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Lamotrigine for Gabapentin Resistant Neuralgic PainDocument Transcript
LAMOTRIGINE FOR GABAPENTIN RESISTANT NEUROPATHIC PAINVíctor Whizar-Lugo, Teresa Figueroa-García, Roberto Cisneros-Corral, RobertoEstrada-Coronado, Claudia Solar-Labastida. Servicios Profesionales de Anestesiologíay Clínica de Dolor. Centro Medico del Noroeste. Tijuana BC, México firstname.lastname@example.orgINTRODUCTIONNEUROPATHIC PAIN is an intriguing entity that may have different underlyingmechanisms. Currently remains as the most difficult pain condition to study, to fullyunderstand, and to treat. There are four categories of drugs that can be named ¨firstchoice¨ of treatment for neuropathic pain: antidepressants, antiepileptics, opioids, andlocal anesthetics. Other drugs listed to treat this type of pain are NMDA receptorantagonists, baclofen, levodopa, clonidine, nonsteroidal anti-inflammatory drugs, andtopical local anesthetics and topical capsaicin. There is no magic drug to release thesuffer of those unfortunates patients with any form of neuropathic pain. Although someresearchers claimed well to excellent response to gabapentin plus antidepressants,there is a group of patients in whom the available medications give moderate analgesiato no pain improvement at all.Lamotrigine (figure 1), is a novel anticonvulsant that have been used as monotherapyand add-on drug in epilepsy, has also been reported to be useful in neuropathic pain (1,2). Its mode of action is through the inhibition of the release of glutamate, possibly bystabilizing the neural membrane through blocking activation of voltage-sensitive sodiumchannels.There is little information on lamotrigine efficacy to treat neuropathic pain statesrefractory to agents such as carbamazepine, gabapentin and antidepressants. Thepurpose of the present study was to examine the potential analgesic effect of crescendodoses of oral lamotrigine in patients with diverse forms of neuropathic pain non-responding to gabapentin.METHODTwenty-five consecutive Mexicans patients with severe neuropathic pain of severaletiologies, who were taking gabapentin from 1200 mg up to 2400 mg daily, were askedto participate in an approved protocol to receive crescendo doses of lamotrigine in orderto treat their pain complaint. The method was explained to each patient and theirrelative, and the written consent form signed. We used the ad-on method, keeping theinitial dose of gabapentin, and adding increasing dose of dispersible lamotrigine,starting at 25 mg twice a day. The dose was augmented 75 mg a day for further twoweeks, followed by weekly increments to 100, 150, 200, 300, 400, 500, and 600 mgdaily. Lamotrigine augmentations were based on pain response and side effects. Assoon as the patient report 50% of pain improvement, gabapentin was slowly reduced
until discontinued. If the patient pain response was poor, gabapentin was continued oreven increased, and well as lamotrigine. All cases were monitored weekly at the office, until good pain relieve was achieved(VAS 5 or less), followed by telephone calls/office visits every week until end of follow-up. Blood test were done monthly.RESULTSAll but two patients were able to finish the study. One patient dropped out due toprotocol violation and another because of no medical reasons. Adequate pain relief wasobtained in 17 patients. Six cases did not respond or had severe lamotrigine sideeffects. Twelve out of 23 patients were able to stop gabapentin, and 11 cases remainedon gabapentin + lamotrigine. In this last group only 5 patients had significant painimprovement. Initial visual analogue scale (i-VAS ) of the 23 patients was 9.1 ± 2.3versus final visual analogue scale (f-VAS) of 3.4 ± 2.0 (< 0.05). Table 1 showsdemographic data, and the results of the 23 patients who finished the protocol. They aregrouped by neuropathic pain categories to allow comparison between groups. Table 2shows the analgesic response by pain etiology groups. There were no alterations onblood analysisDaily lamotrigine median dose in all cases was 451 ± 75.5 mg (DNP 400 ± 53, PHN 425± 58, TGN 500 ± 44, PIHRNP 500 ± 28, and CRNP 425 ± 106). Those patients whowere able to cease gabapentin, were receiving daily lamotrigine median dose of 475 ±76 mg (range 300 – 550), compared to patients taking the mixture lamotrigine +gabapentin who received a median dose of lamotrigine of 500 ± 76 mg and mediandose of gabapentin 999 mg. There was no significative difference between lamotriginedoses on either group (p> 0.01).Table 1. Patients demographic data, pain etiology, anticonvulsivants dose, painimprovement and side effects Case Sex/Age Diagnosis i-GP f-GP f-LTG i-VAS vs Side effects dose dose dose f-VAS 1 F – 55 DNP 2400 None 350 7–3 No 2 F - 57 DNP 2400 600 350 8–2 No 3 M - 67 DNP 1600 None 400 10 – 2 Headache, dizziness 4 M – 70 DNP 1600 None 400 9–2 No 5 M – 72 DNP 900 None 500 8–2 Nausea 6 F – 76 DNP 1600 None 450 7–3 No 7 F – 76 DNP 1200 2000 400 9–7 Ataxia, vomiting 8 M – 56 PHN 2400 None 500 8–2 Moderate rash 9 M – 55 PHN 2000 None 375 9–2 No 10 F - 56 PHN 2000 2400 450 10 – 6 Severe rash, ataxia 11 F – 76 PHN 2400 900 400 9–2 No
12 F – 77 PHN 1200 None 300 7–2 No 13 M - 83 PHN 2000 2400 500 9–7 No 14 M – 62 TGN 2400 2400 500 10 – 8 Blurred vision, dizziness, vomit 15 F – 62 TGN 2000 None 500 10 – 3 No 16 M – 84 TGN 2400 2400 500 10 – 2 No 17 M – 73 TGN 2400 1200 600 10 – 4 No 18 M – 67 TGN 2400 1200 500 10 – 2 No 19 F - 45 CRNP 2400 1600 350 9–6 Severe nausea 20 F – 57 CRNP 1800 None 500 8–2 Nausea, rash 21 M – 34 PIHRP 2400 None 500 8–1 No 22 M – 40 PIHRP 2000 None 550 9–3 No 23 M - 42 PIHRP 2400 2400 500 8–6 NoDNP=Diabetic neuropathy, PHN=Postherpetic neuralgia, TGN=Trigeminal neuralgia, CRNP= Cancer relatedneuropathic pain, PIHRNP=Post inguinal hernia repair neuropathic pain.i-GP= Initial gabapentin dose, f-GP= Final gabapentin dose, f-LTG= Final lamotrigine dosei-VAS= Initial VSA, f-VAS= Final VSAIn blue are patient responders, In bold are patients who did not responseTable 2. Pain improvement by neuropathic pain etiology Pain Etiology n n Patients with pain n Patients without n cases able Lamotrigine Cases improvement Pain Improvement to stop GP median doseDiabetic 7 6 1 5 400 ± 53neuropathy (350 – 500)Post herpetic 6 4 2 3 425 ± 78neuralgia (300 – 500)Trigeminal 5 4 1 1 500 ± 44neuralgia (500 – 600)Post inguinal 3 2 1 2 500 ± 28hernia repair (500 – 550)neuropathic painCancer related 2 1 1 1 425 ± 106neuropathic pain (350 – 500)TOTAL 23 17 6 12 451 ± 75 (300 – 600)
Fig 2. Analgesia vs. lamotrigine dose 10 9.1 9.3 9.3 Mean Pain Intensity 8.9 8 7.6 6.4 (V.A.S.) 6 4.5 4 3.6 3.4 2 37.3 % pain reduction (p< 0.05) 0 0 25 75 100 200 300 400 500 600 Crescendo lamotrigine dose in mg/dayDiscusionLamotrigine, a new anticonvulsivant drug, have been approved to treat patients withepilepsy. In addition, it have been used in many others disorders like absence, atypicalabsence, myoclonic seizures, bipolar illness, and neuropathic pain. Intractable paindisorders like short-lasting, unilateral, neuralgiform headache attacks with conjunctivalinjection and tearing (SUNCT) have responded to lamotrigine 125 to 200 mg daily. Italso reduces peripheral neuropathy symptoms in HIV/AIDS patients, in central post-stroke pain, trigeminal neuralgia, phantom limb pain, stump hypersensitivity (1, 3, 4)Although lamotrigine plays an important role as an adjuvant medicine or maintherapeutic drug in patients with neuropathic pain, there is little information on its use forgabapentin resistant neuropathic pain.Even though our study is an open label trial using different neuropathic pain conditionsthat were not responding to gabapentin, the results are quite convincing that somepatients may have excellent to moderate analgesia using either lamotrigine alone orlamotrigine plus gabapentin. Daily median lamotrigine dose in all cases was 451 ± 75.5mg (DNP 400 ± 53, PHN 425 ± 58, TGN 500 ± 44, PIHRNP 500 ± 28, and CRNP 425 ±106). There was no statistical difference between those patients who were able tocease gabapentin (lamotrigine median dose 475 ± 76 mg), compared to patients takingthe mixture of lamotrigine + gabapentin (lamotrigine median dose 500 ± 76 mg). Painresponse in these two groups was similar (i-VAS 8.3, f-VAS 2.25 ± 0.6 compared to i-
VAS 9.2, f-VAS 4.7 ± 2.3). The overall pain response was statistically significant; i-VASwas 9.1 ± 2.3 versus f-VAS 3.4 ± 2.0 (p < 0.05).In the DNP group, one out of seven patients did no respond to gabapentin 1200 pluslamotrigine 400 mg due to severe lamotrigine side effects. The rest of this group hadexcellent analgesia and five were able to withdraw gabapentin. Luria and coworkers (2)reported 18 patients with painful diabetic neuropathy who responded to 200 mg up to400 mg of lamotrigine and recommended that even higher dose may lead to a betterresponse. Postherpetic neuralgia response was similar to DNP; two out of 6 patientdeveloped lamotrigine side effects with poor analgesia. Four cases in this groupdeveloped side effects, in one instance those effects were intense; a 55 years old menwho was taking 550 mg of lamotrigine reacted with severe rash that disappear afterreducing lamotrigine to 375 mg daily. In the TGN group there was a patient who did notresponded to 500 mg of lamotrigine. This patient was taking 2400 mg of gabapentin aday, and suffering frequent intense pain crisis. Lamotrigine crescendo dose up to 500mg a day resulted in no pain improvement but side effects that needed to withdrawlamotrigine. Four patients with TGN responded well; one responded to 500 mg oflamotrigine without taking gabapentin, and five patients had excellent analgesia usingthe mixture of gabapentin-lamotrigine. These results are opposed to animal’s researchsuggesting that gabapentin rather than lamotrigine may be a superior treatment fortrigeminal pain (5). Nevertheless, others researchers have found that 400 mg oflamotrigine relieve pain in most patients suffering essential TGN, with even better painresponse in those with TGN concomitant with multiple sclerosis (6). Zakrzewska andcoworkers (7) suggested that lamotrigine may be an effective drug for refractory Ticdoloreux, but highlighted the necessity to address concerns about chronic use asmonotherapy.The patients with neuropathic pain due to cancer and surgical nerve damage painresponse were variable. Neuropathic pain secondary to a nerve constriction is a well-known technique to study neuropathic pain in animals (8). Surgical nerve damageduring inguinal hernia restoration has been described in the literature, and has the samepathophysiology that animals nerve constriction pain. Surgical exploration aiming torelease the constricted nerve usually fails and, on the contrary, it intensifies pain. Collinsand cols. were able to fully reverse the pain behavior (paw-withdrawal threshold) of ratswith neuropathic pain produced by ligatures of the sciatic nerve, which were receiving30 mg/kg twice daily of oral lamotrigine. (8). In our study, two out of three patients hadexcellent analgesia using 500 mg of lamotrigine. In such cases, lamotrigine seems to bea better approach to relieve neuropathic pain.As it is showed on figure 2, the analgesic effect of lamotrigine requires time to allowslowly titration, in order to avoid severe reactions. It is obvious that adequate analgesia(50% or more from baseline level) was achieved after most patients reached 3000 t0400 mg a day. The usual analgesic maintenance dose was 300 mg to 500 given in twoor three divided doses. Some cases may require higher doses up to 600 mg daily. Atherapeutic plasma concentration range has not been established, so, a crescendodosing of lamotrigine should be based on therapeutic response vs. side effects.
The commonest side-effects whit lamotrigine include headache, nausea, dizziness,diplopia, ataxia, rash and tremor. Described uncommon sicknesses are blurred vision,somnolence, and vomiting. Very rare side effects include acute kidney or liver failure,drug-induced pseudolymphoma, neutropenia, thrombocitopenia, disseminatedintravascular coagulation. There are cases reports of serious rashes requiringhospitalization and discontinuation of treatment have been reported in association withlamotrigine. Tolerance to lamotrigine has been well documented in elderly people. Dailydose from 75 to 300 mg as monotherapy, and 25-700 mg for add-on therapy for amedian duration of 24.1 and 47.4 weeks respectively, produced lower incidence of drug-related adverse effects than carbamazepine or phenytoin. Patients on lamotriginereported incidences of drowsiness, rash and nonsignificant headache that was half ofthose experienced by patients taking carbamazepine monotherapy. Lamotriginesickness was common in this study (34.7%); four patients had severe side effects, andin other four cases those effects were minor. These drug reactions disappearedlowering the dose.ConclusionsSeveral authors are currently establishing the effectiveness and safeness of lamotrigineas a long-term therapeutic agent in neuropathic pain. Lamotrigine in doses ranging upto 600 mg/day has demonstrated efficacy in a variety of neuropathic pain statesrefractory to gabapentin. Those patients can be treated either by slowly switchinggabapentin to lamotrigine or by using both drugs. Careful, slow dose titration andmonitoring for adverse side effects are mandatory when using this agent.References 1. McCleane GJ. Lamotrigine in the management of neuropathic pain: a review of the literature. Clin J Pain 2000; 321-326. 2. Luria Y, Brecker C, Daud D, Ishay A, Eisenberg E. Lamotrigine in the treatment of painful diabetic neuropathy: A randomized, placebo-controlled study. Progress in Pain Research and Manage 2000:16;857-862. 3. D’Andrea G, Granella F, Ghiotto N, Nappi G. Lamotrigine in the treatment of SUNCT syndrome. Neurology 2001;57:1723-1725. 4. Attal N. Pharmacologic treatment of neuropathic pain. Acta neurol belg 2001;101:53-64. 5. Christensen D, Gautron M, Guilbaud model of trigeminal neuropathic pain. Pain 2001;93:147-153. 6. Lunardi G, Leandri M, Albano C, Cultrera S, Fracassi M, Rubino V, Favale E. Clinical effectiveness of lamotrigine and plasma levels in essential and symptomatic trigeminal neuralgia. Neurology 1997;48:1714-1717. 7. Zakrzewska JM, Chaudhry Z, Nurmikko TJ. Et als. Lamotrigine (lamictal) in refractory trigeminal neuralgia: results from a double-blind placebo controlled crossover trial. Pain 1997;73:223-230.
8. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensations like those seen in man. Pain 19988;33:87-107. 9. Collins SD, Clayton NM, Nobbs M, Bountra C. The effect of lamotrigine and morphine on neuropathic pain in the rat. Progress in Pain Research and Manage 2000:16;281-285.Figure 1. Lamotrigine