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Gabapentin for the Symptomatic Treatment of Painful Neuropathy in Patients With Diabetes Mellitus
A Randomized Controlled Trial
Miroslav Backonja, MD;
Ahmad Beydoun, MD;
Keith R. Edwards, MD;
Sherwyn L. Schwartz, MD;
Vivian Fonseca, MD;
Marykay Hes, BS;
Linda LaMoreaux, MPH;
Elizabeth Garofalo, MD;
for the Gabapentin Diabetic Neuropathy Study Group
JAMA. 1998;280:1831-1836.
ABSTRACT
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Context.— Pain is the most disturbing symptom of diabetic peripheral neuropathy. As many as 45% of patients with diabetes mellitus develop peripheral neuropathies.
Objective.— To evaluate the effect of gabapentin monotherapy on pain associated with diabetic peripheral neuropathy.
Design.— Randomized, double-blind, placebo-controlled, 8-week trial conducted between July 1996 and March 1997.
Setting.— Outpatient clinics at 20 sites.
Patients.— The 165 patients enrolled had a 1- to 5-year history of pain attributed to diabetic neuropathy and a minimum 40-mm pain score on the Short-Form McGill Pain Questionnaire visual analogue scale.
Intervention.— Gabapentin (titrated from 900 to 3600 mg/d or maximum tolerated dosage) or placebo.
Main Outcome Measures.— The primary efficacy measure was daily pain severity as measured on an 11-point Likert scale (0, no pain; 10, worst possible pain). Secondary measures included sleep interference scores, the Short-Form McGill Pain Questionnaire scores, Patient Global Impression of Change and Clinical Global Impression of Change, the Short Form–36 Quality of Life Questionnaire scores, and the Profile of Mood States results.
Results.— Eighty-four patients received gabapentin and 70 (83%) completed the study; 81 received placebo and 65 (80%) completed the study. By intent-to-treat analysis, gabapentin-treated patients' mean daily pain score at the study end point (baseline, 6.4; end point, 3.9; n = 82) was significantly lower (P<.001) compared with the placebo-treated patients' end-point score (baseline, 6.5; end point, 5.1; n = 80). All secondary outcome measures of pain were significantly better in the gabapentin group than in the placebo group. Additional statistically significant differences favoring gabapentin treatment were observed in measures of quality of life (Short Form–36 Quality of Life Questionnaire and Profile of Mood States). Adverse events experienced significantly more frequently in the gabapentin group were dizziness (20 [24%] in the gabapentin group vs 4 [4.9%] in the control group; P<.001) and somnolence (19 [23%] in the gabapentin group vs 5 [6%] in the control group; P = .003). Confusion was also more frequent in the gabapentin group (7 [8%] vs 1 [1.2%]; P = .06).
Conclusion.— Gabapentin monotherapy appears to be efficacious for the treatment of pain and sleep interference associated with diabetic peripheral neuropathy and exhibits positive effects on mood and quality of life.
INTRODUCTION
DIABETES MELLITUS is the most common cause of neuropathy in the Western world.1 In a cohort of 4400 patients with diabetes studied for 20 to 25 years, 45% developed neuropathy during the course of their disease.2 Improved methods to determine the incidence, prevalence, and course of diabetic peripheral neuropathy have been precisely described and applied in large longitudinal studies.3-13 Pain due to diabetic neuropathy affects the feet and ankles
most often and, to a lesser extent, lower extremities above the knees and upper extremities.14 The pain may be severe and often has an unusual "dysesthetic" quality. If inadequately treated, it is frequently associated with mood and sleep disturbances. Attempts to treat diabetic neuropathies can be divided into those directed at modification of the underlying disease process and those directed toward symptom suppression. Improved glycemic control is the mainstay of efforts to modify the incidence and course of the disease, although aldose reductase inhibitors may also play a role.15-18 There is strong evidence that tricyclic antidepressants (TCAs) effectively reduce pain and weaker evidence that anticonvulsants, antiarrhythmics, and topical agents are useful, although dose-limiting adverse effects may reduce the effectiveness of these agents.16-17,19-21
Gabapentin (1-[aminomethyl]-cyclohexaneacetic acid; Neurontin, Parke-Davis, Division of Warner-Lambert Co, Morris Plains, NJ) is an anticonvulsant approved in the United States in 1994 for use in adult patients with partial epilepsy that has been reported anecdotally and in open-label case series to be effective in the treatment of pain syndromes, including painful diabetic neuropathy.22-23 Gabapentin is structurally related to  -aminobutyric acid (GABA), a neurotransmitter that plays a role in pain transmission and modulation. Gabapentin is not metabolically converted to GABA or a GABA antagonist and is not an inhibitor of GABA uptake or degradation.24 Unlike systemically administered GABA, gabapentin readily crosses the blood-brain barrier.25-26 Gabapentin is eliminated entirely by renal excretion and its clearance is reduced in patients with renal insufficiency, especially those with a creatinine clearance of less than 60 mL/min.7 The evidence for each of gabapentin's pharmacological actions, including interaction with the system L-amino acid transporter, alteration of synthesis and release of GABA in the brain, high affinity binding to the  -2- subunit of voltage-activated calcium channels, inhibition of voltage-activated sodium channels, alteration of monoamine neurotransmitter release and blood serotonin levels, and neuroprotection in laboratory models of amyotrophic lateral sclerosis, has been summarized elsewhere in the literature.27
Gabapentin has been shown to be effective in various animal models of chronic neuropathic pain. The analgesic effects of gabapentin were seen in the chronic constriction injury model of neuropathic pain in rats.28 Gabapentin administered intraperitoneally in clinically relevant doses ranging from 10 to 75 mg/kg led to significant dose-related improvement in heat hyperalgesia and mechanoallodynia.29 Heat hyperalgesia was also significantly reduced following intrathecal gabapentin administration, indicating that the antihyperalgesic properties of gabapentin are at least partially modulated through spinal cord mechanisms.29 In addition, gabapentin was effective in significantly reducing late-phase tactile allodynia in both the rat formalin30 and carrageenan footpad tests and hyperalgesia in the rat streptozotocin model (Parke-Davis Pharmaceutical Research, unpublished data, 1997). These findings, coupled with an established favorable safety profile,24 suggest gabapentin as a promising candidate for use in the treatment of neuropathic pain. The purpose of this study was to evaluate the safety and efficacy of gabapentin monotherapy for the treatment of pain associated with diabetic neuropathy.
METHODS
Study Population
All participating clinical sites received investigational review board approval of the study protocol, and all patients provided written informed consent prior to study participation. At screening, eligible patients had pain attributed to diabetic neuropathy for 1 to 5 years, a diagnosis of diabetes mellitus (type 1 or 2), and a pain rating score of at least 40 mm on the 100-mm visual analog scale (VAS) of the Short-Form McGill Pain Questionnaire (SF-MPQ).31 Patients with an average pain score of at least 4 on an 11-point Likert scale and at least 4 observations recorded in daily pain diaries over the next week were randomized. Only patients with a hemoglobin A1c level of 0.11 or less (normal range, 0.048-0.067) were randomized. Exclusion criteria included the presence of other severe pain that could confound assessment or self-evaluation of the pain due to diabetic neuropathy, receipt of any investigational drug within 30 days prior to screening, and amputations other than toes. An additional exclusion criterion was a creatinine clearance of less than 60 mL/min to avoid the necessary dosage adjustments (reductions) that would be required for patients with renal impairment.24 Creatinine clearance was estimated from patients' serum creatinine levels, using the following formulas32: adult male Ccr = (140 - age) x weight in kilograms/(72 x serum creatinine in milligrams per deciliter); and adult female Ccr = [(140 - age) x weight in kilograms/(72 x serum creatinine in milligrams per deciliter)] x 0.85, where Ccr indicates creatinine clearance.
Medication dosages for diabetes control were to remain stable during the study. Medications that could affect symptoms of painful diabetic neuropathy were prohibited with the exception of (1) acetaminophen (up to 3 g/d) or aspirin (up to 325 mg/d for prophylaxis for myocardial infarction or transient ischemic attacks) and (2) serotonin reuptake inhibitors (with no dosage change within 30 days prior to the study or during the study). The following medications were prohibited within 30 days prior to randomization and during the study: TCAs, mexiletine hydrochloride, carbamazepine, phenytoin, valproate sodium, dextromethorphan, opioids, capsaicin, nonsteroidal anti-inflammatory drugs, skeletal muscle relaxants, benzodiazepines, other Schedule II medications, and over-the-counter medications with centrally acting properties.
Study Design
This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study composed of 2 phases, a 7-day screening phase and an 8-week double-blind phase. The 8-week double-blind phase consisted of a 4-week dose titration period followed by a 4-week fixed-dose period.
Screening Phase
Study eligibility was determined and informed consent obtained at the patients' first visit. At this visit, patients completed the SF-MPQ, had their medical history taken, and had physical and neurological examinations. Blood samples for hemoglobin A1c and serum creatinine (for creatinine clearance estimate) were taken. Patients meeting all criteria were given daily pain and sleep diaries and instructed on how to complete them.
Randomization
Diaries kept during the screening phase were collected and reviewed. Patients again completed an SF-MPQ at the end of the screening phase. Patients who remained eligible for the study were randomized in a double-blind fashion (in blocks of 4 according to a computer-generated random code) to receive either placebo or gabapentin. They then filled out a Short Form–36 Quality of Life (SF-36 QOL)33 Questionnaire and Profile of Mood States (POMS),34 and received their blinded medication and additional diaries.
Double-Blind Treatment Phase Titration Period
During the first 4 weeks of the study, patients received gradually titrated dosages of gabapentin (week 1, 900 mg/d; week 2, 1800 mg/d; week 3, 2400 mg/d; and week 4, 3600 mg/d) or placebo. Gabapentin (300 mg per capsule) and placebo were supplied to investigational sites in identical gray-gray capsules in blinded fashion. All patients were provided an equal number of capsules and instructed to follow a dosing schedule of 3 times per day. Because this was the first trial to evaluate gabapentin's efficacy in this patient population, all patients' dosages were titrated to tolerability up to 3600 mg/d regardless of any efficacy achieved at lower dosages. If intolerable adverse reactions occurred, the dosage was decreased 1 dose step to 900, 1200, 1800, or 2400 mg/d. Patients were reminded by telephone twice weekly to complete their daily diaries and were queried about adverse effects. Patients visited the clinic and completed an SF-MPQ at week 2 and week 4.
Fixed-Dose Period
During the second 4 weeks of the double-blind treatment phase, patients' treatment remained at their maximum tolerated dosage and daily diaries were continued. At study end (week 8) or early termination, the SF-MPQ, SF-36 QOL Questionnaire, and POMS were completed. Patients turned in the daily pain and sleep interference diaries and completed the Patient Global Impression of Change (PGIC). Investigators independently completed the Clinical Global Impression of Change (CGIC).
Efficacy and Safety Measurements
The primary efficacy parameter was a pain severity rating, recorded by patients in daily diaries using an 11-point Likert scale (0, no pain; 10, worst possible pain). Secondary efficacy parameters were the SF-MPQ scores, the weekly mean sleep interference score from the daily sleep diary, the PGIC, and the CGIC. Patients recorded pain and sleep information in the diaries on awakening for the preceding 24-hour period. The SF-MPQ consisted of 3 sections. In the first section, 15 items that described pain during the past week were rated from 0 (no pain) to 3 (severe pain). The second section was the 100-mm VAS, which rated the patient's pain during the previous week from no pain to worst possible pain. The third section was the Present Pain Intensity (PPI) Scale, which rated pain on a 6-point scale from 0 (no pain) to 5 (excruciating pain). Sleep interference was rated on an 11-point scale that described how pain had interfered with the patient's sleep during the past 24 hours (0, "did not interfere"; 10, "unable to sleep due to pain"). The PGIC was a 7-point scale on which patients rated any change in their overall status that they had experienced since beginning study medication from much improved to much worse. The CGIC was also a 7-point scale on which the clinician rated the change observed in the patient's overall status since the beginning of the study. Quality of life was assessed by the POMS and the SF-36 QOL Questionnaire. The POMS consisted of 65 measures of mood during the previous week, resulting in 6 mood scores: tension/anxiety, depression/dejection, anger/hostility, vigor/activity, fatigue/inertia, confusion/bewilderment, and total mood disturbance. The SF-36 QOL Questionnaire measured each of the following 8 health concepts: physical functioning, role limitations due to physical problems, social functioning, bodily pain, general mental health, role limitations due to emotional problems, vitality, and general health problems.
The safety of gabapentin was assessed using adverse event data (occurrence, intensity, and relationship to study drug) and the results of physical and neurological examinations, including peripheral sensory examinations. All patients randomized to treatment were evaluated for safety.
Statistical Analysis
Power Calculation
Published results of clinical trials in painful diabetic neuropathy indicate wide variation in placebo response, ranging from approximately 10% to 40%.19, 35-38 Response in these trials was based on measures such as "global pain relief of moderate or better" and "at least moderate improvement"; the trial with the longest duration of placebo administration (6 weeks) had the smallest placebo response (10%). Therefore, in this trial of 8 weeks' duration, we considered 30% a conservative estimate of placebo response, that is, at least moderate improvement on the CGIC. A gabapentin response of 55% to 60% on the same scale would be considered a clinically important finding. A sample size of 75 patients per group would provide more than 90% power to detect a difference of 30% and more than 80% power to detect a difference of 25% between placebo and gabapentin, given the assumptions stated herein.
Analyses
All testing was 2-sided at the .05 level and was done using SAS statistical software (SAS Institute Inc, Cary, NC) procedures. All analyses were conducted using the intent-to-treat population, defined as all randomized patients who received at least 1 dose of study medication. Patients with no data recorded for a particular parameter were automatically excluded from the analyses of that parameter. For each analysis of covariance (ANCOVA), adjusted (least squares) means were obtained from the model and 95% confidence intervals for the difference between placebo and gabapentin were constructed.
The end-point mean pain score and sleep interference score were calculated as the mean score for the last 7 diary entries while the patient was taking the study drug. The end-point mean pain score was analyzed for the intent-to-treat population (except for patients with no pain diary data during either screening or treatment) using ANCOVA. The model included main effects for treatment and center, using the screening mean pain score as the covariate. Consistency across sites was assessed by a second ANCOVA model that included a treatment-by-center interaction term. The end-point mean sleep interference score was analyzed for the intent-to-treat population (except for patients with no sleep diary data during either screening or treatment), using the screening mean sleep score as the covariate. The last observations for total pain score, VAS, and PPI of the SF-MPQ were analyzed, using ANCOVA with the respective scores at randomization as the covariates. The CGIC and PGIC were analyzed using a modified ridit transformation with the Cochran-Mantel-Haenszel procedure, adjusting for center. Each domain of the SF-36 QOL Questionnaire was analyzed separately using ANCOVA, with the response at randomization used as covariate. Supplemental analyses were performed at each week; the Hochberg procedure39 was used to adjust for multiple measurements over time of the mean pain, mean sleep interference, and SF-MPQ scores. Each item of the POMS and the overall score of mood disturbance was analyzed separately using ANCOVA, with scores at randomization as the covariate.
RESULTS
Of the 165 patients randomized, 84 were randomized to gabapentin and 81 to placebo. Patient demographics and baseline characteristics were similar between groups (Table 1). Approximately 75% of patients in each group had type 2 diabetes. The majority of patients had neuropathic pain involving the foot/toe and calf, and the mean pain score at baseline was similar between treatment groups. The pain descriptors of the SF-MPQ were similar between the placebo and gabapentin groups and between patients with type 1 and type 2 diabetes at baseline. Fifty-six gabapentin-treated patients (67%) achieved the 3600 mg/d dosage. Of the 84 patients randomized to gabapentin, 70 (83%) completed the study, 7 (8%) withdrew because of adverse events, 1 (1%) withdrew because of lack of efficacy, and 6 (7%) withdrew for other reasons. Of the 81 patients randomized to placebo, 65 (80%) completed the study, 5 (6%) withdrew because of adverse events, 5 (6%) withdrew because of lack of efficacy, and 6 (7%) withdrew for other reasons. A summary profile of the trial is presented in Figure 1.
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Table 1.—Patient Demographics and Baseline Characteristics
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Figure 1.—Profile of the randomized controlled trial. Asterisks indicate provided at least 1 efficacy assessment.
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Efficacy
Differences between gabapentin and placebo were significant at end point for the mean pain score, mean sleep interference score, and total pain, VAS, and PPI scores of the SF-MPQ (Table 2). When each week's results were analyzed separately, there was a significant difference (P<.05) between the gabapentin and placebo groups in mean pain scores from week 2 through week 8. Significant differences (P<.05) between patients randomized to the 2 groups were also observed in mean sleep interference scores at week 1 through week 8 (Figure 2). On the SF-MPQ, patients taking gabapentin had significantly lower mean total pain (P<.01), mean VAS (P<.01), and mean PPI (P<.05) scores at weeks 2, 4, and 8 when compared with (Figure 3). Of the patients who assessed PPI at the termination visit, 12 (15%) of 80 patients taking placebo and 21 (26%) of 82 patients taking gabapentin gave a rating of no pain. As measured by both PGIC and CGIC scales, patients treated with gabapentin had significantly (P = .001) greater improvement in pain than patients randomized to placebo (Figure 4). Approximately 60% of patients receiving gabapentin had at least a moderate improvement on the PGIC scale, whereas only 33% of patients receiving placebo had that degree of improvement. Additionally, 2 gabapentin-treated patients reported a score of worse on the PGIC scale, whereas 13 patients receiving placebo reported this score. Three gabapentin-treated patients scored worse on the CGIC scale compared with 10 patients receiving placebo. Gabapentin had a significant effect on 4 items of the POMS (anger/hostility, P = .02; vigor/activity, P = .01; fatigue/inertia, P = .01; and total mood disturbance, P = .03) compared with placebo. Gabapentin also had a positive effect on quality of life, as seen by significant differences from placebo on the bodily pain (P = .01), mental health (P = .03), and vitality (P = .001) scores of the SF-36 QOL Questionnaire. All other items of the QOL Questionnaire trended in the direction of a positive effect of gabapentin; however, none were significantly different than placebo.
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Table 2.—Summary of Analysis of Baseline and Last Observation or End Point for Efficacy Variables*
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Figure 2.—A, Weekly mean pain score as measured on an 11-point Likert scale from 0 (no pain) to 10 (worst possible pain). B, Weekly mean sleep interference scores as rated on an 11-point Likert scale that described how pain had interfered with the patient's sleep during the past 24 hours, from 0 (did not interfere) to 10 (unable to sleep due to pain). Asterisks indicate P<.05; daggers, P<.01.
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Figure 3.—A, Total score from the Short-Form McGill Pain Questionnaire. Patients assessed pain based on 15 sensory and affective descriptors on a scale of 0 (none) to 3 (severe). Total pain score was the sum of intensity ratings for all 15 descriptors. B, Visual analog scale score from the Short-Form McGill Pain Questionnaire. Patients placed a slash on a 100-mm line from 0 (no pain) to 100 (worst possible pain). C, Present Pain Intensity of the Short-Form McGill Pain Questionnaire. Present pain intensity was indicated using a scale of 0 (no pain), 1 (mild pain), 2 (discomfort), 3 (distressing), 4 (horrible), and 5 (excruciating). Asterisks indicate P<.05; daggers, P<.01.
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Figure 4.—A, The Patient Global Impression of Change (PGIC) was a 7-point scale on which patients rated any change in their overall status that they had experienced since beginning study medication. B, The Clinical Global Impression of Change (CGIC) was a 7-point scale on which the clinician rated the change observed in the patient's overall status since the beginning of the study. P = .001 using the Cochran-Mantel-Haenszel test.
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Safety
A total of 7 gabapentin-treated patients (8%) withdrew from the study because of a total of 13 adverse events: dizziness and somnolence (2 patients each), abdominal pain, asthenia, body odor, headache, diarrhea, abnormal thinking, nausea, confusion, and hypesthesia (1 patient each). A total of 5 patients (6%) who received placebo withdrew because of a total of 8 adverse events: dyspepsia, constipation, flatulence (2 patients each), infection, and somnolence (1 patient each). The most frequently reported adverse events are shown in Table 3. Most adverse events in patients treated with gabapentin were of mild or moderate intensity. There were no significant changes in hemoglobin A1c levels from baseline to the end of treatment in either group, indicating that glycemic control was maintained during the study. Neurological examination data revealed no group differences in the rate of disease progression. Specifically, the proportion of patients with a change from normal or decreased at baseline to absent at study termination was similar between groups (<14% in each case) for the 3 sensory modalities tested (temperature, light touch, and pin prick). Additionally, evaluation of reflex changes and changes in gait showed no difference between groups.
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Table 3.—Most Frequently Reported Adverse Events*
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COMMENT
We have determined the efficacy and safety of gabapentin in reducing pain attributed to peripheral neuropathy in a population of patients with diabetes mellitus by conducting a large, double-blind, placebo-controlled, randomized, parallel-group trial. Gabapentin monotherapy proved effective in decreasing pain associated with diabetic peripheral neuropathy. Several aspects of the study design and conduct are important to consider in interpreting the results. We chose to perform a large, simple clinical trial in which patient diagnosis was made clinically and was not dependent on electrophysiological data. This type of trial is appropriate, especially when the treatment is designed to affect symptoms rather than alter the disease process. The Michigan Neuropathy Screening Instrument, a questionnaire and clinical screening examination, predicted the result of electrophysiological tests in 28 of 29 patients with diabetes,40 demonstrating that a history and physical examination alone are adequate for the diagnosis of neuropathy in this population. A similar strategy was used in 2 large clinical trials of mexiletine for the symptomatic relief of diabetic peripheral neuropathy.41-42
Because the study end point of pain was subjective, we explored the possibility that the occurrence of adverse events resulted in unblinding of the study, biasing the result of our efficacy analysis (Table 2). Dizziness and somnolence, the 2 most frequent adverse events, were also those with the largest difference in incidence between the gabapentin and placebo groups. To assess the effect that patients with these events had on the primary efficacy variable we excluded their data and reanalyzed the efficacy data. After excluding data from patients who reported dizziness, the mean pain score between groups differed by –1.19 (P = .002), favoring the gabapentin group (gabapentin [n = 62] mean, 4.02; placebo [n = 75] mean, 5.21). After excluding data from patients who reported somnolence, the mean pain score between groups differed by –0.81 (P = .03), also favoring the gabapentin group (gabapentin [n = 63] mean, 4.19; placebo [n = 75] mean, 5.21). Thus, inclusion of patients who experienced these central nervous system adverse effects in the original analysis did not account for the overall efficacy seen in the trial.
Recent systematic reviews discuss treatment regimens that intended to modify the incidence of neuropathy in a cohort of patients with diabetes, alter the course of an established neuropathy, or reduce symptoms alone.15-18 These reviews support the effectiveness of long-term glycemic control in a reduction of the incidence of neuropathy in patients with diabetes, the potential use of aldose reductase inhibitors to slow the progression of neuropathy, and the effectiveness of TCAs to reduce pain. A systematic review of the results of controlled clinical trials for the reduction of pain in peripheral neuropathy due to any cause revealed "clear evidence" for the effectiveness of TCAs; "consistent support" for intravenous and topical lidocaine, carbamazepine, and topical aspirin; and "contradictory" trial data for the effectiveness of mexiletine, phenytoin, topical capsaicin, oral nonsteroidal anti-inflammatory medications, and opiates. Intravenous morphine was considered "probably effective." Codeine, propranolol, lorazepam, and phentolamine were considered "ineffective."20
The magnitude of effect on pain observed with gabapentin treatment is similar to that reported in trials of TCAs,37 and the onset of action is more rapid. By the first week (900 mg/d), an improvement was observed in the mean sleep interference scores (Figure 2) and by the second week (1800 mg/d), improvements were seen for all pain rating scales (Figure 2 and Figure 3). Gabapentin's positive effect on quality of life measures (Table 2) suggests that this effect is clinically significant.
Dose-limiting adverse effects remain a problem for patients with neuropathic pain. The effectiveness of TCA therapy is often limited by intolerable adverse effects (sedation, urinary retention, orthostatic hypotension, cardiac arrhythmias) or a delayed onset of action.21
In this study, gabapentin appeared to be well tolerated, with 56 (67%) of the 84 patients achieving the forced maximum dosage of 3600 mg/d. The frequency of dizziness and somnolence may be attributed in part to the high dosage chosen for study. Since efficacy was achieved before completion of the titration phase of the study (Figure 2 and Figure 3), dose titration while observing the therapeutic response might reduce the incidence of dizziness and somnolence we observed.
Gabapentin monotherapy produced rapid onset of clinically meaningful pain relief with relatively minor and potentially avoidable adverse effects in this trial. Gabapentin is a promising new agent for use in patients with neuropathic pain when therapeutic options are limited and offers advantages over currently available treatments as a first-line agent.
AUTHOR INFORMATION
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We acknowledge the additional members of the Gabapentin Diabetic Neuropathy Study Group: David Bell, MD; Vera Bril, MD; Enrique J. Carrazana, MD; Richard Guthrie, MD; Bruce Henson, MD; Jonathan Jaspan, MD (deceased); Michael P. Merchut, MD; Michael Pfeifer, MD; Neelan Pillay, MD; Daniel Porte, Jr, MD; Julio Rosenstock, MD; Melvin Stjernholm, MD; Donald Studney, MD; Albert Tahmoush, MD; Aaron I. Vinik, MD; and Peter Weissman, MD. Additionally, we acknowledge Lee Hayes for her extensive contributions and leadership in the design and early development of this study, and we thank Judith Bammert Adams, PharmD, and Mark Aills, MPH, for their editorial and technical contributions to the manuscript.
Mss Hes and LaMoreaux and Dr Garofalo are employees of Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co, and own stock and hold options to purchase further stock in the company. Drugs and compensation for study expenses were supplied by Parke-Davis, the study sponsor.
Corresponding author: Miroslav Backonja, MD, Department of Neurology, University of Wisconsin, 600 Highland Ave, Madison, WI 53792 (e-mail: backonja{at}neurology.wisc.edu).
Reprints: Marykay Hes, 2800 Plymouth Rd, Ann Arbor, MI 48105.
From the Department of Neurology, University of Wisconsin, Madison (Dr Backonja); the Department of Neurology, University of Michigan (Dr Beydoun), and Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co (Mss Hes and LaMoreaux and Dr Garofalo), Ann Arbor; Neurological Consultants, PC, Bennington, Vt (Dr Edwards); the Diabetes and Glandular Disease Clinic, San Antonio, Tex (Dr Schwartz); and the Diabetes Program, University of Arkansas for Medical Sciences, Little Rock (Dr Fonseca).
REFERENCES
1. Johnson PC, Doll SC, Cromey DW. Pathogenesis of diabetic neuropathy. Ann Neurol. 1986;19:450-457.
FULL TEXT
|
ISI
| PUBMED
2. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabete Metab. 1977;3:173-182, 245-256.
ISI
| PUBMED
3. Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
FREE FULL TEXT
4. Diabetes Control and Complications Trial (DCCT) Research Group. Effect of intensive diabetes treatment on nerve conduction in the Diabetes Control and Complications Trial. Ann Neurol. 1995;38:869-880.
FULL TEXT
|
ISI
| PUBMED
5. Dyck PJ, Melton LJ, O'Brien PC, Service FJ. Approaches to improve epidemiological studies of diabetic neuropathy: insights from the Rochester Diabetic Neuropathy Study. Diabetes. 1997;46(suppl 2):S5-S8.
6. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993;43:817-824.
FREE FULL TEXT
7. Dyck PJ, Litchy WJ, Lehman KA, Hokanson JL, Low PA, O'Brien PC. Variables influencing neuropathic endpoints: the Rochester Diabetic Neuropathy Study of healthy subjects. Neurology. 1995;45:1115-1121.
ABSTRACT
8. Dyck PJ, Karnes JL, O'Brien PC, Litchy WJ, Low PA, Melton LJ. The Rochester Diabetic Neuropathy Study: reassessment of tests and criteria for diagnosis and staged severity. Neurology. 1992;42:1164-1170.
FREE FULL TEXT
9. Dyck PJ, Kratz KM, Lehman KA, et al. The Rochester Diabetic Neuropathy Study: design, criteria for types of neuropathy, selection bias, and reproducibility of neuropathic tests. Neurology. 1991;41:799-807.
FREE FULL TEXT
10. Proceedings of a consensus development conference on standardized measures in diabetic neuropathy Neurology. 1992;42:1823-1839.
FREE FULL TEXT
11. Albers JW, Brown MB, Sima AAF, Greene DA, for the Tolrestat Study Group for the Early Diabetes Intervention Trial. Nerve conduction measures in mild diabetic neuropathy in the Early Diabetes Intervention Trial: the effects of age, sex, type of diabetes, disease duration, and anthropometric factors. Neurology. 1996;46:85-91.
FREE FULL TEXT
12. Report and recommendations of the San Antonio Conference on Diabetic Neuropathy Diabetes. 1988;37:1000-1004.
ISI
| PUBMED
13. Peripheral Nerve Society. Diabetic polyneuropathy in controlled clinical trials: consensus report of the Peripheral Nerve Society. Ann Neurol. 1995;38:478-482.
FULL TEXT
|
ISI
| PUBMED
14. Fields HL. Painful dysfunction of the nervous system. In: Fields HL, ed. PainNew York, NY: McGraw-Hill Information Services Co; 1987:133-169.
15. Dejgaard A. Pathophysiology and treatment of diabetic neuropathy. Diabet Med. 1998;15:97-112.
FULL TEXT
|
ISI
| PUBMED
16. Pfeifer MA, Schumer MP, Gelber DA. Aldose reductase inhibitors: the end of an era or the need for different trial designs? Diabetes. 1997;46(suppl 2):S82-S89.
17. Calissi PT, Jaber LA. Peripheral diabetic neuropathy: current concepts in treatment. Ann Pharmacother. 1995;29:769-777.
ABSTRACT
18. Fedele D, Guigliano D. Peripheral diabetic neuropathy, current recommendations and future prospects for its prevention and management. Drugs. 1997;54:414-421.
ISI
| PUBMED
19. Max MB. Thirteen consecutive well-designed randomized trials show that antidepressants reduce pain in diabetic neuropathy and postherpetic neuralgia. Pain Forum. 1995;4:248-253.
20. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain. 1997;73:123-139.
FULL TEXT
|
ISI
| PUBMED
21. Feldman EL, Stevens MJ, Greene DA. Treatment of diabetic neuropathy. In: Mazzaferri EL, Bar RS, Kreisberg RA, eds. Advances in Endocrinology and MetabolismSt Louis, Mo: Mosby–Year Book Inc; 1994:393-428.
22. Rosner H, Rubin L, Kestenbaum A. Gabapentin adjunctive therapy in neuropathic pain states. Clin J Pain. 1996;12:56-58.
FULL TEXT
|
ISI
| PUBMED
23. Stacey BR, Tipton KD, Owen GT, Sinclair JD, Glick RM. Gabapentin and neuropathic pain states: a case series report. Reg Anesth. 1996;2(suppl):65.
24. Neurontin prescribing information. In: Physicians' Desk Reference.Montvale, NJ: Medical Economics Co Inc; 1995:1856-1858.
25. Vollmer KO, Von Hodenberg A, Kolle EU. Pharmacokinetics and metabolism of gabapentin in rat, dog, and man. Arzneimittelforschung. 1986;36:830-839.
PUBMED
26. Ojemann LM, Friel PN, Ojemann GA. Gabapentin concentrations in human brain [abstract]. Epilepsia. 1988;29:694.
27. Taylor CP, Gee NS, Su TZ, et al. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res. 1998;29:233-249.
ISI
| PUBMED
28. Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33:87-107.
FULL TEXT
|
ISI
| PUBMED
29. Xiao WH, Bennett GJ. Gabapentin relieves abnormal pain in a rat model of painful peripheral neuropathy. Soc Neurosci Abstracts. 1995;21:897.
30. Shimoyama N, Shimoyama M, Davis AM, Inturrisis CE, Elliott KJ. Spinal gabapentin in antinociceptive in the rat formalin test. Neurosci Lett. 1997;222:65-67.
FULL TEXT
|
ISI
| PUBMED
31. Melzack R. The Short-Form McGill Pain Questionnaire. Pain. 1987;30:191-197.
FULL TEXT
|
ISI
| PUBMED
32. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41.
ISI
| PUBMED
33. Ware JE Jr, Snow KK, Konsinski M, Gandek B. SF-36 Health Survey: Manual and Interpretation Guide. Boston, Mass: The Health Institute, New England Medical Center; 1993.
34. McNair DM, Lorr M, Droppleman LF. Profile of Mood States: Manual. San Diego, Calif: Educational and Industrial Testing Service; 1981.
35. McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A. Anticonvulsant drugs for management of pain: a systematic review. BMJ. 1995;311:1047-1052.
FREE FULL TEXT
36. Max MB, Kishore-Kumar R, Schafer SC, et al. Efficacy of desipramine in painful diabetic neuropathy: a placebo-controlled trial. Pain. 1991;45:3-9.
FULL TEXT
|
ISI
| PUBMED
37. Max MB, Lynch SA, Muire J, Shoaf SE, Smoller B, Dubner R. Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med. 1992;326:1250-1256.
ABSTRACT
38. Max MB, Culnane M, Schager SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology. 1987;37:589-596.
FREE FULL TEXT
39. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika. 1988;75:800-802.
FREE FULL TEXT
40. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care. 1994;17:1281-1289.
ABSTRACT
41. Stracke H, Meyer UE, Schumacher HE, Federlin K. Mexiletine in the treatment of diabetic neuropathy. Diabetes Care. 1992;15:1550-1555.
ABSTRACT
42. Oskarsson P, Ljunggren JG, Lins PE. Efficacy and safety of mexiletine in the treatment of painful diabetic neuropathy. Diabetes Care. 1997;20:1594-1597.
ABSTRACT
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References
APPI Online CME 2007;2007:2-2.
FULL TEXT
Relief of Idiopathic Subjective Tinnitus: Is Gabapentin Effective?
Piccirillo et al.
Arch Otolaryngol Head Neck Surg 2007;133:390-397.
ABSTRACT
| FULL TEXT
Cannabis in painful HIV-associated sensory neuropathy: A randomized placebo-controlled trial
Abrams et al.
Neurology 2007;68:515-521.
ABSTRACT
| FULL TEXT
Pain Management in Elderly Patients
Hix
Journal of Pharmacy Practice 2007;20:49-63.
ABSTRACT
Pharmacologic Treatments for Pain Associated With Diabetic Peripheral Neuropathies
Abrams
Journal of Pharmacy Practice 2007;20:103-109.
ABSTRACT
Painful Diabetic Neuropathy: A Management-Centered Review
Huizinga and Peltier
Clin. Diabetes 2007;25:6-15.
ABSTRACT
| FULL TEXT
Efficacy and Safety of {alpha}-Lipoic Acid Supplementation in the Treatment of Symptomatic Diabetic Neuropathy
Foster
The Diabetes Educator 2007;33:111-117.
ABSTRACT
| FULL TEXT
A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain
Wernicke et al.
Neurology 2006;67:1411-1420.
ABSTRACT
| FULL TEXT
Gabapentin in the operating room: clear for discharge?
Markman
Neurology 2006;67:1116-1117.
FULL TEXT
The Search for New Off-Label Indications for Antidepressant, Antianxiety, Antipsychotic and Anticonvulsant Drugs
Chouinard
Focus 2006;4:528.
FULL TEXT
The use of "off-label" drugs.
Broadman and Semenov
Anesth. Analg. 2006;103:250-251.
FULL TEXT
The impact of therapy on quality of life and mood in neuropathic pain: what is the effect of pain reduction?
Deshpande et al.
Anesth. Analg. 2006;102:1473-1479.
ABSTRACT
| FULL TEXT
Consensus Guidelines: Treatment Planning and Options
Argoff et al.
Mayo Clin Proc. 2006;81:S12-S25.
ABSTRACT
| FULL TEXT
Diabetic Peripheral Neuropathic Pain: Case Studies
Belgrade et al.
Mayo Clin Proc. 2006;81:S26-S32.
ABSTRACT
| FULL TEXT
Small-fiber neuropathy: answering the burning questions.
Fink and Oaklander
Sci Aging Knowl Environ 2006;2006:pe7-pe7.
ABSTRACT
| FULL TEXT
Effect of oral gabapentin on postoperative epidural analgesia
Turan et al.
Br J Anaesth 2006;96:242-246.
ABSTRACT
| FULL TEXT
Gabapentin: An Alternative to the Cyclooxygenase-2 Inhibitors for Perioperative Pain Management
Turan et al.
Anesth. Analg. 2006;102:175-181.
ABSTRACT
| FULL TEXT
Placebo response in clinical trials of depression and its implications for research on chronic neuropathic pain
Dworkin et al.
Neurology 2005;65:S7-S19.
ABSTRACT
| FULL TEXT
Clinical trials studying pharmacotherapy and psychological treatments alone and together
Haythornthwaite
Neurology 2005;65:S20-S31.
ABSTRACT
| FULL TEXT
Mechanisms of neuropathic pain and their implications for the design of clinical trials
Rowbotham
Neurology 2005;65:S66-S73.
ABSTRACT
| FULL TEXT
From The Cover: Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans
Iannetti et al.
Proc. Natl. Acad. Sci. USA 2005;102:18195-18200.
ABSTRACT
| FULL TEXT
Recent advances in the diagnosis and management of diabetic neuropathy
Rathur and Boulton
J Bone Joint Surg Br 2005;87-B:1605-1610.
FULL TEXT
Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis
Rog et al.
Neurology 2005;65:812-819.
ABSTRACT
| FULL TEXT
Management of Neuropathic Pain
Galluzzi
JAOA: Journal of the American Osteopathic Association 2005;105:S12-S19.
ABSTRACT
| FULL TEXT
Use of Antiepileptic Drugs in the Treatment of Chronic Painful Diabetic Neuropathy
Vinik
J. Clin. Endocrinol. Metab. 2005;90:4936-4945.
ABSTRACT
| FULL TEXT
Practical Management of Patients With Painful Diabetic Neuropathy
Corbett
The Diabetes Educator 2005;31:523-540.
ABSTRACT
| FULL TEXT
Contemporary assessment and management of neuropathic pain
Irving
Neurology 2005;64:S21-S27.
ABSTRACT
| FULL TEXT
Efficacy and Safety of Opioid Agonists in the Treatment of Neuropathic Pain of Nonmalignant Origin: Systematic Review and Meta-analysis of Randomized Controlled Trials
Eisenberg et al.
JAMA 2005;293:3043-3052.
ABSTRACT
| FULL TEXT
Reduction of Hepatic and Adipose Tissue Glucocorticoid Receptor Expression With Antisense Oligonucleotides Improves Hyperglycemia and Hyperlipidemia in Diabetic Rodents Without Causing Systemic Glucocorticoid Antagonism
Watts et al.
Diabetes 2005;54:1846-1853.
ABSTRACT
| FULL TEXT
Morphine, Gabapentin, or Their Combination for Neuropathic Pain
Gilron et al.
NEJM 2005;352:1324-1334.
ABSTRACT
| FULL TEXT
Combination Therapy for Neuropathic Pain -- Which Drugs, Which Combination, Which Patients?
Raja and Haythornthwaite
NEJM 2005;352:1373-1375.
FULL TEXT
Evaluating the Patient with Peripheral Nervous System Complaints
Scott and Kothari
JAOA: Journal of the American Osteopathic Association 2005;105:71-83.
ABSTRACT
| FULL TEXT
Treatment of chronic pain in persons with dementia: An overview
Rubey
AM J ALZHEIMERS DIS OTHER DEMEN 2005;20:12-20.
ABSTRACT
Pregabalin relieves symptoms of painful diabetic neuropathy: A randomized controlled trial
Lesser et al.
Neurology 2004;63:2104-2110.
ABSTRACT
| FULL TEXT
Contemporary Management of Neuropathic Pain for the Primary Care Physician
Chen et al.
Mayo Clin Proc. 2004;79:1533-1545.
ABSTRACT
XP13512 [({+/-})-1-([({alpha}-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: I. Design, Synthesis, Enzymatic Conversion to Gabapentin, and Transport by Intestinal Solute Transporters
Cundy et al.
J. Pharmacol. Exp. Ther. 2004;311:315-323.
ABSTRACT
| FULL TEXT
XP13512 [({+/-})-1-([({alpha}-Isobutanoyloxyethoxy)carbonyl] aminomethyl)-1-cyclohexane Acetic Acid], A Novel Gabapentin Prodrug: II. Improved Oral Bioavailability, Dose Proportionality, and Colonic Absorption Compared with Gabapentin in Rats and Monkeys
Cundy et al.
J. Pharmacol. Exp. Ther. 2004;311:324-333.
ABSTRACT
| FULL TEXT
The Effects of Intrathecal Gabapentin on Spinal Morphine Tolerance in the Rat Tail-Flick and Paw Pressure Tests
Hansen et al.
Anesth. Analg. 2004;99:1180-1184.
ABSTRACT
| FULL TEXT
Topiramate vs placebo in painful diabetic neuropathy: Analgesic and metabolic effects
Raskin et al.
Neurology 2004;63:865-873.
ABSTRACT
| FULL TEXT
Polyneuropathy in the diabetic patient--update on pathogenesis and management
Ziegler
Nephrol Dial Transplant 2004;19:2170-2175.
FULL TEXT
Adjuvant Analgesics in Cancer Pain Management
Lussier et al.
The Oncologist 2004;9:571-591.
ABSTRACT
| FULL TEXT
The Analgesic Effects of Gabapentin in Monitored Anesthesia Care for Ear-Nose-Throat Surgery
Turan et al.
Anesth. Analg. 2004;99:375-378.
ABSTRACT
| FULL TEXT
Gabapentin for Neuropathic Cancer Pain: A Randomized Controlled Trial From the Gabapentin Cancer Pain Study Group
Caraceni et al.
JCO 2004;22:2909-2917.
ABSTRACT
| FULL TEXT
Diabetic Somatic Neuropathies
Boulton et al.
Diabetes Care 2004;27:1458-1486.
FULL TEXT
Case 16-2004 - A 76-Year-Old Woman with Numbness and Pain in the Feet and Legs
Amato and Oaklander
NEJM 2004;350:2181-2189.
FULL TEXT
Gabapentin for the treatment of painful diabetic neuropathy: dosing to achieve optimal clinical response
Gomez-Perez et al.
British Journal of Diabetes & Vascular Disease 2004;4:173-178.
ABSTRACT
The Analgesic Effects of Gabapentin After Total Abdominal Hysterectomy
Turan et al.
Anesth. Analg. 2004;98:1370-1373.
ABSTRACT
| FULL TEXT
Understanding co-morbidities affecting children with epilepsy
Pellock
Neurology 2004;62:S17-23.
ABSTRACT
| FULL TEXT
Pulsed Magnetic Field Therapy in Refractory Neuropathic Pain Secondary to Peripheral Neuropathy: Electrodiagnostic Parameters--Pilot Study
Weintraub and Cole
Neurorehabil Neural Repair 2004;18:42-46.
ABSTRACT
Pharmacologic Management of Foot Pain in the Older Patient
Martin
J. Am. Podiatr. Med. Assoc. 2004;94:98-103.
ABSTRACT
| FULL TEXT
Gabapentin in the treatment of neuropathic pain
Bennett and Simpson
Palliat Med 2004;18:5-11.
ABSTRACT
Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study
Kochar et al.
QJM 2004;97:33-38.
ABSTRACT
| FULL TEXT
Gabapentin in the prophylaxis of chronic daily headache: A randomized, placebo-controlled study
Spira and Beran
Neurology 2003;61:1753-1759.
ABSTRACT
| FULL TEXT
Advances in Neuropathic Pain: Diagnosis, Mechanisms, and Treatment Recommendations
Dworkin et al.
Arch Neurol 2003;60:1524-1534.
ABSTRACT
| FULL TEXT
Pregabalin for the treatment of postherpetic neuralgia: A randomized, placebo-controlled trial
Dworkin et al.
Neurology 2003;60:1274-1283.
ABSTRACT
| FULL TEXT
Painful Sensory Neuropathy
Mendell and Sahenk
NEJM 2003;348:1243-1255.
FULL TEXT
Controlled-release oxycodone for pain in diabetic neuropathy: A randomized controlled trial
Gimbel et al.
Neurology 2003;60:927-934.
ABSTRACT
| FULL TEXT
Diabetic neuropathy: achieving best practice
Tesfaye
British Journal of Diabetes & Vascular Disease 2003;3:112-117.
ABSTRACT
Painful diabetic neuropathy -- current understanding and management for the primary care team
Kirby
British Journal of Diabetes & Vascular Disease 2003;3:138-144.
ABSTRACT
Treatment of restless legs syndrome with gabapentin: A double-blind, cross-over study
Garcia-Borreguero et al.
Neurology 2002;59:1573-1579.
ABSTRACT
| FULL TEXT
Gabapentin and the Neurokinin1 Receptor Antagonist CI-1021 Act Synergistically in Two Rat Models of Neuropathic Pain
Field et al.
J. Pharmacol. Exp. Ther. 2002;303:730-735.
ABSTRACT
| FULL TEXT
Drug points: Gabapentin induced cholestasis
Richardson et al.
BMJ 2002;325:635-635.
FULL TEXT
Use of anticonvulsants for treatment of neuropathic pain
Backonja
Neurology 2002;59:S14-17.
ABSTRACT
| FULL TEXT
Elevated Spinal Cyclooxygenase and Prostaglandin Release During Hyperalgesia in Diabetic Rats
Freshwater et al.
Diabetes 2002;51:2249-2255.
ABSTRACT
| FULL TEXT
Gabapentin
Rosenquist
J Am Acad Orthop Surg 2002;10:153-156.
FULL TEXT
The Impact of Clinical Trials on the Treatment of Diabetes Mellitus
Nathan
J. Clin. Endocrinol. Metab. 2002;87:1929-1937.
ABSTRACT
| FULL TEXT
Pharmacology of Opioid and Nonopioid Analgesics in Chronic Pain States
Martin and Eisenach
J. Pharmacol. Exp. Ther. 2001;299:811-817.
ABSTRACT
| FULL TEXT
Double-blind, randomized trial of bupropion SR for the treatment of neuropathic pain
Semenchuk et al.
Neurology 2001;57:1583-1588.
ABSTRACT
| FULL TEXT
Clinical case study.
Haglund et al.
AM J HOSP PALLIAT CARE 2001;18:429-431.
Is Massage Useful in the Management of Diabetes? A Systematic Review
Ezzo et al.
Diabetes Spectr. 2001;14:218-224.
ABSTRACT
| FULL TEXT
Lamotrigine reduces painful diabetic neuropathy: A randomized, controlled study
Eisenberg et al.
Neurology 2001;57:505-509.
ABSTRACT
| FULL TEXT
Complex regional pain syndrome
Harden
Br J Anaesth 2001;87:99-106.
ABSTRACT
| FULL TEXT
Gabapentin: resistant neuropathic pain and malignancy
Ross et al.
Palliat Med 2001;15:348-349.
Differential Effect of Gabapentin on Neuronal and Muscle Calcium Currents
Alden and García
J. Pharmacol. Exp. Ther. 2001;297:727-735.
ABSTRACT
| FULL TEXT
Upregulation of Dorsal Root Ganglion {alpha}2{delta} Calcium Channel Subunit and Its Correlation with Allodynia in Spinal Nerve-Injured Rats
Luo et al.
J. Neurosci. 2001;21:1868-1875.
ABSTRACT
| FULL TEXT
{gamma}-Aminobutyric Acid Type B Receptors with Specific Heterodimer Composition and Postsynaptic Actions in Hippocampal Neurons Are Targets of Anticonvulsant Gabapentin Action
Ng et al.
Mol. Pharmacol. 2001;59:144-152.
ABSTRACT
| FULL TEXT
Drug treatment of neuropathic pain
DTB 2000;38:89-93.
ABSTRACT
| FULL TEXT
New Antiepileptic Drugs: Into the New Millennium
Tatum et al.
Arch Fam Med 2000;9:1135-1141.
ABSTRACT
| FULL TEXT
Pharmacologic treatment of pain in polyneuropathy
Sindrup and Jensen
Neurology 2000;55:915-920.
ABSTRACT
| FULL TEXT
Lack of efficacy of riluzole in the treatment of peripheral neuropathic pain conditions
Galer et al.
Neurology 2000;55:971-975.
ABSTRACT
| FULL TEXT
Gabapentin in Pain Management
Mao and Chen
Anesth. Analg. 2000;91:680-687.
FULL TEXT
Gabapentin Enhances the Analgesic Effect of Morphine in Healthy Volunteers
Eckhardt et al.
Anesth. Analg. 2000;91:185-191.
ABSTRACT
| FULL TEXT
Gabapentin vs Amitriptyline for the Treatment of Peripheral Neuropathy
Fudin et al.
Arch Intern Med 2000;160:1040-1041.
FULL TEXT
Gabapentin for treatment of thalamic pain syndrome
Holtom
Palliat Med 2000;14:167-167.
|
