neur opathic pain. In addition, compared to adults, the common causes of neuropathic pain in adu lts are rare in children. Diabetic neuropathy, trigeminal neuralgia, postherpetic neuralgia (PHN) (Hempenstall et al., 2005 ) and central post-stroke pain are conditions that seldom aff ect children, but are major causes of neuropathic pain in adults. Moreover, most of the adult literature from which pediatric neuropathic pain management is extrapolated is based on common adult aetiologies. Causes of neuropathic pain in children are heterogeneous (Wal co et al., 2010 ) ( Table 48.1 ). According to the latest defi nition of neuropathic pain f or adults (Treede et al., 2008 ) \200\224CRPS type 1 would not fi t into the classifi catio n as there is no evidence of direct nerve disease or injury. However, given its fre- quency and response to anti-neuropathic pain medications, CRPS type 1 in children will be conside red in this chapter. Type 2 (with nerve injury) Plexus injuries Congenital Traumatic Childhood cancer Tumor related Treatment related Autoimmune neuropathy Guillain \200\223Barr syndrome Hereditary neurodegenerative disorders Fabry disease Charcot \200\223Marie \200\223Tooth disease Toxic and metabolic neuropathies Lead, mercury, alcohol Infection (HIV) Mitochondrial disorders Erythromelalgia Primary Secondary Burns Hematological Sickle cell disease With clearer diagnostic instruments for pediatric neuropathic pain, and improved recognitio n and understanding, it is likely that the prevalence in children is more than we would lik e to think. Neuropathic pain is oft en part of a mixed picture alongside nocic- eptive pain , for example, vaso-occlusive pain in sickle cell disease (Niscola et al., 2009 ). Central causes Spinal cord injury Congenital Traumatic Brain Traumatic Tumor A paucity of randomized controlled trials (RCTs) in children, a lack of validated neuropath ic pain scales in children, uncertainty over defi nitions of neuropathic pain and diagnosis has led to a lack of data and over-reliance on extrapolation of adult studies, case report s and expert opinion (Level 4). For these reasons many of the drugs described are used off -license. a proven track record over time (Finnerup et al., 2005 ; Saarto and Wiff en, 2005 ). Th e m echanism of action of TCAs in neuropathic pain is separate from its mode of action in depre ssion (Max et al., 1987 ). Th is is refl ected in the lower doses required for neuro- pathi c pain. Th e multimodal mechanism of action comprises blockade of serotonin and noradrenali ne reuptake, interaction with sodium and calcium ion channels, as well as some antihis- tam ine and anticholinergic antagonism. Th e onset of pain relief is generally quicker (1 \200 \2232 weeks) than its antidepressant eff ect. Th e metabolism of TCAs is dependent upon cyt ochrome P450 (CYP) metabolism (CYP2D6) and susceptible to genetic poly- morphism. Th erefor e, in \200\230poor metabolizers \200\231 (up to 25% of the population) an increase in plas ma levels can be seen (Lotsch and Geisslinger, 2006 ). Drugs Th e drugs used in the symptomatic management of neuropathic pain in children are pre sented in a step-wise, practical manner, based on our clinical experience in pediatric prac tice, the implica- tions of committing children to certain therapies, and best quality evid ence (Levels 1 and 2). Th e evidence comes from adult studies as very few clinical trials h ave been conducted in children with neu- ropathic pain, and the literature is predominantly case series or iso- lated case reports. With inadequate or partial pain relief, additional drugs can be added in combination (with exceptions noted in the text \200\224see Table 48. 2 for detailed dosing and side eff ect information for fi rst-, second-, and third-line med ications). Th ere are no published RCTs in children. In adults, the NNT (number needed to treat) for T CAs in neuropathic pain is just over 2. Th is equates to roughly one in every two patients receiving a 50% reduction in pain with a TCA (Finnerup et al., 2005 , 2010 ). Studies looki ng at the effi cacy of TCAs in neuropathic pain have looked at adults with a range of \200 \230classic \200\231 neuropathic pain conditions such as PHN, painful neuropathies, traumat ic nerve injury, and trigeminal neuralgia (Saarto and Wiff en, 2005 ). First-line agents Tricyclic antidepressants Tricyclic antidepressants (TCAs) such as amitri ptyline and nortriptyline are commonly used to treat neuropathic pain, with CHAPTER 48 drugs for neuropathic pain 497 Table 48.2 Commonly used \201 rst-, second-, and third-line drugs; dosages and side e \200 ects Drug group Drug name Dose Side e \200 ects First line TCA Amitriptyline <50 kg: 0.1 mg/kg PO QHS, increase as tolerated every 4 \200\2236 days by 0.25 mg/kg increm ents until good analgesia occurs, limiting side e \200 ects or to a max of 0.5 \200\2232 m g/kg. Decrease by same rate if unhelpful. >50 kg: start at 10 mg, increase as tolerated by 10 mg increments every 4 \200\2236 days until a maximum of 75 mg Decrease by same rate if u nhelpful Sedation, dry mouth, blurred vision, urinary retention, tachycardia, constipation, prolonga tion of QTc interval, orthostatic hypotension Nortriptyline See above See above 2 - ligand Gabapentin <50kg: Day 1: 3 \200\2235 mg/kg PO QHS Day 2: 3 \200\2235 mg/kg BID Day 3: 3 \200\2235 mg/k g TID Escalate more slowly if required Maintenance 20 \200\22330 mg/kg/day TID Sedation, dizziness, caution in renal failure >50kg and adolescents: Day 1: 300 mg PO QHS Day 2: 300 mg BID Day 3: 300 mg TID Escalate do se as tolerated until good analgesia, limiting side e \200 ects or a maximum dose of 3600 mg/day. Additional bene \201 t may not be seen beyond 2400 mg/day Decrease by same rate if unhelpful. Pregabalin <50kg: 1 \200\2232 mg/kg/day PO BID. Titrate upwards weekly to e \200 ect >50kg: start at 75 mg PO BID. See above Titrate upwards weekly to e \200 ect, to a maximum dose of 600 mg BID Decrease by same rate if unhelpful. Topical Lidocaine 5% patch Each plaster or patch is applied over intact, dry and non-irritated skin for a period of 12 h on and 12 h o \200 . A maximum of 3 plasters is recommended at any one time Skin irritation Second line SSNRI Duloxetine >50 kg: starting dose 30 mg PO daily for 1 week before increasing to 60 mg Dry mouth, sedation, dizziness, loss of appetite, nausea, constipation Venlafaxine 1 \200\2232 mg/kg per day divided BID or TID increased weekly to a maximum of 225 mg/day See above, prolongation of QTc interval Topical Capsaicin Can be administered in the form of creams, lotions and patches in a range of 0.025 \200\223 8% by weight. 8% capsaicin patch involves a single 60 min application with up to 12 weeks o f e \200 ective subsequent analgesia in adults Initial local burning discomfort Th ird line Weak mu opioid receptor agonist Tramadol 1 \200\2233 mg/kg PO every 6 h Also available in extended-release 12 h formulation, and in combination with acetaminophen (Tramacet \204 ) Initial 0.2 \200\2230.5 mg/kg PO every 4 h PRN. After 2 weeks convert total daily dose to long-acting preparation and keep short-act ing preparation for breakthrough. No ceiling e \200 ect; dose escalation can proceed with careful titration, but at high daily doses (180 mg), e \203 cacy should be re-assessed and opioid switch or alternative options considered. An adequate trial should last between 4 \200\2236 weeks; and discontinued if there is no improvement in pain or function Nausea, vomiting, pruritus, constipation, hallucinations, sedation Opioid Morphine Nausea, vomiting, pruritus, constipation, hallucinations, sedation, dry mouth, respiratory depression, urinary retention, caution in hepatic and renal failure, tolerance, dependence, addiction, opioid-induced hyperalgesia, immunosuppression, endocrine dysfunction (infertil ity) Oxycodone Initial 0.1 \200\2230.2 mg/kg PO every 4 \200\2236 h as needed. After 2 weeks convert to lo ng- acting preparation, and keep short acting dose for breakthrough See above Cannabinoid Nabilone <50 kg: 10 mcg/kg PO BID >50 kg: 1 mg BID Sedation, dizziness, nausea, vomiting BID = twice daily; PO = orally; QHS = every night at bedtime; TID = three times daily. SECTION 6 pharmacological interventions 498 Topical lidocaine 5% plasters (patches) (see also Zempsky, Chapter 47, this volume) Th e pu rported mode of action is due to the local anesthetic action of lidocaine, which stabilizes neuronal membranes causing down- regulation of sodium channels (Rosielle, 2008 ). TCAs confer additional advantages in that they are inexpensive, have once-daily dosing, and can be helpful for patients in whom sleep is a problem. Side eff ects of TCAs are predomin antly anti- cholinergic and antihistaminic ( Table 48.2 ). Cardiac toxicity is a concern du e to the risk of prolongation of the QTc interval, and there have been case reports of sudd en death in children with arrhythmias (Varley, 2001 ). While there is currently no publishe d evidence-based guideline, it is our practice for every child to have a baseline electroca rdiogram (ECG) to rule out conduction abnor- malities before commencing a TCA. Adverse eff ects can be mini- mized by starting the TCA at a low dose at night (see Table 48.2 ). Most experience of TCAs in children is with nocturnal amitriptyl- ine since sedation is common a nd this can be capitalized upon to aid sleep. Nortriptyline is similar to amitriptyline but is a secondary amine so exhibits fewer side eff ects. Topical lidocaine 5% medicated plasters provide an alternative pharmacological non-systemic option in the treatment of neu- ropathic pain with good evidence in adults supporting its use in herpetic neuralgia (Binder et al., 2009 ) and focal peripheral neu- ropathy (Meier e t al., 2003 ). Lidocaine plasters are also eff ective in combination with other antineuropa thic analgesics and reduction in co-analgesic consumption was demonstrated in a retrospecti ve observational study in adults. Th eir effi cacy in children for neuro- pathic pain is su pported by case series (Nayak and Cunliff e, 2008 ). Systemic absorption of lidocaine is ve ry low so side eff ects are minimal and therefore advantageous for children. Additional ben - efi t comes from the patch providing a physical barrier to painful touch and a cool sensa tion from the patch itself. It is applied for 12 h followed by 12 h off over the focal pain ful area. Cost can be prohibitive in some countries, and it is not licensed for use in many countries, e.g. Canada. A less expensive 5% lidocaine gel is also available and is eff ect ive in PHN (Rowbotham et al., 1995 ). Desiprimine, another TCA, is no longer used in children fol- lowing several reports of sudd en death (Biederman et al., 1995 ). Should TCAs not be helpful, they should be weaned slowl y and not stopped abruptly. Children should be advised that vivid dreams may occur as the d rug is tapered. Alpha-2-delta ligands Th e alpha-2-delta ( 2 - ) ligands, sometimes referred to as ga bap- entinoids (gabapentin and pregabalin), are eff ective treatments in many forms of neur opathic pain (Backonja et al., 1998 ; Freynhagen et al., 2005 ; Rowbotham et al., 1998 ; Se rpell, 2002 ). Gabapentin binds to voltage-gated calcium channels at the 2 - subunit (Gee et al., 1996 ), as well as modulating gamma-aminobutyric acid (GABA) synthesis, releas e, and metabolism. Gabapentin and pre- gabalin are lipophilic analogs of GABA which interac t with the 2 - subunit common to all voltage-gated calcium channels, which explains t heir therapeutic eff ect in neuropathic pain. Th ere is evi- dence to suggest that these dr ugs selectively target those calcium channels that display abnormal activity (Li et al., 20 06 ), as well as evidence of 2 - upregulation with nerve injury (Boroujerdi et al., 2 011 ; Luo et al., 2002 ). Second-line agents Selective serotonin and noradrenaline reuptake inhibitors Balanced selec tive serotonin and noradrenaline reuptake inhibitors (SSNRIs) such as duloxetine and venlaf axine cause an increase in serotonin and noradrenaline, which work either presynaptically t o reduce nociceptive transmission or postsynaptically to increase endogenous spinal inhibit ion (Smith, 2006 ). SSNRIs are predomi- nantly used as antidepressants, although the analge sic mode of action is independent of the antidepressant eff ect. Duloxetine has proven effi cacy in painful diabetic polyneuropa- thy (Wernicke et al., 2006 ), depression, generalized anxiety, and fi bromyalgia (Hauser et al., 2009 ) in adults. Ho wever, the role of duloxetine in pediatric neuropathic pain is not clear. Venlafaxine also has well-documented effi cacy in painful diabetic polyneuropa- thy (Rowbotham et al., 2004 ), but not PHN in adults (Grothe et al., 2004 ). SSNRIs cannot currently be recommended as fi rst-line treat- ments in pediatrics, and should only be used as a second-line agent if t here is a contraindication to or failure of TCAs. According to the adult literature, select ive serotonin reuptake inhibitors (SSRIs) such as fl uoxetine and citalopram are poorly eff ective in neuropathic pain which may partially be explained by a predilection for facilita - tory serotonin (5-HT)-3 receptors by SSRIs rather than inhibitory 5-HT1 receptors (Mattia et al., 2002 ); however, more good quality trials are needed. As it stands, there is littl e to suggest that they are more eff ective than TCAs, so their use in neuropathic pain is c ur- rently not recommended. Gabapentin has been used extensively in pediatric practice (Golden et al., 2006 ). Th ough it has been superseded by other anticonvulsants in the treatment of epilepsy, its use in pe diatric neuropathic pain is now established. Th ere have been numer- ous case reports and s eries in pediatric neuropathic pain and CRPS (McGraw and Kosek, 1997 ; Rusy et al., 2001 ; Wheeler et al., 2000 ), as well as strong evidence from the adult literature to support its use. Gabapentin has also been successfully used in neurologically-impaired children with u nexplained (neuro) irritability, improving behavior and pain scores, which has con- tribute d to the familiarity of the drug in pediatrics (Haney et al., 2009 ; Hauer et al., 2007 ). Th ere is less experience with pregabalin than gabapentin in the treatment of pediatric neu ropathic pain. Pregabalin is eff ective in adults (Freynhagen et al., 2005 ), but there is no strong evidence that it is any better than gabapentin. Th ere is limited evidence to sup port its used in children (Vondracek et al., 2009 ). Pregabalin demonstrates a similar effi cacy and side eff ect profi le to gabapentin; however, it has the advantage of twice daily (BID) dosing. In adults, pregabalin has been licensed for generalized anxiety disorder, pa in- ful diabetic neuropathy, and been shown to be eff ective in fi bro- myalgia. Th e incre ased cost of pregabalin in some countries might make it prohibitive and favor gabapentin as a fi rst-line treatment. SSNRIs do not have anticholinergic eff ects so have an improved side eff ect profi le compa red to TCAs in adults. Duloxetine appears to be safe from an adverse cardiac conduction eff ect in adults (Wernicke et al., 2007 ). Venlafaxine has been linked with cardiac conductio n abnormalities and increases in blood pressure, so a baseline ECG and blood pressure monit oring is recommended (Rowbotham et al., 2004 ). SSNRIs should not be used in conjunc- tion with a TCA, given the risk of precipitating serotonin syndrome. When discontinuing SSNRIs t he dose should be tapered to avoid a withdrawal response. CHAPTER 48 drugs for neuropathic pain 499 Topical capsaicin cream (see also Zempsky, Chapter 47, this volume) Capsaicin is derived fr om chili pepper and has been used for its medicinal properties for over 150 years. Its mech anism of action was originally thought to be due to depletion of substance P at periph- era l nerve endings, though this does not fully explain its analgesic action. Capsaicin has a c omplex mechanism of action; it activates the transient receptor potential vanilloid 1 (TRPV 1) receptor which initially results in sensory neuronal depolarization causing burning and itching, but over time leads to localized \200\230defunctionalization \200\231 of cutaneou s nociceptors and analgesia (Anand and Bley, 2011 ). Opioids Th e term opioid refers to any compound synthetic or natural that activates the mu receptor; opiates specifi cally refer to drugs which derive directly from Papaver somniferu m . Central inhibitory sys- tems are the site of action of opioids which are agonists at in hibi- tory opioid receptors found in the brain, spinal cord, and periphery (see Hathway, Ch apter 44, this volume); the action of endogenous opioid peptides is much less than that see n with opioid drugs. Th e historical dogmatic view that opioids do not demonstrate effi cacy in neuropathic pain has long been refuted. Opioids have shown consistent analgesic effi cacy in treatment of n europathic pain (Eisenberg et al., 2006 ), especially supporting the use of morphine, oxyco done (and tramadol), and have considerably faster onset of action compared to other agents. Little evidence exists to favor the use of fentanyl, buprenorphine, or meperidine in neuro pathic pain ahead of other opioids, so will not be discussed further. We do not use codeine in children at our institutions due to unpredictable analgesic eff ects and signifi cant a dverse eff ects caused by its genetic polymorphism (Ciszkowski et al., 2009 ; Madadi and Ko ren, 2008 ). Problems surrounding the use of opioids relate not to their effi cacy but to b oth their short- and long-term side eff ects, especially when used in children ( Table 48.2 ). Long-term eff ects on sexual hormone production (Katz and Mazer, 2009 ) and immune func tion (Vallejo et al., 2004 ) have signifi cant implications for children. For this rea- son opioids are not considered fi rst- or second-line treatments for neuropathic pain in child ren, unless the pain is acutely severe or in neuropathic cancer pain. Before committing a c hild to opioid ther- apy, risk factors for abuse should be screened including previous subs tance abuse, history of psychiatric disease, and family history of drug abuse (National Opi oid Use Guideline Group (NOUGG), 2010 ; Zacny et al., 2003 ). Particular care is required w hen treating adolescents. We advocate using an opioid contract system when initiating thera py; we include a generic example of a contract for children and adolescents (see Figure 48. 1 ) based on NOUGG rec- ommendations (NOUGG, 2010 ). Low-concentration formulations of capsaicin are supported by modest evidence but require da ily application which may limit its use in children (Derry et al., 2009 ). Th e newer high concentration preparation 8% capsaicin patch (Qutenza \204 ) has been used with success i n adults with focal peripheral neuropathic pain (Backonja et al., 2008 ). It should be cons idered as a second-line topical inter- vention in children with focal neuropathic pain wher e lidocaine patches are either unavailable or have failed to show improvement in symptoms a ft er an adequate trial. Topical capsaicin is available in a variety of strengths and formu- lations to manage pain ( Table 48.2 ). Although it is generally safe in terms of toxicity, the initial burning dis comfort with applica- tion can result in problems with compliance, especially in children. Th ese problems usually diminish with time, but the drug can take up to 4 weeks to produce benefi t, requiring considerable patience in young patients. Th e newer stronger 8% capsaic in patch involves a single 60 min application with up to 12 weeks of eff ective subse- quen t analgesia. Pretreatment with a topical anesthetic agent (e.g. EMLA ) may help with com pliance, but its effi cacy in children is not yet known. Th ird-line agents Tramadol Tramadol has a unique dual mode of action whereby it inhibits t he reuptake of central serotonin and noradrenaline as well as being a weak mu receptor agon ist (fi ve to eight times weaker than mor- phine). Th is unique mechanism of action may exp lain its effi cacy in neuropathic pain. Morphine Morphine is the gold standard opioid and the one with which most practitioners tre ating children have most experience. It is a natural derivative of Papaver somniferum (opiu m poppy). Tramadol is eff ective in adults with PHN (Boureau et al., 2003 ) and painful diabetic neur opathy (Harati et al., 1998 ; Sindrup et al., 1999 ). A Cochrane review demonstrated its us efulness in neuro- pathic pain with a NNT of 3.5 (Hollingshead et al., 2006 ). Morphine is the prototypical mu receptor agonist, given orally its bioavailability is low ( 30%) and duration of action is 3 to 5 h, or 12 h if using a sustained-release preparation. It is metabolized in the liver to morphine 3-glucoronide (M3G) and morphine 6-glucuro- nide (M6G); the latter is a more potent analgesic than morphine itself. Both M3G and M6G are re nally excreted and morphine should be used with caution in patients with any degree of rena l insuffi ciency (see Strassels, Chapter 45, this volume). Tramadol is oft en seen as occupying a middle ground before starting a pure opioid agonist. Th e abuse potential of tramadol is thought to be less than that of opioids in adults (Cic ero et al., 2005 ). Caution is required when combining tramadol with a TCA, SSNRI, or SSRI, given the risk of precipitating serotonin syndrome. Th is may not be an issue when tramado l is combined with low- dose TCA (e.g. amitriptyline 10 mg). Tramadol is metabolized by the CYP enzyme system (CYP2D6) and is therefore suscepti- ble to genetic polymorphism and vari able pharmacokinetics (e.g. poor metabolizers). Such variation in response to tramadol may be reduced by the introduction of the new similar compound tapenta- dol, which neither requ ires metabolic activation nor is dependent on isomer-related pharmacodynamics. However, RCT s in neuro- pathic pain are lacking and as such the use of tapentadol in children cannot cu rrently be recommended. Morphine is eff ective in peripheral neuropathic pain and mixed neuropathic pain in adults (Eisenberg et al., 2006 ), with particular evidence in painful diabetic neuropathy, PHN, an d phantom limb pain (Dworkin et al., 2007 ). It has been shown to be as eff ective as gabap entin in one trial (Gilron et al., 2005 ). Morphine is a versatile drug which can be administered via a number of routes. For chronic neuropathic pain, the oral route is typically used. Both short-acting and long-acting oral preparations are available, in addition to injectable forms. If the decision is made to dis continue opioid therapy, it should be carefully tapered under medical supervision to avoid withdrawal. SECTION 6 pharmacological interventions 500 Patient/Family/Health Care Team Agreement for Opioid Th erapy History 1. Family history of substance use (alcohol, illicit drugs, prescription drugs) yes no If yes, please describe: ________________________________________________________________________ 2. Personal history of substance use (alcohol, illicit drugs, prescription drugs): yes no If yes, please describe: ________________________________________________________________________ 3. Age of \201 rst alcoholic drink? _______________________ 4. Have you ever passed out/blacked out? yes no 5. Psychiatric History: a. Self harm yes no b. Intentional overdose yes no c. Suicide attempts yes no d. Trauma/abuse yes no 6. Have you ever been diagnosed with: a. Depression yes no b. Anxiety yes no 7. Education History: a. Learning disability yes no b. ADD/ADHD yes no 8. History of sleep apnea a. Snoring yes no b. Sleep study positive yes no 9. Using sedating medications yes no If yes, please list: ________________________________________________ Side E \200 ects: Opioids can help pain but they can also have side e \200 ects. Th ese may include: Sleepiness, confusion, dizziness \200 Decreased breathing \200 Constipation \200 Naus ea and/or vomiting \200 Itchiness \200 Di \203 culty urinating I understand to let my team know if I experience any of these side e \200 ects. Goals of Opioid Th erapy: I understand that the goals of opioid therapy are: 1. Improve function (such as school attendance, physical activity, seeing friends). 2. Decr ease pain scores by at least 30% (eg. from 10/10 to 7/10) 3. Personal goal(s): ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ I further understand that if the above goals are not achieved within 4 weeks of starting th erapy this therapy will be considered unhelpful and adjusted or discontinued. Our team will work together with you to wean this medication gradually to avoid negative e \200 ects/wi thdrawal. Opioid therapy will be reviewed at least once a month and adjustments made as needed. Figure 48.1 An example of an opioid contract for children and adolescents. CHAPTER 48 drugs for neuropathic pain 501 Agreement: I understand that I am receiving opioid medication from Dr. _____________to treat my chroni c pain condition. I agree to the following: 1. I/my child will not seek opioid medications from another physician. Only Dr. _____________will prescribe opioids for me/my child. In exceptional circumstances (such as my doctor \200\231s absence) other anesthesiologists in the Sick Kids pain clinic may p rescribe. 2. I/my child will not take opioid medications in larger amounts or more frequently than is prescribed by Dr. _________________. 3. I/my child will not give or sell my medication to anyone else, including family members; nor will I/my child accept any opioid medication from anyone else. 4. I/my child will not use over-the-counter opioid medications such as 222 \200\231s and Ty lenol No. 1. 5. I understand that if my/my child \200\231s prescription runs out early for any reason (f or example, if I lose the medication, or take more than prescribed), Dr. _____________ may not prescribe extra medications for me; I will have to wait until the nex t prescription is due. 6. I/my child will not stop the opioid medication suddenly, as this may cause withdrawal. 7. I will \201 ll my/my child \200\231s prescriptions at one drugstore of my choice; drug store name: 8. I will store my medication in a secured location. 9. I agree to monitor for side e \200 ects of opioids (such as itchiness, nausea/vomiting, constipation, sleepiness/lethargy) and notify the chronic pain team if they are present. 10. I will not drive when starting or increasing the dose of opioids, and will discuss my a bility to drive with Dr._____________ prior to driving. 11. I/my child agree(s) to provide a urine sample upon request for opioid screening purpose s.