a . Randomized Double-blind Study Comparing the Efficacy of Gabapentin With Amitriptyline on Diabetic Peripheral Neuropathy Pain Candis M. Morello, PharmD; Susan G. Leckband, RPh, BCP; Carol P. Stoner, PharmD, BCPS; David F. Moorhouse, MD: Gregory A. Sahagian, MD Background: Reports of gabapentin use in diabetic pe- ripheral neuropathy pain stimulate a need for con- trolled trials to determine its comparative efficacy to the therapeutic standard of amitriptyline hydrochloride. Objectives To determine the efficacy of gabapentin com- pared with amitriptyline in treating diabetic peripheral neuropathy pain. Design: Prospective, randomized, double-blind, double- dummy, crossover study’ Setting: Veterans Affairs San Diego Healthcare Sys- tem, Ambulatory Care Clinic jents: Twenty-eight veterans were referred by their primary care providers, Two patients withdrew before ran- domization because of no neuropathic pain after wash: out; a third withdrew for unexpected surgery that re- quired analgesics, Three patients withdrew because of adverse effects and 1 for protocol violation, Interventions: Patients with stable glycemic control and neuropathic pain randomized to 6 weeks of therapy with gabapentin, 900 to 1800 mg/d, oF amitriptyline hydro- chloride, 25 to 75 mg/d, with a I-week washout before Main Outcome Measures: ain relief measured by pain scale with verbal descriptors and global pain score as- sessment at treatment end, Results: Participants and investigators were blinded, throughout. Mean dosages were of gabapentin, 1565 mg/d, and of amitriptyline hydrochloride, 59 mg/d. Sixty-five percent of patients reached maximum dose with gabap- centin and 54% with amitriptyline. Mean score diary analy sis showed pain relief with gabapentin and amitripty- line was not significantly different (P =.26). Global data ‘were obtained from 21 of 25 enrolled patients who com- pleted the study. Moderate or greater pain relief was ex- perienced in 11 (52%) of 21 patients with gabapentin and 14 (67%) of 21 patients with amitriptyline. There were no significant period or carry-over effects (P= 35) Conelustons: Although both drugs provide pain relief, mean pain score and global pain score data indicate no sig. nificant difference between gabapentin and amitriply- line. Gabapentin may be an alternative for treating dia- betic peripheral neuropathy pain, yet does not appear 10 offer considerable advantage over amitriptyline and is more expensive, Larger trials are necessary to define gabapen- tn’ place in treating diabetic peripheral neuropathy pain. Arch Intern Med. 1999;159:1931-1937 IABETIC PERIPHERAL neu- ropathy (DPN) is one of the most common symp- tomatic, long-term com plications in patients with, of burning, shooting, tingling, and allo- dynia.’ Typically, the sensorimotor neuropathy presents in a distal symmet- ric pattern, with a glove-and-stocking, distribution From the Veterans Afrs ‘an Diego Healtheare System (Drs Morele, Stoner. Moorhouse, and Sahagian and Ms Leckband), andthe Department of Neurosciences, University of California at San Diego Medical Center (rs Moorhouse and Sahagln), San Diego, Calif both type 1 and type 2 diabetes mellitus." ALinitial diagnosis, 7.5% of patients will already experience DPN pain, and ap- proximately 45% will be afflicted with this, complication after 25 years. At this time, however, the exact cause of DPN is not well understood." Two main types of diabetic neuropa- thy involve the autonomic or somatic nervous systems.*? The most common \ype of DPN is somatic or sensorimotor neuropathy with peripheral symptoms Although DPN pain is prevalent among patients with diabetes, current treatment options, including antidepres- sants, anticonvulsants, antiarrhythmies, and topical capsaicin, are limited by their variable efficacy and adverse effects. Amitriptyline hydrochloride is effecive in approximately 60% to 75% of patients treated for DPN, which is consistently greater than that reported with other agents.°” Of concern with all available drug therapies are the extensive adverse ef (©1999 American Medical Association. All rights reserved, Downloaded From: http:/jamanetwork.com/ on 09/13/2017PATIENTS AND METHODS PATIENTS From March 1997 to December 1997, patents whowerevet trans were refered by primary care provers, neuro fists dabtologiste and aneshesolgisteat he Veterans Al {irs san Diego Hesthcare System (VASDHS) Patients were included they were 18 years o olde, had diabetes mel tuswith stable lyemic control defined asahemoglobin level between 0.049 (4.3%) and 0.079 (7.9%) within 3 ‘months, experienced chronic dll pin for more than 3 ‘months, during which both the quality and location were Consistent with DPN pan, as diagnosed bya neurologist (DEM andGAS), and had an estimated creatinine clear nce of 050 mile (30 mln) Cable ¥ snd Fable 2)” Patients were exchded from the study they bad non- DPN pain more severe than DPN pain, allergy or adverse reaction to gabapentin or amitriptyline; severe depression by diagnosis orasasessed with the Beck Inventory" were pregnant; were receiving eaten for st cures; had ca Alorascular symptoms of postural hypotension, symptom Sic coronary arity or peripheral vascular disease or acre- Blinn clearance of le than 0.30 mL/s (<30 m/min). Patient who had received prior treatment with abapen- tn oramitrptyline wereno\ excluded regardless of whether treatment was deemed a succes or fale. Patients were excluded, however if thelr previous dosage exceeded the Studys maximum dosage of ether drug ‘Use ofan medications for DPN pal that patents were taking before the study was discontinued for? weeks be- fore entering the study and throughout the study period Allother regular use of analgesics was discontinued: how- ‘ever, patients were allowed up to + doses per day of acet- aminophen, 325 mg, for severe pain or pain other than DPN. ‘The study was approved by both the University of Caifor- ris at San Diego and VASDHS human subjects commit- tees, and all patients gave informed, waitten consent ‘TREATMENT. “The study consisted of two G-weck treatment periods with 4 Leweek washout period between teatment arms. The nei Tologst (DFM andG-AS) and lineal pharmacist (CMM SG, and CPS) screened referred patients for study inclusion, and baseline demographics were obtained. Pat dentsreciving treatment for DPN pain began.a2-week wash ‘out period belore ratdomizaion, Pallets were given a dally pain diary and were randomized by the VASDHS clinical re arch pharmacist, he only unblinded investigator forthe Sdy, fo recelve ther gabapentin or amiripiylie ina Alou Bind design per protoclal oer investigators and patients remained Blinded unl study termination. At the tnd ofeach eaten period, patients were scen within 24 Hours fora neurologic examination and to administra global pal asessment rating. The ciniel pharmacist (CMM, Strand CP'S) conducted pl count to acer sty callon compliance athe end of each teatment period. Fol towinga l-wek washout period, patents were crossed over tothealtemative drug therapy. although 1 week wa sufl- ‘dent forthe complete elimination of ether study drug e- Teac evaluation was based onthe patient’ pan ratings r= corded during the inal week of each treatment th allowing, Sn addtional 5 weeks for dsipation of drug effects, fects, particularly anticholinergic effects of the tricyclic antidepressants. In 1003, gabapentin, a y-aminobutyric acid ana log, received Food and Drug Administration approval for adjunctive treatment of partial seizures, with and with- ut secondary generalization in adults with epilepsy.” Despite extensive studies," gabapentin’s mechanism of action is unknown, Yet, even without this mechanism of faction fully elucidated, there has been an increasing num- berof ease reports of gabapentin's use in neuropathic pain syndromes such as reflex sympathetic dystrophy, post- herpetic neuralgia, migraine, trigeminal neuralgia, eryth- romelalgia, Guillain-Barré syndrome, or other intrac- table pain states in dosages ranging from 900 to 2400 mg/d." Most recently, a placebo-controlled clinical triaP” in patients with DPN pain has established the ef- ficacy of gabapentin to provide pain relief. Gabapentin, with ts low adverse effect and drug in- teraction profile, may offer an effective treatment for DPN pain. The primary purpose of this study was to determine the comparative efficacy of gabapentin with amitripty- line, the standard therapy, in the treatment of DPN pain. —_—_ dy Twenty-eight patients were eligible for study; 3 with- drew before randomization: 2 because of no neuro- pathic pain alter washout and 1 for unexpected surgery requiring analgesics, Twenty-five patients were en- rolled in the study. Because of adverse elfects, protocol violation, oF voluntary withdrawal, + patients withdrew from the study (2 each from the gabapentin and amitrip- tyline treatmentarms).In addition, 3 patients were crossed over early per protocol because of intolerable adverse ef- fects (2) or intolerable pain (1); 1 of whom also dropped cout of the study. Thus, whereas 21 patients underwent both treatment arms ofthe study, 19 completed 6 weeks of treatment with both study drugs (Figure 1). For sta- Uistical analyses of mean pain diary scores, all patients ‘were included to prevent bias of study results by omit- ling those with eatly crossover due to intolerable pain or adverse effects. Data analysis excluding early cross- ‘over patients did not produce statistically significant dil. ferences (P=.13) ‘Of the 25 enrolled patients, 12 were initially ran- domized to the gabapentin treatment arm, 11 of whom, crossed over to amitriptyline. During the gabapentin treat ment arm, 1 patient experienced adverse events (diar- thea and ankle edema) and voluntarily withdrew from the study. Inaddition, 2 patients taking gabapentin were crossed over to amitriptyline early (week 4) because of Intolerable adverse effects (sedation and dizziness) or in- tolerable pain, respectively; 1 of whom eventually with- drew from the study because of adverse events. Thirteen of the 25 patients were initially random- ized to the amitriptyline treatment arm, 11 of whom (©1999 American Medical Association. All rights reserved, Downloaded From: http:/jamanetwork.com/ on 09/13/2017During each treatment period, drug dosage was t- trated for 2 days to minimize adverse effects, alter wich the dosage was adjusted based om the patient’ clinical re sponse and adverse elfects (Table 3 znd Table 4). Daily closes of gabapentin ranged from 900 to 1800 mg, and ami teipryline hydrochloride, from 25 to 75 mg. To preserve the double-blind study design, placebo was used to maintain a Setimes-per-day dosage regimen foreach study drug (Table 3). Patents received 2 bottles of study medication and were instructed to take the 9 aM and 3 PM doses from the First boutleand the 9 pu dase from the second botle, which were labeled accordingly The clinical pharmacist called patients on days 2,4, and 6 ofthe first week and days 1 and 4of the fourth week. fof each treatment ari to assess pain control and adverse lfets Patients were interviewed for frequency and sever- ity of the 20 most common adverse eflects of the 2 study. drugs and any other adverse effects experienced, The pur- post ofthe call was toadjist drug dosage tothe maximum tolerated for pain control without intolerable adverse ef- fects, Patients continued to take the maximum tolerated dosage for the remainder of the treatment ar EVALUATION The Pain Scale Rating System and Global Rating Scale were used to measure poi rele, Patients rated their pin by com- pletinga daily pan diary in which they chose rom a scale F 13 words describing pain intensity, ranging from none toextremely intense.” These verbal descriptors were quh- ‘fled, based om a ratio-scale technique described by Gracely tal.” which has been shown to be reliable and consistent in previous studies” involving human clinical and ex perimental pain; it distinguished active treatment from con trol. The pain diary was collected atthe end ofeach treat ‘ment period. A neurologist evaluated patients at baseline and at the end of each treatment arm. In this evaluation, the neurologist asked patients to make a global rating of their overall pain relief (complete lot, moderate, slight ‘none, or pain worse) at the end each treatment ari com pared with their baseline pain before entering the sty. STATISTICAL ANALYSIS For statistical purpose, the verbal descriptors in the pain diary were converted to numerical equivalents using the Pain Scale Rating System as described by Gracely eta.” The mean pain scores in each final treatment week were compared within patients by paired. 2-tailed est. Period. and sequence elfects were examined for scores in the final {reatment week by attest. Global Rating Seale scores were sd with a paired, 2-tailed Wileaxon signed rank test ‘A L-sample sign test was used to analyze the frequency and severity of adverse elects between amitriptyline and gaba- pentin, and the Wileoxon signed rank test was used to ana Iyze the frequency and severity of adverse eflects with time for each medication STUDY DRUG PREPARATION Swidy drugs were prepared at a Food and Drug Adminis Uration-repistered repackaging facility. Since this was @ double-blind design all capsules were identical in taste, color, size, and shape. Table 1. Patient Characteristics Table 2. Painful Diabetic Neuropathy Charactristies suay croup Wo. oF characteris characters rratete® Sex, MF Duration of pain, ane 80.9 57242 Etnicty Ditton of pin We a 5 [can Amatican 2 5 ‘ge, ean +80, y enastos 4 ype of abet, 12 ae Feat gs, hands, thigh 1 Duration fdas, mean «$0, naan ualiyo pain Ciba teste, Ho, of patents Pins and nodes 18 Dat 16 Tingling 7 Ineln 16 Bring 16 Metra 9 Stare 10 Stories 7 aching a Troglitazone 1 Stoctiag a Diba conto. mean « 8D ‘oda 7 Ina hemoglbin 0071 20.005 ramping 7 Final harogotin A 0.080 0.008 coi 6 este clearance, mLef 126037 biog 4 “To cont hemoglobin A toa percentage, die by 03 Dat ae presented as number of patents une omer indeed 4 Tocamerereanin earance tom mies pe second milters et mit, dd by 0.01667. crossed over to gabapentin, During the amitriptyline teat ‘ment arm, 1 patient experienced adverse events (bilateral ankle edema and dizziness), which resulted in discontinu- ation of drug use,and 1 voluntarily withdrew from the study after crossover because of increasing pain from arthritis that exceeded DPN pain. One patient taking amitr line crowed over to gabapentin ary (eek boca Intolerable adverse elect (edaton and constipation), (©1999 American Medical Association. All rights reserved, Downloaded From: http:/jamanetwork.com/ on 09/13/2017Table 3. Dose Titration to Maximum Tolerated” Dove Lever oor Dosage Sra borage Toa Daly Dosage Intaon phase day T__—_-Paabo Pacebo 72mg afamirpaine or Pacsbo Pract 307mg of gabapentin Initiation phase ay 2 Pacbo or 300 mg of, Pracebo 251mg of anitipyine or ‘atapenin Pracebo 200 mg of eabapenin ‘6 mga sbaretin nal Pracabo or 300 mg of Praca or300mg 281mg af amitrpyine or 25mg of anitipyine or ‘atapenin ‘of gabapentin ‘200 go eabapenin ‘00 mga sbaretin nel Pracebo or 300 mg of Praceboor 300mg 225mg ofastitylin org of amino ‘gatagenin of gabapentin 2x 300 mg of gabapentin 200 mg gabapentin Lael 2x plactboor? 300 Placebo or 300mg «3x 25mgafamiighyina or 75 mgatamirgnyine or rmgfgatapenin ‘of gabapentin ‘3x 200mg of gabapentin 800 go gabapentin “Amine was ve a anptyinehyéocloe. Table 4. Dosage Titration Algorithm” Fig Ee Fs TWoioieahe—Tolernis——_leabe Pamnconl __Aaverae Eets Adverse tacts _Aavere Eats Nopan Manan at Mainainat ——_Reduceto samalow! same lel ‘lowe eva Toleatlepan Adraneto —Advarceto edie to higherlvel —higherleel lover ee Intlerablepain Adranoeto Avance to Crossover or Nighrlvel —higherlel — dscorue Patents wee bephoned on days 24 and ofthe st eck and ays 1 ‘and ofthe fourth week of each rement am a assess pn cota and ‘verse eect The clinical characteristics ofthe patients enrolled in the study were consistent with the general diabetic population, with the exception of a higher male-to- female ratio (Table 1). Study patients experienced typi- cal features of DPN pain (Table 2), for which they had received prior treatment, including amitriptyline (14), nonsteroidal anti-inflammatory drugs (3), nortriptyline hydrochloride (1), gabapentin (1), carbamazepine (1), opioid analgesics (1), and capsaicin (1). Only 1 patient hhad prior treatment with 2 medications and 1 with + medi- cations. AL the time of study enrollment, only 1 patient was receiving gabapentin and 9 receiving amitriptyline required washout before study entry PAIN RELIEF: PAIN INTENSITY SCORE ANALYSIS After excluding data of patients who did not fully com- plete both treatment arms, the weekly mean pain scores of the remaining 19 patients are shown in Figure 2. In patients treated with gabapentin followed by amitripty- line, pain scores steadily declined during the first 2 weeks of dosage titration, followed by a plateau effect of pain relie, The pain returned during the L-week washout pe- riod and then declined during the second treatmet A similar response was seen in patients treated with ami triptyline followed by gabapentin. ‘Comparing the baseline pain scores in 21 patients who underwent both treatment arms to the end-of- treatment pain scores, there was a statistically signifi- cant difference in pain score reduction in patients treated with both gabapentin (P<.001) and amitriptyline (P<.001) by 2-talled, paired Student (test. However, the Arie eae in=t3) v Tae in ast ave Eee, 1 Pate hence ot Proc Vakon 1 PE Css Inala ees Eats Y Tan bara fi Catopenin ss feamon 2 (eet) Fate aan Banca fvetProoel Von Patent any ssn Be Ison hve ec atta Css Be 1 Pan hr Bae ttre J Garened Was Wen fy Goo iret apa Wal iar Cee ") Fuly Compl Te ek al v=o) Fal ood To 6k Ta ie=10) gure 1. Profle of he tua. DPW nates cide perineal europa ‘ont was gen a8 ania aroha mean difference between drugs in pain intensity scores during the final week of treatment favored amitriptyline bby 0.001 unit (05% confidence interval, -0.074 100.256), in which 0.35 units was the difference between modes ate and mild pain.” Thus, there was no statistically sig- nificant difference in pain intensity scores between gaba- pentin and amitriptyline by the end of treatment (P=.26) PAIN RELIEF: GLOBAL PAIN SCORES ANALYSIS Based on the global description of pain relief for pa tients who underwent each treatment arm (fable 5: (©1999 American Medical Association. All rights reserved, Downloaded From: http:/jamanetwork.com/ on 09/13/2017moderate of greater pain relief was experienced in 11 ADVERSE EFFECTS (52%) of 21 patients during gabapentin treatment and 14 (67%) of 21 patients during amitriptyline treatment. Symptoms possibly related to study drugs caused 3 pa- There was no statistically significant difference in pain tients to withdraw from the study (1 receiving gabapen- relief between groups (P>-1 by 2-tailed, paired Wile Unand 2 receiving amitriptyline) and 2 patients (1 each coxon signed rank test), significant period or carryover receiving gabapentin and amitriptyline) to cross over early effects were not detected, and there was no correlation to the alternative treatment arm. Seventeen patients re- between global score and maximum dosage achieved, ceiving amitriptyline and 18 patients receiving gabapen- lin experienced adverse effects (Table 6). With the ex- PAIN RELIEF: ception of weight gain with amitriptyline, there was no CHANGES FROM BASELINE statistically significant difference in occurrence of ad- verse effects between drugs (P>.05). Prevalent adverse Figure 3 shows the mean changes in pain intensity dur-_elfects included sedation, dry mouth, dizziness, pos- ing the first 6 weeks of each study drug for the 19 pa- tural hypotension, weight gain, ataxia, and lethargy ‘dents who fully completed their first treatment arm. Mean Comparing the frequency and severity of adverse el (4SE) pain diary scores decreased by 0.310.004 unit Feetsat study weeks 1 and 4 showed that, with amitrip- when patients were treated with gabapentin and tyline,dry mouth worsened with time (P<.005) and pru- 0.44 40.089 unit with amitriptyline. Although the mean __rilus was worse than with gabapentin at week I (P<.03) pain score change [rom baseline favored amitriptyline, but was not statistically significant from gabapentin at there was no statistically significant difference by paired week 4. The frequency and severity of dizziness with gaba- test (P=.3), pentin diminished with time (P =.02). AVERAGE DOSAGE AND PATIENT COMPLIANCE ‘re Fes es in tise Fem pens Anne After dosage titration based on individual response, the Woe mean dosages of gabapentin and amitriptyline hydro- chloride were 1565 and 59 mg, respectively. Of patients treated with gabapentin, 65% reached 1800 mg/d, 26% 2 reached 1200 mg/d, and 9% were maintained with ©00 mg/d. With amitriptyline, 54%, 20%, and 17% of pa- tients reached 75, 50, and 25 mg/d, respectively. Medi- cation compliance, defined asthe total percentage of doses taken, was 94.8% with gabapentin and 96.4% with ami- ipryline we BES Se Stat £8 PNB] cthisstudy was designed to evaluate the efficacy and safet of gabapentin compared with amitriptyline, the current gure. andy opin nny scores. Westy mean an wensty ‘ete etea be opus we cance plait ames orate standard of therapy for DPN pain. Study results indicate Sak tesnent ams. ach cave depicts a sole gop of pants cehing that, although both gabapentin and amitriptyline pro- ‘th arms of consecuie rgteaments andthe enenng washout Peed. vide statistically significant pain reliefby the end of teat- wah group eaecng ce, elie ram amp yar ment, there was no statistically significant difference be- aopenth lsu) fom gabapentin ante ce) Fou ly sig feta despre ash nen tegument pa Sars Ao tween the 2 drugs, as measured by daily pain diary scores Satstaly snifear dence ere found beveen each wet) pain score and global ratings of pain reliel. As expecteé latin each eaten group ante twee Gs gabapentin at week ser cronine nab cul ta one 7, anityine a ea gabapentin at week 8 (Tay ans of line provided moderate or greater pain relief in 67% of Yaranct and Fer Poet Least Scan Oerence post hoc tor patients, which is consistent with previously reported el eamprig weet) ean pai scores enen drugs) licacy rates.*® Gabapentin provided moderate or greater Table 5, Global Ratings of Pain Reliet in Patents With Diabelc Peripheral Neuropathy Pals Rll at Ea of Treatment Pero, 2 ain Tota compet, ug Att moderate it ___one worse Lo, andmoeraio Gabaperin 2 2 1 2 5 Sh Amity hycoctoide 19 8 0 uu o a ~ Data ae he 2 patients who wer ated with Both gabapentin and apne. There was no static intent erence betwen gabapentin and aninptne(®>.1 by 2aled. pated Wlcorn signed ants "Tol doesnt ea te sum a the components because of rounding, (©1999 American Medical Association. All rights reserved, Downloaded From: http:/jamanetwork.com/ on 09/13/2017‘Ome esau Figur Pan nest score change tom tase Fah cure ped ‘epesers he mean change pa ines sa ram bene re st {resent atm the patents ceed gata 2d 10 who. ‘nese amine aac fore 6 weeks emer A ‘03Santretucton nase ference between moderate and mid ‘Aitoigh mean changeable pi ele are amy, thee fas sunt Sct erste a eco ene pared test 3) pain reliein 52% of patients and reduced pain diary scores by 0.31 unit, indicating a less-than-moderate impact on pain relief compared with a0.44-unit reduction with ami- triptyline (Figure 3). This is similar to the recently re- ported efficacy of 6% for gabapentin compared with 33% for placebo.” The limited number of patients enrolled in our study introduces the probability ofa type Il (B) error. Sample size could not be determined since there were no pub- lished studies describing gabapentin’ ellicacy in DPN pain atstudy initiation. Post hoc analysis revealed that a sample size of approximately 260 patients per paired crossover study would be necessary to provide 80% power to de- tect a mean difference between treatments of approxi- rately one third of the difference between mild and mod- crate pain at a .05 significance level. Larger controlled trials are needed to determine if there is any detectable difference in efficacy between amitriptyline and gabs- pentin Accepting patients with well-controlled diabetes right have limited the study size, yet hyperglycemia ean decrease the pain threshold, thereby interfering with study results, Our patients maintained a stable hemoglobin A,, level throughout the study, reducing the potential of hy- perglycemia interference. Allowing patients who had re- ceived prior treatment with either gabapentin or ami- triptyline into the study may have potentially introduced bias, since those who were taking one of these drugs and in whom DPN pain had been successfully controlled would not likely Volunteer to discontinue use ofthe drug, whereas those who entered the study were more likely to experience treatment failure. Dosage ranges in this study were based on current literature and practice standards at the VASDHS. Re- view of amitriptyline for neuropathic pain within our in- stitution indicated that 25 to 75 mg/d was the most preva- lent dosage range. Gabapentin dosage remained within Table 6, Adverse Etlects To, fF "antptyine Hraroninoe ‘Soaston 7 Dry mouth Dzeneee 2 Petra hypotesion Woght gant ana Constipation Lethargy Edema | Headache Prunus Unpleasant tse Nausea adr dysppsia Diasthen Burd son Other ‘Anya tect, 1 “Incidence and sever warsened wit tine (P05) pene an stent esd wtb ne (= 2) per [lncidence an seventy worse than gabapentin at week 1 (P08) ut at stately sgiicant compared wih gabapentin 3 eek the manufacturers guidelines forseizure treatment, Higher dosage ranges may have achieved greater efficacy and should be evaluated in future studies. To measure the fll, potential of each drug, it might be useful to titrate the dosage upward, either to complete pain relief of to the maximum tolerated dosage All study patients were initiated with a 2-day dos- age titration to diminish the occurrence of benign Fects, Although gabapentin is often cited as having a rela- lively safe adverse effect profile, both gabapentin and amitriptyline had a similar rate of adverse effects, The fre- jquency and severity of reported adverse effects did not appear to subside with time, with the exception of wors- ening dry mouth with amitriptyline and resolving di ziness with gabapentin. Similarly, dizziness and somno- lence were predominant adverse events reported by Backonja etal”; however, this was attributed toa forced 4-week dosage titration to 3600 mg/d. This information may be useful for patients when initiating therapy with either agent, since a slower dosage titration may de- ‘crease the frequency and severity of adverse effects akan] Both gabapentin and amitriptyline in the dosages used in this study appear to provide pain relief in DPN pain; hhowever, mean pain diary and global pain relief score data indicate no statistical difference between them, With the exception of weight gain, dry mouth, and dizziness, the Irequency and severity of adverse effects were similar with each drug. Although gabapentin provides pain relief in pa tients with DPN pain, it should be reserved as an alte native to patients in whom a less costly agent fails, such as amitriptylin oF for whom tricyelic antidepressants (©1999 American Medical Association. All rights reserved, Downloaded From: http:/jamanetwork.com/ on 09/13/2017are contraindicated. Our results suggest that larger con- uwolled tials are necessary to further define gabapen- tun’s place in the treatment of DPN pain. Accepted for publication January 25, 1999, We acknowledge Stephen D. Funk, PharmD, VASDHS research clinical pharmacist, who maintained the integrity of the double-blind design as the unblinded investigator; Veterans Affairs Clinical Research Pharmacy Coordinat- ing Center at Albuquerque, NM, Mike R. Sather, RPh, MS, Frank Lucddeke, and Roy W. Fetter, who aided inthe prepa- ration of study drug: Christopher S. Morello, PhD, Univer- sily of California al San Diego, who performed statistical analysis of the data; Patricia Hlavin, MD, independent phy sician reviewer of adverse events for the study duration; and Philip 0. Anderson, PharmD, manuscript reviewer Corresponding author: Candis M. Morello, PharmD, Veterans Affairs San Diego Healthcare System, Pharmacy Service (119), 3350 La Jolla Village Dr, San Diego, CA 92161, — EES h— 1. 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