Drug Use Evaluation: Newer Antiepileptic Drugs Executive Summary

Drug Use Research & Management Program Oregon State University, 3303 SW Bond Av CH12C, Portland, Oregon 97239 4501 Phone 503 494 9954 Fax 503 494 1082 Drug Use Evaluation: Newer Antiepileptic Drugs Executive Summary Background Newer Antiepileptic Drugs (AEDs) are all approved for the treatment of various seizure disorders, however their use for other mental health and pain conditions has increased, sometimes without strong evidence of effectiveness. The clinical evidence currently does not support the use of the newer AEDs, except lamotrigine which is not covered in this report, for the treatment of bipolar disorder The majority of clinical evidence does not support the use of topiramate or oxcarbazepine for neuropathic pain. No data suggests pregabalin is superior to gabapentin for neuropathic pain. Utilization Analysis The Oregon FFS program spends nearly $1 million quarterly on drugs in the AED class While the use of pregabalin has increased dramatically in the last 2 years, topiramate, levetiracetam, oxcarbazepine, and gabapentin represent the cost centers in this class In 2006, 3367 unique patients used an AED and 50% used at least one drug for at least 90 continuous days (chronic users) Users of gabapentin, carbamazepine, and topiramate made up 2/3 of all chronic AED users More than 1 in 10 (12%) chronic users were documented as receiving two AEDs concurrently Of these patients a small number had documented use of concurrent AEDs that would be considered irrational (pregabalin/gabapentin & oxcarbaepine/carbamazepine) because the drugs are structurally related to each other Diagnostic data suggest that almost 30% were being treated for seizure disorder. Patients using more than one AED were twice as likely to have documented seizure disorder. Roughly 15% of subjects had a diagnosis of neuropathic pain and 6 7% had a diagnosis of bipolar disorder. 70 80% of chronic users of levetiracetam and zonisamide and 50% of patients using oxcarbazepine were documented to have a seizure disorder Approximately 40% of subjects using topiramate did not have a diagnosis documented Prescriptions written by psychiatry or neurology specialists varied between drugs, with gabapentin having the lowest proportion of specialty prescribing and zonisamide having the largest proportion. Recommendations The College of Pharmacy to develop policy recommendations based on DUR board deliberations

Background In addition to their established uses in the treatment of various types of seizure disorders, many of the antiepileptic drugs (AEDs) have been tried for the treatment of bipolar disorder and neuropathic pain. With the exception of lamotrigine, the use of some of the newer AEDs for these indications is often off label and is not well supported by evidence based findings. This literature review will focus on the appropriate use of gabapentin (Neurontin, generics), oxcarbazepine (Trileptal), pregabalin (Lyrica), and topiramate (Topamax) for indications other than seizure disorders. Of the four AEDs, only pregabalin and gabapentin have FDA approved indications for the treatment of neuropathic pain disorders (topiramate is indicated for the treatment of migraine). None of the AEDs are indicated for the treatment of bipolar affective disorder. (Table 1) Table 1. FDA Approved Indications for Certain AEDs FDA Approved Indications Bipolar Affective Pain Disorder Antiepileptic Mania Depression Migraine TGN PHN DPN Drug Gabapentin X Pregabalin X X Topiramate X Oxcarbazepine The Oregon Drug Effectiveness Review Project recently coordinated a systematic review of AED for treatment of bipolar mood disorder, neuropathic pain, and fibromyalgia. 1 The findings of this review are summarized below. Gabapentin (Neurontin, generics) Gabapentin is not indicated nor is it recommended for the treatment of bipolar affective disorder. 2 There is, however, a substantial body of evidence that supports its use in neuropathic pain. In addition, its use is recommended for the treatment of reflex sympathetic dystrophy, complex regional pain syndrome, painful diabetic neuropathy and post herpetic neuralgia by a number of different treatment guidelines. 3,4,5 Most placebo controlled trials of gabapentin in neuropathic pain show evidence of some beneficial effects across different types of neuropathic pain in terms of improvement in symptom rating scores, responder rates, speed of response, duration of response, sleep interference, and certain domains of quality of life questionnaires. 1 Currently there is no evidence to suggest that gabapentin is superior to amitriptyline or carbamazepine. It is, however, an effective alternative. Its number needed to treat (NNT) for any neuropathic pain syndrome is 3.7. 1 Summary: Gabapentin is not recommended for the treatment of bipolar affective disorder. Its use in various neuropathic pain syndromes is well supported by the literature and several treatment guidelines. Gabapentin is now available as a generic. Pregabalin (Lyrica) Pregabalin is structurally similar to its predecessor gabapentin. There is no evidence available that supports its use in bipolar affective disorder. Available placebo controlled trials of pregabalin in neuropathic pain show evidence of some beneficial effects across different types of neuropathic pain in terms of improvement in symptom rating scores, responder rates, speed of response, duration of response, sleep interference, and certain domains of quality of life questionnaires. 1 Current evidence does not demonstrate clinically significant differences between gabapentin and pregabalin in terms of analgesic efficacy or side effects. 1 Although, some data suggests that pregabalin is more likely to cause adverse effects at higher doses compared to gabapentin. 1

Summary: There is no evidence to support the use of pregabalin in bipolar disorder. Evidence suggests that pregabalin is effective for the treatment of neuropathic pain. There is no data that supports its superiority over gabapentin. Topiramate (Topamax) Topiramate is a newer AED indicated for both seizure disorders and the prophylaxis of migraine headaches. Currently available literature demonstrates mixed results in terms of its efficacy in the treatment of pain syndromes. In the majority of studies, topiramate failed to show treatment benefit compared to placebo. 1 Its use in psychiatry has increased both as a mood stabilizer and as a treatment adjunct for the promotion of weight loss. Because weight loss is not a covered diagnosis under the Oregon Health Plan, this review will focus on the evidence supporting its use as a mood stabilizer. Four randomized placebo controlled studies (two with active comparators) examining the use of topiramte as monotherapy for the management of acute mania were available for review after inclusion period for the DERP report. Each of these studies failed to demonstrate topiramate s superiority over placebo. In the two trials using lithium as an active comparator, lithium was statistically significantly superior to topiramate. (Table 2) Table 2. Studies examining topiramate monotherapy for acute mania 6 Study Population Outcome Measure Results PDMD 004 3 week RCT, vs. PCB, vs. Li YMRS (mean change from baseline) PDMD 005 3 week RCT, vs. PCB PCB=111 TOP=107 (200mg) TOP=107 (400mg) Li=113 PCB=98 TOP=107 (400mg) TOP=98 (600mg) YMRS (mean change from baseline) PCB = 7.7, TOP 200 = 5.8 (p=0.223) PCB = 7.7, TOP 400 = 6.2 (p=0.324) TOP 200 = 5.8, Li = 12.9 (p<0.001) TOP 400 = 6.2, Li = 12.9 (p<0.001) PCB = 7.7, Li = 12.9 (p=0.001) PCB = 7.7, TOP 400 = 8.2 (p=0.729) PCB = 7.7, TOP 600 = 7.9 (p=0.808) PDMD 006 3 week RCT, vs. PCB PCB=106 TOP=105 (400mg) YMRS (mean change from baseline) PCB = 6.4, TOP 400 = 5.1 (p=0.263) PDMD 008 3 week RCT, vs. PCB, vs. Li PCB=112 TOP=115 (400mg) Li=114 YMRS (mean change from baseline) PCB = 8.4, TOP 400 = 8.2 (p=0.976) TOP 400 = 8.2, Li = 13.8 (p<0.001) PCB = 8.4, Li = 13.8 (p<0.001) RCT = Randomized Controlled Trial PCB = Placebo, TOP=Topiramate, Li = Lithium YMRS=Young Mania Rating Scale In another randomized, placebo controlled study reviewing the use of topiramate as an adjunct to valproate or lithium therapy, the authors similarly found that topiramate was no different than placebo in the reduction of the Young Mania Rating Scale (YMRS). 7 Summary: The majority of evidence has failed to demonstrate topiramate s superiority over placebo for the treatment of neuropathic pain. There is no evidence to suggest that topiramate is effective when used alone or in combination with a mood stabilizer for the treatment of Bipolar I Disorder. Oxcarbazepine (Trileptal) Oxcarbazepine is chemically related to its predecessor carbamazepine. Carbamazepine is indicated for the treatment of bipolar affective disorder and certain neuropathic pain syndromes. Currently available

literature does not support the use of oxcarbazepine in the treatment of neuropathic pain. The following table presents data from studies available for review after the DERP report. Table 3. Studies evaluating the efficacy of oxcarbazepine in neuropathic pain. Study Population Outcome Measure Results Beydoun et al 8 16 week RCT study vs. PCB Grosskopf et al. 9 16 week RCT study vs. PCB OXC 600mg = 83 OXC 1200mg = 87 OXC 1800mg = 88 PCB = 89 OXC 1200mg = 71 PCB = 70 Primary = VAS Others = GATE, onset of therapeutic effect, durability of treatment effect, sleep disturbances, QOL Primary = VAS Others = GATE, onset of therapeutic effect, durability of treatment effect, sleep disturbances, QOL VAS = NSS improvement over PCB for ITT population. Only 1800mg group showed improvement over PCB in completer analysis in mean VAS score. Other measures = NSS differences compared to PCB VAS = NSS improvement over PCB Other measures = NSS differences compared to PCB RCT = Randomized Controlled Trial PCB = Placebo, OXC = oxcarbazepine VAS = Visual Analog Pain Scale, GATE = Global Assessment of Therapeutic Effect, QOL = Quality of Life NSS = no statistically significant, ITT = Intent to treat Very little data exists that evaluates the use of oxcarbazepine in bipolar affective disorder. The only study with a meaningful number of enrolled patients (n=116) found that oxcarbazepine was not statistically significantly superior to placebo in the treatment of manic symptoms in children and adolescents with bipolar disorder. 10 A systematic review of the available studies determined that additional double blind randomized studies with adequate follow up periods are necessary to determine its place in therapy. 11 Although the data around the use of oxcarbazepine for bipolar patients is limited, it has been clinically viewed as an acceptable alternative to carbamazepine. 12 Summary: Available evidence does not support the use of oxcarbazepine in neuropathic pain syndromes. Also, its place in the treatment of bipolar disorder has not been defined. Methods Trend analysis An AED was defined as topiramate, levetiracetam, oxcarbazepine, gabapentin, pregabalin, carbamazepine, zonisamide, or tiagabine. Using pharmacy claims from between 1/1/05 and 3/21/07, trends in AED costs and utilization were quantified as a monthly per member per month (PMPM) value. Costs were defined as ingredient cost (paid amount + copay amount + other insurance paid dispensing fee) and utilization was defined as the number of prescriptions dispensed. Dual Medicare/Medicaid enrollees were excluded from trend analyses. Finally, total and average costs for 30 days were quantified during the first quarter of 2007 for all enrolled patients. AED User Analysis For calendar year 2006, AED users were identified. For each AED user those with at least 90 consecutive days of therapy (chronic use cohort) were identified using the time interval between the first fill and final fill plus the final fill day supply. In addition, the sum of each patient s day supply for that AED had to be at least 75% of the total interval to ensure a minimum level of adherence. Demographic information such as age, sex, and race were quantified in all AED users as well as the chronic use cohort. From the chronic use cohort the prevalence of patients on more than one AED was characterized. Duplicate AED use was defined as being prescribed two unique AED with a continuous overlap of at least

90 days. The prevalence of each unique combination was summarized with specific attention given to irrational combinations such as pregabalin and gabapentin, and carbamazepine and oxcarbazepine. Among all users, chronic users, and duplicate users we characterized the prevalence of diagnoses that may be common for AED users. Specifically, we used ICD9CM codes from medical claims submitted during 2006 to quantify the number of patients with a number of conditions known to be treated with AEDs. Seizure disorder was defined as epilepsy (ICD9CM 345xx), or convulsions (ICD9CM 7803x). Bipolar disorder was defined as bipolar affective disorder (ICD9CM 2964x, 2965x, 2966x, 2967x). Neuropathic pain was defined as disorders of peripheral nervous system (ICD9CM 350x), diabetes with neurological manifestations (ICD9CM 2506x), and Herpes zoster with nervous system complications (ICD9CM 0531x). Additionally, the prevalence of anxiety disorders (ICD9CM 300xx), fibromyalgia (ICD9CM 7291x), and migraine were quantified (ICD9CM 346xx). Finally, we quantified which prescriptions were associated with prescribers with a psychiatry or neurology background. Psychiatry background was defined as being certified as a psychiatrist or child psychiatrist. Neurology was defined as being certified as a neurologist or neuropsychiatrist. Results Trend Analyses From 2005 to 1 st quarter 2007 utilization of AEDs increased 14% and costs increased 21%. Figures 1 and 2 show the PMPM utilization and cost changes occurring for each AED during this period. The summary in table 4 shows the largest increase was observed for pregabalin, which emerged on the market in September 2005 and has experienced a 3 fold increase in growth and cost since. The use and costs of topiramate, levetiracetam, and oxcarbazepine have also grown considerably in this time period. The 52% increase in cost PMPM for oxcarbazepine appears mainly driven by a combination of cost inflation and increased dosing rather than utilization, which was stable throughout the period. Costs PMPM for gabapentin and zonisamide both decreased due to patent expiration and generic drug competition. According to 2007 claims data, Oregon FFS pays nearly $1 million dollars quarterly on these AEDs. Topiramate (38%), levetiracetam (17%), and oxcarbazepine (14%) represent more than 2/3 of this expenditure. Figure 1: AED Utilization 2005 2007 (rx dispensed PMPM x1000) 8.0 Rx PMPM (x1000) 7.0 6.0 5.0 4.0 3.0 2.0 GABAPENTIN CARBAMAZEPINE TOPIRAMATE LEVETIRACETAM PREGABALIN OXCARBAZEPINE ZONISAMIDE TIAGABINE 1.0 0.0 Mar 07 Jan 07 Nov 06 Sep 06 Jul 06 May 06 Mar 06 Jan 06 Nov 05 Sep 05 Jul 05 May 05 Mar 05 Jan 05

Figure 2: Individual (left axis) and total (right axis) AED Costs 2005 2007 (Ingredient cost PMPM) Cost PMPM ($) $1.60 $1.40 $1.20 $1.00 $0.80 $0.60 $0.40 $0.20 $4.50 TOPIRAMATE LEVETIRACETAM $4.00 GABAPENTIN OXCARBAZEPINE $3.50 PREGABALIN CARBAMAZEPINE $3.00 ZONISAMIDE $2.50 TIAGABINE HCL Total $2.00 $1.50 $1.00 $0.50 $0.00 $0.00 Mar 07 Jan 07 Nov 06 Sep 06 Jul 06 May 06 Mar 06 Jan 06 Nov 05 Sep 05 Jul 05 May 05 Mar 05 Jan 05 Table 4: Oregon FFS AED trend summary and ingredient Costs and average Cost / 30 days 1 st Quarter 2007 % Change 2005 to 2007 First Quarter 2007 Costs Drug PMPM utilization PMPM cost Total Cost % Average Cost / 30 days TOPIRAMATE (TOPAMAX) 18.9% 32.2% $346,063 (37.7%) $280 LEVETIRACETAM (KEPPRA) 28.9% 50.2% $158,092 (17.2%) $269 OXCARBAZEPINE (TRILEPTAL) 0.0% 51.6% $127,339 (13.9%) $246 GABAPENTIN (NEURONTIN, generics) 1.5% 32.4% $116,861 (12.7%) $79 PREGABALIN (LYRICA) 279.3% 301.5% $76,701 (8.4%) $144 CARBAMAZEPINE (TEGRETOL, TEGRETOL XL, generics) 7.2% 4.0% $64,017 (7.0%) $50 ZONISAMIDE (ZONEGRAN, generics) 1.8% 56.0% $17,558 (1.9%) $87 TIAGABINE (GABITRIL) 54.5% 12.4% $10,238 (1.1%) $209 Total 13.7% 21.4% $916,869 $156 AED User Analysis A total of 3367 unique FFS patients had at least one fill for an AED drug in 2006, of which 1689 (50%) were considered a chronic user of an AED. The demographics, shown in table 5, suggest that the two groups were similar in terms of measurable patient characteristics. The average age was 35 years, however the range was from the very young (<1) to the very old (90). Racial and gender breakdown are consistent with overall population characteristics.

Table 5: Demographics of all AED users and chronic users 2006 All Users Chronic Users n=3367 n=1689 Age Mean 35.3 34.9 Range <1 90 1 89 Female 2137 (63.5%) 1028 (60.9%) Race White 2944 (87.4%) 1503 (89.0%) Hispanic 135 (4.0%) 61 (3.6%) American Indian 130 (3.9%) 51 (3.0%) Black 73 (2.2%) 32 (1.9%) Asian 34 (1.0%) 18 (1.1%) other 51 (1.5%) 24 (1.4%) The plurality of chronic AED users were taking gabapentin (31%), followed by carbamazepine (26%), and topiramate (25%). Table 6 summarizes the distribution of specific AED use as well as the prevalence of any AED duplication and specific irrational duplications. Approximately 12% of all chronic users used 2 different AEDs concurrently for at least 90 days. Twenty two patients, (11% of all duplicate users) were identified as using either gabapentin and pregabalin or carbamazepine and oxcarbazepine together. Table 6: Distribution of AED users among chronic users (>=90 days continuous therapy) 2006 Drug n=1689 GABAPENTIN 529 (31.3%) CARBAMAZEPINE 443 (26.2%) TOPIRAMATE 418 (24.7%) OXCARBAZEPINE 206 (12.2%) PREGABALIN 195 (11.5%) LEVETIRACETAM 185 (11.0%) ZONISAMIDE 65 (3.8%) TIAGABINE 28 (1.7%) Duplicate Therapy 199 (11.8%) % of pregabalin patients also on gabapentin 13 (6.7%) % of oxcarbazepine patients also on carbamazepine 9 (4.4%) Table 7 shows the breakdown of every AED combination. The more common duplications include topiramate with carbamazepine, gabapentin, and levetiracetam; and carbamazpine with levetiracetam. However, the overall number of subjects on duplicate AEDs was small. Table 8 summarizes the prevalence of specific diagnoses which are commonly treated, both on and offlabel, with AEDs. In general, the prevalence of diagnoses among all users and chronic users were similar. Between 46% and 53% of AED users had at least one diagnosis for a disease of interest. Roughly 1/3 of subjects had a diagnosis indicating a seizure disorder. 6 7% of patients had a diagnosis of bipolar disorder and 15 16% had a diagnosis code indicating neuropathic pain. When the cohort was restricted to only the 199 patients who received duplicate AEDs, the prevalence of seizure disorder doubled to nearly 60% while the other two remained relatively unchanged or decreased. The prevalence of migraine and anxiety disorder was approximately 10%. Table 9 summarizes the prevalence of specific diagnoses among chronic drug users by drug. These data indicate that 73 81% of use for zonisamide

Table 7: Prevalence of concurrent combinations among chronic users (n=1689) 2006 ZONISAMIDE CARBAMAZEPINE GABAPENTIN LEVETIRACETAM n 62 422 502 169 194 152 25 395 CARBAMAZEPINE 11 (17.7%) 24 (4.8%) 30 (17.8%) 9 (4.6%) 7 (4.6%) 2 (8.0%) 35 (8.9%) GABAPENTIN 2 (3.2%) 24 (5.7%) 5 (3.0%) 5 (2.6%) 13 (8.6%) 1 (4.0%) 23 (5.8%) LEVETIRACETAM 8 (12.9%) 30 (7.1%) 5 (1.0%) 10 (5.2%) 8 (5.3%) 2 (8.0%) 29 (7.3%) OXCARBAZEPINE 3 (4.8%) 9 (2.1%) 5 (1.0%) 10 (5.9%) 3 (2.0%) 0 (0.0%) 11 (2.8%) PREGABALIN 2 (3.2%) 7 (1.7%) 13 (2.6%) 8 (4.7%) 3 (1.5%) 0 (0.0%) 11 (2.8%) TIAGABINE 0 (0.0%) 2 (0.5%) 1 (0.2%) 2 (1.2%) 0 (0.0%) 0 (0.0%) 0 (0.0%) TOPIRAMATE 4 (6.5%) 35 (8.3%) 23 (4.6%) 29 (17.2%) 11 (5.7%) 11 (7.2%) 0 (0.0%) ZONISAMIDE 11 (2.6%) 2 (0.4%) 8 (4.7%) 3 (1.5%) 2 (1.3%) 0 (0.0%) 4 (1.0%) OXCARBAZEPINE PREGABALIN TIAGABINE TOPIRAMATE Table 8: Diagnostic information of all, chronic and concurrent AED users 2006 All Users >=90 Days Therapy Duplicate therapy n 3367 1689 199 seizure disorder 917 (27.2%) 581 (34.4%) 114 (57.3%) bipolar disorder 246 (7.3%) 107 (6.3%) 8 (4.0%) neuropathic pain 517 (15.4%) 273 (16.2%) 26 (13.1%) migraine 341 (10.1%) 133 (7.9%) 18 (9.0%) anxiety disorder 383 (11.4%) 164 (9.7%) 11 (5.5%) fibromyalgia 201 (6.0%) 89 (5.3%) 11 (5.5%) any of above 2020 (60.0%) 1065 (63.1%) 149 (74.9%)

Table 9: Diagnostic information for chronic AED users by drug 2006 TOPIRAMATE TIAGABINE PREGABALIN OXCARBAZEPINE LEVETIRACETAM GABAPENTIN CARBAMAZEPINE ZONISAMIDE n 62 422 502 169 194 152 25 395 seizure disorder 72.6% 61.6% 16.3% 80.5% 45.4% 19.1% 20.0% 31.9% bipolar disorder 3.2% 5.7% 4.8% 1.2% 11.9% 6.6% 12.0% 8.6% neuropathic pain 3.2% 6.2% 35.9% 4.1% 5.2% 48.0% 12.0% 10.6% migraine 1.6% 2.8% 7.2% 2.4% 3.1% 8.6% 12.0% 19.5% anxiety disorder 8.1% 5.7% 10.8% 4.1% 8.2% 13.2% 8.0% 12.2% fibromyalgia 4.8% 1.4% 7.8% 0.6% 1.5% 15.1% 4.0% 6.1% any of above 79.0% 68.5% 58.4% 75.7% 61.9% 67.1% 48.0% 63.5% Table 10: Prescribed by clinician with psychiatry or neurology certification ZONISAMIDE TOPIRAMATE TIAGABINE PREGABALIN OXCARBAZEPINE LEVETIRACETAM GABAPENTIN CARBAMAZEPINE All Use 30.9% 7.5% 47.4% 38.3% 11.8% 23.8% 30.5% 56.2% Chronic Use 34.4% 9.0% 51.5% 41.2% 15.1% 24.0% 36.7% 59.7%

and levetiracetam may be for treating a seizure disorder. Nearly 50% of subjects using oxcarbazepine were documented with seizure disorder. Between 36 48% of gabapentin and pregabalin use is among subjects with a neuropathic pain diagnosis. The prevalence of migraine was highest among topiramate users at 20%. About 40% of topiramate users did not have a diagnosis for an approved or commonly used off label condition. Finally, table 10 shows the proportion of all users and chronic users who were prescribed an AED by a physician certified in either psychiatry or neurology. Patients using zonisamide and levetiracetam comprised the largest proportion of specialty prescribing among the studied AEDs. Conclusion and Recommendations Antiepileptic drugs are a costly and growing class of drugs. The use of AEDs for non evidenced based conditions is concerning because of previous experience with gabapentin. While gabapentin and pregabalin are FDA approved and have demonstrated effectiveness for select neuropathic pain conditions, data do not support the use of topiramate or oxcarbazepine for this condition. Similarily, the use of AEDs, except for lamotrigine, for bipolar affective disorder is not supported in the literature. Analysis of pharmacy and medical claims indicate the seizure disorder remains the predominate diagnosis for all studied AEDs except gabapentin and pregabalin where diagnoses of neuropathic pain are common. Bipolar and anxiety disorders appear to be the treated condition in a small proportion of subjects ranging from 6 10%. 1 Goodman F, Glassman P, Maglione M. Drug Class Review on Antiepileptic Drugs in Bipolar Mood Disorder, Neuropathic Pain, and Fibromyalgia. 2006. Available at: ttp://www.ohsu.edu/drugeffectiveness/reports/final.cfm. Accessed May 15, 2007. 2 Anonymous. Australian and New Zealand clinical practice guidelines for the treatment of bipolar disorder. Aust N Z J Psychiatry 2004;38(5):280 305. 3 Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60(11):1524 34. 4 Scottish Intercollegiate Guidelines Network (SIGN). Management of diabetes. A national clinical guideline. Scottish Intercollegiate Guidelines Network (SIGN). Edinburgh, Scotland. 2001. 5 Anonymous. Washington Department of Labor and Industries, Washington State Medical Association. Guideline for the use of Neurontin in the management of neuropathic pain. Seattle (WA): Washington Department of Labor and Industries, Washington State Medical Association; 2002. 6 Kushner SF, Khan A, Lane R, et al. Topiramate monotherapy in the management of acute mania: results of four double blind placebo controlled trials. Bipolar Dis. 2006;8:15 27. 7 Chengappa R, Schwarzman LK, Hulihan JF, et al. Adjunctive topiramate therapy in patient receiving a mood stabilizer for bipolar I disorder: a randomized, placebo controlled trial. J Clin Psychiatry. 2006;67(11):1698 1706. 8 Beydoun A, Shairbani A, Hopwood M, et al. Oxcarbazepine in painful diabetic neuropathy: results of a doseranging study. Acta Neurol Scand. 2006;113:395 404. 9 Grosskopf J, Mazzola J, Wan Y, et al. A randomized, placebo controlled study of oxcarbazepine in painful diabetic neuropathy. Acta Neurol Scand. 2006;114:177 180. 10 Wagner KD, Kowatch RA, Emslie GJ, et al. A double blind, randomized, placebo controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry. 2006;163:1179 86. 11 Mazza M, Di Nicola M, Martinotti G, et al. Oxcarbazepine in bipolar disorder: a critical review of the literature. Expert Opin Pharmacother. 2007;8:649 56. 12 American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar affective disorder. 2nd edition. 2002. Available at: http://www.psych.org/psych_pract/treatg/pg/bipolar.watch.pdf. Accessed May 15, 2007.