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. 12. I understand that if I break these conditions, Dr. _________________ may choose to ceas e to write opioid prescriptions for me. Patient \200\231s signature: Parent/Guardian signature: Physician/Advanced Practice Nurse signature: Figure 48.1 (Continued) Oxycodone Oxycodone is a semisynthetic opioid which is 1.5 to 2 times the potency of morphi ne. It exerts its analgesic eff ect through both mu and kappa agonism, which has been sugge sted for its effi cacy in neuropathic pain (Nielsen et al., 2007 ). It has a higher oral bi oavail- ability than morphine at 75% due to minimal fi rst-pass metabo- lism. It is demethy lated to noroxycodone and oxymorphone by hepatic CYP2D6, both of which are less active than oxycodone, and then conjugated to inactive glucoronides. Oxycodone has a com- parable eff ect to morphine in neuropathic pain in adults. It has an NNT of 2.6, which means that 1 in every 2.6 patients with neuro- pathic pain will get a 50% reduction in neuropathic pain wit h oxy- codone (Finnerup et al., 2005 ). It is available orally as immediate release (4 \200 \2236 h) and modifi ed release (OxyContin \204 12 h), in addi- tion to preparations combi ned with acetaminophen (Percocet \204 ) and naloxone (Targin \204 ). Generally speaking we do not support the use of combination analgesics, as the presence of acetaminophen can prevent the upward titration of the opioid analgesic. Parenteral preparations are also avai lable. Unfortunately, oxycodone is one of the most abused opioids in North America, and car ries a stigma which may limit its use amongst children (Sproule et al., 2009 ). When switch ing from another opioid, it is important to be cog- nizant of the phenomenon of incomplete cross-tolerance whereby a less than equianalgesic dose is required of the second opioid. We recommend converting to a dose of two-thirds of an equianalgesic dose of the second opioid with generous breakthrough analgesia until steady state is reached. Methadone Methadone is a synthetic opioid with multiple mechanisms of action making it uniq ue amongst opioids. Originally used for opi- oid addiction and dependence, methadone is now used for neu- ropathic pain, particularly for palliative cancer pain management in adults. It comes as a racemic mixture which consists of S- and D-methadone. It has more affi nity than morphine for delta recep- tors and less for mu receptors. It is also a N-methyl-D-aspa rtate (NMDA) receptor antagonist as well as noradrenaline and serot- onin reuptake inhibito r, which may explain its eff ectiveness in the treatment of neuropathic pain. Methadone is metabolized in the liver by the CYP enzyme family (CYP3A4, CYP1A2, and CYP2D6) to inactive metabolites. Individual pharmacogenetics may there- fore go some way to explain the variati on in response to the drug. It is excreted via the fecal route and does not accumulate in r enal failure (Layson-Wolf et al., 2002 ). In adults, methadone has signifi cantly better effi cacy than pla- cebo in mixed neuropathi c and nociceptive pain (Morley et al., 2003 ); however, whether it is better than other opi oids is not cer- tain. Th eoretically, the additional NMDA antagonism of metha- done sugges ts that neuropathic pain should respond better than other opioids but a Cochrane review has not demonstrated addi- tional effi cacy of methadone over other opioids in either cancer p ain or neuropathic pain within that population (Nicholson, 2007 ). More trials are needed a s anecdotally methadone is perceived to have additional benefi t than other opioids in reca lcitrant neuro- pathic pain. SECTION 6 pharmacological interventions 502 Methadone is usually taken orally once a day, has a high bio- availability (80%), and accum ulates with chronic use. Th e half-life is unpredictable: 12 to 18 h aft er a single oral d ose, and 10 to 75 h aft er chronic use. In general, the half-life of methadone increases wi th patient age. Methadone is approximately fi ve to ten times more potent than morphine; ho wever, conversion ratios depend on the pre-switch opioid dose. Th e general principle of co nversion is that the higher the opioid dose, the lower the conversion ratio, and when comme ncing methadone to \200\230start low and go slow \200\231. Care should be taken when combi ning methadone with a TCA, SSNRI, or SSRI due to its eff ect on serotonin and noradrenaline reuptake. SSRIs also decrease methadone metabolism and increase plasma levels. Carbamazepi ne and phenytoin interact with methadone by lowering plasma levels by up to 50%. High doses (>200 mg) can result in torsades de pointes, and methadone should only be pre- scribed by an experienced specialist physician. well tolerated. Ketamine is usually presented as a racemic mix- ture of two enantiomers: S( +)-ketamine and R( \210\222)-ketamine. Th e S(+) enantiomer alone formulation is available in some countries. Ketamine mediates analgesia primarily through non-competitive antagonism at the NMDA receptor at the spinal cord and within the CNS. Reduction in presynaptic relea se of glutamate may also explain some of the analgesic eff ect. Th e S(+) enantiomer has th ree to four times greater affi nity for the NMDA receptor and therefore provides greater an algesia than the R( \210\222) enantiomer at equipotent doses. Ketamine also has a weak eff ect on opioid receptors, not antagonized by naloxone, as well as antagonistic eff ects on m us- carinic, nicotinic, and monoaminergic receptors. It also exhibits local anesthetic prop erties possibly by blocking neuronal sodium ion channels (Bergman, 1999 ). Ketamine is metabolized in the liver to norketamine which has a lower anesthetic potency bu t greater analgesic potency than ketamine. Oral ketamine therefore is a more potent analges ic than parenteral. Norketamine is then hydroxylated and conjugated by CYP enzyme system in the liver before being excreted via the kidneys. Cannabinoids Cannabinoids represent a relatively new pharmacological option as part of a mu ltimodal treatment plan for the management of neu- ropathic pain (Lynch and Campbell, 2011 ). With the increasing knowledge of the endocannabinoid system and compelling preclini- cal work indicating that cannabinoid agonists are analgesic there is increasing attention on t heir potential role in the management of neuropathic pain. Th ere are no studies in childre n, but a systematic review of randomized trials of cannabinoids for the treatment of adults with chronic non-cancer pain concluded that cannabinoids are safe and modestly eff ective in neuropathic pain (Lynch and Campbell, 2011 ). Th ere were no serious adverse eff ects re ported. Adverse eff ects that were reported were generally well tolerated, mild to moderate in severity and led to withdrawal from the studies in only a few cases. Cannabinoids studi ed included smoked canna- bis, oromucosal extracts of cannabis-based medicine, nabilone, dr o- nabinol, and a novel tetrahydrocannabinol (THC) analog. Given that safety and eff ective ness have not been established in patients younger than 18 years of age, caution is recomme nded in prescrib- ing cannabinoids to children predominantly because of psychoac- tive eff ects. In practice we recommend the use of nabilone titrated from a very low dose at night ( 0.005 mg/kg) \200\224and increased to 0.025 mg/kg BID. Nabilone can be compounded \200\224w e have used it in very young children through to adolescents. Empirically about one-third o f the children obtain some benefi t, one-third obtain benefi t but limited by side eff ects , and one-third do not obtain benefi t. Systematic reviews of intravenous (IV) ketamine as an adjuvant to opioid analgesia have fai led to show a clear benefi t in acute peri- operative pain (Bell et al., 2005 ; Elia and Tr amer, 2005 ). IV ketamine infusions may relieve neuropathic pains of diff erent origins, in clud- ing PHN (Sang, 2000 ), peripheral neuropathy, and refractory neu- ropathic pain syndr omes, including CRPS in adults (Schwartzman et al., 2009 ; Sigtermans et al., 2009 ). Topic al ketamine (see also Zempsky, Chapter 47, this volume) can be eff ective for allodynia in CRPS type 1 (Finch et al., 2009 ). Studies in children with neuro- pathic pain are limited to case reports (Takahashi et al., 1998 ), with successful use in opioid-refractory cancer pain (Klepstad et al., 2001 ). Ketamine is not currently recommended as a frontline treat- ment for neuropathic pain in children as the racemic preparation is hampered by problematic side eff ects and more trials are needed. Dosage (for analgesia): 0.1 to 0.5 mg/kg PO every 6 h, can be titrated upwards by 0.1 mg/kg per dose. For weight greater than 50 kg the usual oral dose range is 10 to 100 mg every 6 h, and by IV infusion is: 0 to 0.25 mg/kg/h. Intravenous lidocaine infusion Lidocaine works by blocking conduction of sodium ion channel s to reduce spontaneous action potentials in nerve cells. Th e analge- sic properties of IV lidocaine outlast its pharmacokinetic predicted half-life, and analgesia can last for many weeks aft er a single infu- sion (Carroll, 2007 ). Fourth-line agents Ketamine Ketamine, an anesthetic agent and analgesic, is a phencyclidine derivative that can be administered orally, parenterally, topically, intranasally and via the intrathecal or epidural route for neuro- pathic pain. As an analgesic, ketamine has bee n used extensively in cancer pain and refractory neuropathic pain, usually as an adjuvant w ith opioids. Side eff ects include unpleasant psychomi- metic eff ects, confusion, dysphori a, hallucinations, tachycardia, and hypertension. Th ese adverse eff ects are usually dose depend- ent and less pronounced in the lower doses required for analge- sia. Th ere is cons iderable experience with the use of ketamine in children, and the psychomimetic eff ects ap pear to be reasonably IV lidocaine has been used with success to treat not only neu- ropathic pain in adults but also CRPS types 1 and 2, cancer pain, and fi bromyalgia (McCleane, 2007 ). An infusion shou ld be admin- istered in a hospital setting with ECG monitoring, but the treat- ment is gene rally safe and well tolerated. Th ere is no consensus on infusion dosages or duration but t he pharmacokinetic profi les of lidocaine in adults and children are similar; an infusion r ate of 1 mg/kg/h has been used with success in children (Wallace et al., 1997 ). IV lidocai ne represents a useful option in the treatment of neuropathic pain in cases refractory to c onventional therapy or cases limited by side eff ects of oral medications. While plasma lev - els of lidocaine can be measured (levels between 2 and 5 mcg/ml are thought to be therape utic); we are not aware that this is done CHAPTER 48 drugs for neuropathic pain 503 in routine clinical practice. Doses should be adjusted in cases of hepatic and renal insuff i ciency to avoid toxicity. the combination provided better analgesia than either drug alone. Combinations of oxycodone and gabapentin have also demon- strated combined improved effi cacy at lower dosages than either drug alone (Hanna et al., 2008 ), however a trial with oxycodone and pregabalin show ed no enhanced dual eff ect (Zin et al., 2010 ). If based solely on effi cacy then opioids would deserve to be second- line treatments for neuropathic pain, however the choice of med i- cation needs to be considered also in terms of potential risks and tolerability, especia lly in the pediatric population. Th e relatively improved side eff ect profi le and long-te rm superior health-related quality of life indices of 2 - ligands as compared to opio ids makes them the better fi rst-line choice. Mexiletine Mexiletine is an oral type 1b antiarrhythmic agent that is analo- gous to lidoca ine in its mechanism of action. It also acts by block- ing sodium channels and has been sho wn to be of some benefi t in adults with painful diabetic neuropathy, though not much super ior to placebo (Duby et al., 2004 ). Its oral preparation is an advantage as opposed to IV lidocaine, however its use in children is limited (Wallace et al., 2000 ) although there ar e pediatric case reports of its effi cacy in erythromelalgia (Jang et al., 2004 ; Nathan et al., 2005 ). Key recommendations Th e algorithm in Figure 48.2 is based upon the current literature and our clinical experience in treating neuropathic pain cognizant of risks and long-term eff e cts in children, and extrapolating the best quality evidence from controlled trials in adul ts with neuro- pathic pain. Th is algorithm should be followed in the context of an interdi sciplinary approach also incorporating physical and psycho- logical strategies. Other anticonvulsants Older anticonvulsant drugs such as carbamazepine and phenytoin, typic ally used in adults with trigeminal neuralgia, have been super- seded by newer drugs which are generally safer more eff ective (e.g. gabapentin). In addition the need for monitoring of liver function with these drugs makes them less appealing in children (Dworkin et al., 2 007 ). Th e evidence in adults for the use of lamotrigine, oxcarbazepine, valproate, topira mate, lacosamide, and levetira- cetam in neuropathic pain has not been convincing, so their place in pediatric neuropathic pain management is uncertain at this time and should only b e considered in recalcitrant cases (Finnerup et al., 2010 ). Aft er a reasonable trial of 4 to 6 weeks of the selected fi rst-line medication, and only partial analgesia (NRS \211 4/10) or troublesome side eff ects, an additional co-analgesi c should be commenced. In acute severe neuropathic pain scenarios (e.g. Guillain \200\223Ba rr syn- drome or cancer pain), one may escalate more quickly and have a lower threshold for combination strategies Miscellaneous Other oral NMDA receptor antagonists such as dextromethorphan, memantine, and riluzide have showed only minor or no improve- ment in neuropathic pain in adults (Finneru p et al., 2005 , 2007 ), with little experience in children. Magnesium is also an NMDA rece ptor antagonist that has been shown to be of benefi t in neu- ropathic pain in animal model s (Rondon et al., 2010 ). Its obvi- ous benefi t over ketamine is the improved side eff ect profi le, but the drug needs to be given as an IV infusion and further work is required be fore its role can be fully clarifi ed. Th ird-line medications can be added if there is some pre-existing benefi t of fi rst or second line, or alone de novo if not. Th e decision to use fourth-line medications with limited evi- dence, such as ketamine or I V lidocaine, should only be made at specialist pediatric centers Conclusion Neuropathic pain in children can be debilitating with signifi cant impact on moo d, sleep, and function, whilst posing a diffi cult chal- lenge to health care practitioners . Th e challenge is made more prob- lematic with an over reliance on evidence extrapolated from studies in adults, whose neuropathic pain conditions are uncommon in children and may be quite separate phenomena. Clearly, specifi c screening and diagnostic tools for neuropat hic pain in children are required, in addition to good quality multicentre drug trials. In our experience, the early identifi cation and treatment of neuropathic pain in children can oft en result in eff ective sustained reversal of symptoms in many cases, likely due in pa rt to the plasticity of the developing nervous system. Botulinum toxin A has been used extensively in the treatment of spasticity in children with cerebral palsy (Lukban et al., 2009 ), and there is emerging data that it may also be eff ective in neuropathic pain (Francisco et al., 2012 ). Trials have not shown consistent ben- efi t yet (Dworkin et al., 2010 ), but familiarity with the drug in chil- dren suggests it might have a role. Combination strategies Frequently a single fi rst-line drug is insuffi cient in alleviating pain to an acceptable level, or side eff ects become limiting at the higher dose range. In these situations adding in a second agent can provide an additive or synergistic eff ect t o improve analgesia and reduce side eff ects. Th e combination of nortriptyline and gabapen tin has been demonstrated in an RCT to be superior in neuropathic pain than either drug alo ne (Gilron et al., 2009 ). Many RCTs that provide good evidence for combination strategies in adults with neuropathic pain involve opioids as the co-analgesic. Th e combi- nation of an 2 - ligand with an opioid has been studied for pain- ful diabetic neuropathy and P HN in adults (Gilron et al., 2005 ). In fact, morphine was slightly more eff ective than ga bapentin but Future directions for pharmacological management will include pharmacogenomics, with a view to tailoring specifi c drug regimens for individual patients, and stem cell research which also carries promise (Braz et al., 2012 ). However, it must be reiterated that the pharmac ological management alone of neuropathic pain is very unlikely to fully alleviate symptoms. Drugs must form part of an interdisciplinary approach incorporating physical, psychologica l, and occasionally interventional techniques to achieve successful outcomes in children wi th neuropathic pain. SECTION 6 pharmacological interventions 504 Diagnose NeP Pain: \200 History \200 Physical exam \200 Special tests \200 Focal sy mptoms only?* Case example A 13-year-old girl diagnosed with Charcot \200\223Marie \200\223Tooth dis- ease (CMT) type 1A (confi rmed by genetic testing \200\224 PMP22 gene duplication) was referred to the chro nic pain clinic with a 2-month history of neuropathic pain in the hands and feet. CMT disea se is a hereditary polyneuropathy condition presenting with distal weakness and muscular at rophy (myopathy). It is a slowly progressing, demyelinating disease of peripheral nerves, a nd is also known as hereditary motor and sensory neuropathy (HMSN) of which there are sever al subtypes. Clinical features include loss of refl exes, pes cavus foot deformity, and ham mer- toes. It is an increasingly recognized cause of neuropathic pain in children. Th e pai n was described as a constant burning, tingling and itchy \200\230deep \200\231 sensation. Th ere was intermittent stabbing pain in her toes. Th ere were no autonomic symptoms such as changes in color, sweating, temperature or hair or nail growth, suggestive of CRPS. She rated the pain intensity as 7/10 on the numeric pain scale (NRS) at the clinic appointment. Th e range of pain inten- sity scores varied between 6 to 10/10. Th e average pain score w as 7/10. She reported that the pain needed to be 4/10 or less to fi nd it manageable. When asked to score how unpleasant she found her pain she rated it as 8/10. Her sleep was distur bed by pain; taking at least 1 h to fall asleep, and waking her two to three times per nigh t due to allodynia from the bed sheets. She was frustrated rather than depressed; she repor ted lethargy, reduced energy and diffi culty concentrating at school. She was missing 1 day of school per week because of pain. Her physical activities were signifi cantly aff ected in that she had stopped participating in gym and swimming. Th ere was some evidence of fear avoid- ance to her pain behaviors on a background of mild anxiety. Previous pharmacologica l interventions had not been helpful at either reducing pain or improving function; these i ncluded acetaminophen and ibuprofen, and a topical compound of keta- mine, ketoprofen, and lidocaine. Neither physical nor psycho- logical interventions had been tried. She lived wit h her parents and two younger brothers, all of whom were healthy. Physical examination reve aled an age-appropriate, somewhat shy 13-year-old girl in no acute distress (150 cm tall, w eight 48 kg). Pain was outlined on the palmer aspect of both hands and feet with reduced se nsation. Allodynia and hyperalgesia were present over the toes. Wrist and ankle deep tendon refl exes were reduced. Neuropathic pain secondary to CMT disease aff ecting the hands and feet was diagnosed; with signifi cant pain related disability. Education was provided rega rding the nature of neuropathic pain and a pain management plan comprising pharmacologi- ca l, physical, and psychological strategies was developed in col- laboration with the patient and her parents. She was started on gabapentin 100 mg PO once daily to be slowly increased in a step-wise manner to 300 mg PO three times daily as tolerated. Poor sleep ? YES NO 1st line 1st line 2- ligand Tricyclic Antidepressants YES YES E \200ective ? E \200ective ? NO NO Tricyclic Antidepressants 2- ligand NO YES NO YES 2nd line E \200ective ? E \200ective ? SSNRI Follow YES E \200ective ? NO Tramadol Opioid Cannabinoid YES E \200ective ? NO Ketamine IV lidocaine YES E \200ective ? Follow NO Re-assess for focal neuropathic pain, topical agents could be used either along with or in lieu of sy stemic neuropathic medication. In this case 5% lidocaine patch would be the \201rst line followed by capsaicin. Figure 48.2 Drug treatment for neuropathic pain (NeP); an algorithm. CHAPTER 48 drugs for neuropathic pain 505 Braz , J. M. , Sharif-Naeini , R. , Vogt , D. , Kriegstein , A. , Alvarez-Buylla , A. , Rub enstein , J. L. , et al . ( 2012 ). Forebrain GABAergic neuron precursors integrate into ad ult spinal cord and reduce injury-induced neuropathic pain . Neuron , 74 (4), 663 \200\223 675. Physical strategies comprised education around promoting nor- mal function, desensitization , and a graded exercise program. A psychological evaluation was scheduled to evaluate to wh at extent cognitive and emotional factors were contributing to pain and pain related disabi lity; with a view to teaching some relaxa- tion and distraction strategies. Th e patient wa s reviewed in the pain clinic 6 weeks later. Th e gabapentin had been increased to 100 mg P O three times daily resulting in excessive daytime somnolence, with marginal ben- efi t in pain relief. Furthermore, she had diffi culty swallowing the pills given their relatively l arge size. Given that pain was worse at night with subsequent sleep disturbance, she was sw itched to amitriptyline 10 mg PO every night at bedtime aft er an ECG was reported as norma l. She was advised that the dose could be doubled if well-tolerated and additional analgesi a was required. Th e next time she was seen in clinic, her pain was better control- led, wi th an average pain intensity score of 1/10 using the NRS. She had stabilized on a 20 mg dos e of amitriptyline, which was well tolerated. She also found physical strategies (ice packs , mas- sage) and psychological strategies (distraction, relaxation) help- ful. She reported improved sleep, mood (less frustration), and function (participating in school, hobbies, a nd seeing friends). Carroll , I. ( 2007 ). Intravenous lidocaine for neuropathic pain: diagnostic utility and t herapeutic effi cacy . Curr Pain Headache Rep , 11 , 20 \200\22324. Cicero , T. J. , Incia rdi , J. A. , Adams , E. H. , Geller , A. , Senay , E. C. , Woody , G. 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