Gabapentin vs. Amitriptyline in Painful Diabetic Neuropathy: An Open-Label Pilot Study

280 Journal of Pain and Symptom Management Vol. 20 No. 4 October 2000 Original Article Gabapentin vs. Amitriptyline in Painful Diabetic Neuropathy: An Open-Label Pilot Study Carlo Dallocchio, MD, Carlo Buffa, MD, Paolo Mazzarello, MD, and Silvia Chiroli, MD Department of Neurology and Rehabilitative Medicine-S. Giacomo Hospital (C.D., C. B.), Novi Ligure; Biochemical and Evolutionist Genetic Institute, National Research Council (P.M.), Pavia; and Medical Division, Parke-Davis SpA, Milan, Italy (S.C.) Abstract The objective of this study was to compare the efficacy and tolerability of gabapentin and amitriptyline monotherapy in ful diabetic neuropathy. This was a 12-week, open-label, prospective, randomized trial. Twenty-five type-ii diabetic patients with attributed to diabetic neuropathy and a minimum of 2 on a intensity scale ranging from 0 (no ) to 4 (excruciating ) were randomized to receive either gabapentin, titrated from 1,200 mg/day to a maximum of 2,400 mg/day, or amitriptyline, titrated from 30 mg/day to a maximum of 90 mg/day. Both drugs were titrated over a 4-week period and maintained at the maximum tolerated dose for 8 weeks. The main outcome measures were weekly intensity and intensity, measured on two categorical scales. Thirteen patients received gabapentin and 12 received amitriptyline. All 25 patients completed the trial. Gabapentin produced greater reductions than amitriptyline (mean final s were 1.9 vs. 1.3 points below baseline s; P 0.026). Decreases in s also were in favor of gabapentin (1.8 vs. 0.9 points; P 0.004). Adverse events were more frequent in the amitriptyline group than in the gabapentin group: they were reported by 11/12 (92%) and 4/13 (31%) of patients, respectively (P 0.003). Side effects were the main limiting factor preventing dose escalation. Gabapentin produced greater improvements than amitriptyline in and associated with diabetic neuropathy. Additionally, gabapentin was better tolerated than amitriptyline. Further controlled trials are needed to confirm these preliminary results. J Pain Symptom Manage 2000;20:280 285. U.S. Cancer Pain Relief Committee, 2000. Key Words Gabapentin, amitriptyline, diabetic neuropathy,, Introduction Gabapentin (GBP) is an anticonvulsant whose efficacy has been recently demonstrated Address reprint requests to: Paolo Mazzarello, MD, Istituto di Genetica, Biochimica ed Evoluzionistica, CNR, Via Abbiategrasso 207, I-27100 Pavia, Italy. Accepted for publication: November 6, 1999. in a double-blind, placebo-controlled trial of treatment of ful diabetic neuropathy. 1 Classically, tricyclic antidepressant (TCA) agents have been considered the first-line therapy for ful diabetic neuropathy. 2 4 No studies have been published comparing efficacy and side effects of GBP vs. TCAs. The aim of this study was to perform a preliminary comparison of the efficacy and safety U.S. Cancer Pain Relief Committee, 2000 0885-3924/00/$ see front matter Published by Elsevier, New York, New York PII S0885-3924(00)00181-0

Vol. 20 No. 4 October 2000 GBP vs. AMI in Painful Diabetic Neuropathy 281 of GBP with a TCA, amitriptyline (AMI), in elderly patients with ful diabetic neuropathy. In this trial, AMI was chosen as the comparative drug because it is considered the gold standard in the treatment of diabetic neuropathy and its efficacy has been demonstrated in several clinical trials. 5 7 Other TCAs, such as desipramine, 8 imipramine, 9 and nortriptyline, 10 have been studied in diabetic neuropathy or other ful conditions. Some reviews indicate that AMI is the most effective TCA in the treatment of neuropathic and note that it is probably the least tolerated one due to side effects that are frequently dose limiting. 11,12 Methods This was an open-label pilot study with a 12- week. Patients were randomly allocated to therapy with either GBP or AMI. Patients eligible for inclusion were male or female, aged 60 years, with type-ii diabetes (stabilized glycemic values) and clinically relevant lower limb polyneuropathy with significant and s lasting at least 6 months. On examination, patients had to exhibit either absence of Achilles reflexes or reduction of vibration sensitivity. Eligible patients also had to obtain a intensity of at least 2 on a 4-point (0 4) categorical scale (0, no ; 1, mild ; 2, moderate ; 3, severe ; 4, excruciating ). Each patient was asked to rate the average experienced during the previous use of GBP or AMI; presence of renal, hepatic or cardiovascular insuffiency; diabetic neuropathy not meeting the above criteria; neuropathy of different etiology; and current/previous diagnosis of psychiatric disorder. The use of other adjuvant analgesics, such as other TCAs, mexiletine, carbamazepine, or other anticonvulsants, was forbidden throughout the study. In cases of previous administration of such drugs, they had to be discontinued at least 1 month prior to randomization. Benzodiazepines were allowed if their dose had been stable for at least 1 month before randomization and was kept unchanged throughout the study. GBP and AMI were administered as monotherapy, with a three-time daily dosing schedule. GBP was started at 400 mg/day and AMI was started at 10 mg/day. During the first week of study, the dosage was titrated in all patients up to 1,200 mg/day GBP or 30 mg/day AMI. Over the following 3 weeks, doses were further increased in an effort to reduce s to 1 or less. Titration up to a maximum of 2,400 mg/day GBP or 90 mg/day AMI was performed by weekly increments of 400 mg/day for GBP or 20 mg/day for AMI. However, in case of intolerable side effects, doses were increased up to the maximum tolerated dosage. Thereafter, through the last 8 weeks of study, doses were kept constant. The primary efficacy parameter was the at the last visit. A secondary efficacy parameter was the, measured on a 4-point categorical scale similar to the scale. Each patient was also asked to describe the quality of the perceived and to specify whether s were ful or just tingling sensations. Safety profiles of the drugs were compared by recording the occurrence of adverse events. The small size of data sets dictated that distribution-free methods should be used for the analyses since assumptions about the distribution of variables and homogeneity of variances could not be made. Two-tailed tests were used for the analyses with a significance level of P 0.05. Gender (female/male) and antidiabetic therapy (oral antidiabetic agents or insulin) were compared in the two groups (GBP and AMI) by Fisher s exact test. The Mann-Whitney U-test for independent samples was used to compare the two groups for age, of diabetes, of and s (months), and baseline s of and. Within-group differences were compared with baseline values by using the Wilcoxon matched-pairs signed-ranks test. The Mann- Whitney U-test was applied to differences from baseline values to assess the effects of both treatments. Fisher s exact test was used to compare the frequencies of adverse events observed in the two treatment groups. Results A total of 25 patients were enrolled and all of them completed the trial. Thirteen individuals (seven males and six females) were treated with GBP at the mean dose of 1785 351 mg/ day, while 12 patients (four males and eight fe-

282 Dallocchio et al. Vol. 20 No. 4 October 2000 Patient no. Gender Age Diabetes Pain (months) Type of Table 1 Data for GBP-Treated Patients Type of Antidiabetic therapy Maximum dose (mg/day) Adverse events 1 F 80 13 36 Burning Tingling Oral 1,600 3 2 4 3 Dizziness 2 F 70 15 36 Cramping Tingling Insulin 1,600 2 2 2 2 Dizziness 3 M 61 12 48 Burning Tingling Insulin 2,400 4 2 4 2 4 M 68 3 12 Burning Painful Oral 2,000 4 1 4 1 5 F 62 15 36 Shooting Painful Insulin 1,600 3 1 3 1 6 M 72 11 48 Aching Painful Insulin 2,400 2 0 2 0 Somnolence 7 F 75 11 30 Shooting Painful Oral 1,600 3 1 3 1 8 M 60 5 24 Cramping Painful Oral 1,600 3 1 3 1 9 F 69 10 36 Burning Tingling Oral 1,200 3 1 2 0 10 F 71 15 24 Cramping Painful Oral 2,000 2 0 3 1 11 F 79 16 48 Stabbing Tingling Oral 1,600 2 0 3 1 12 F 78 17 30 Cramping Tingling Insulin 1,600 3 1 3 1 Ataxia 13 M 73 10 36 Cramping Tingling Oral 2,000 4 1 3 2 Pain/ d as follows: 0, no /; 1, mild /; 2, moderate /; 3, severe /; 4, excruciating /.

Vol. 20 No. 4 October 2000 GBP vs. AMI in Painful Diabetic Neuropathy 283 Patient no. Gender Age Diabetes Pain (months) Type of Type of Table 2 Data for AMI-Treated Patients Antidiabetic therapy Maximum dose (mg/day) Adverse events 1 F 79 7 24 Shooting Painful Oral 40 3 3 2 2 Somnolence, dry mouth 2 M 68 20 36 Burning Tingling Insulin 50 3 1 2 2 Somnolence, dry mouth, constipation 3 M 83 25 48 Burning Tingling Insulin 30 4 3 4 3 Dizziness, somnolence, constipation 4 F 70 8 24 Shooting Painful Oral 60 3 2 3 2 Constipation, somnolence, orthostatic hypotension 5 F 71 4 12 Cramping Tingling Insulin 40 2 1 2 1 Somnolence, dry mouth 6 M 68 3 8 Burning Painful Insulin 60 2 1 2 1 Dry mouth, weight increase 7 F 69 5 24 Shooting Tingling Oral 60 2 1 3 2 8 F 66 4 12 Burning Tingling Oral 60 3 1 2 1 Dizziness 9 M 63 4 18 Shooting Painful Oral 60 2 1 2 1 Dizziness, visual disturbances 10 F 71 8 24 Cramping Tingling Oral 50 3 1 3 2 Dizziness 11 F 76 6 12 Cramping Tingling Oral 40 2 1 3 2 Somnolence, dizziness, constipation, weight increase 12 M 62 15 36 Cramping Painful Insulin 90 4 2 3 2 Dry mouth, dysuria Pain/ d as follows: 0, no /; 1, mild /; 2, moderate /; 3, severe /; 4, excruciating /.

284 Dallocchio et al. Vol. 20 No. 4 October 2000 Group Table 3 and End-Point Pain Scores for Gabapentin and Amitriptyline Variable Change in P value vs. baseline P value between treatments Gabapentin Mean 2.9 1.0 1.9 0.01 Standard deviation 0.8 0.7 0.8 0.026 Amitriptyline Mean 2.8 1.5 1.3 0.01 Standard deviation 0.8 0.8 0.6 males) received AMI at the mean dose of 53 16 mg/day. The data of each GBP-treated patient and AMI-treated patient are reported in Tables 1 and 2. The two groups were comparable at baseline for age (mean: 71 7 years in the GBP group; 71 6 years in the AMI group), of diabetes (mean: 12 4 years for GBP; 9 7 years for AMI), (mean: 2.9 0.8 for GBP; 2.8 0.8 for AMI), and (mean: 3.0 0.7 for GBP; 2.5 0.7 for AMI). However, of was significantly longer in the GBP group (mean: 34 11 months vs. 22 12 months for AMI) (Mann- Whitney U-test, P 0.026). Pain Score Pain s are shown in Tables 1 3. In the GBP and AMI groups, the mean final s were 1.0 (1.9 lower than baseline value, Wilcoxon test, P 0.01) and 1.5 (1.3 below baseline, Wilcoxon test, P 0.01), respectively. The efficacy of GBP in reducing was significantly superior in comparison with AMI (Mann-Whitney U-test, P 0.026). The goal of therapy was to achieve a intensity of 1 or less. In seven GBP-treated patients (nos. 4, 5, 7, 8, 9, 12, and 13) and eight AMI-treated patients (nos. 2, 5, 6, 7, 8, 9, 10, and 11), the final of 1 was attained and considered satisfactory by patients, who refused any further increase in the dose. In three GBP-treated patients (nos. 6, 10, and 11), a of 0 was attained, while this goal could not be achieved in any AMI-treated patients. Three GBP-treated patients (nos. 1, 2, and 3) and four AMI-treated patients (nos.1, 3, 4, and 12) did not achieve the goal of reducing to 1 or 0. In the GBP-treated patient no. 1, the maximum dosage of 2,400 mg/day was reached (notably without side effects, but a further increase in the dosage was not allowed by the protocol), while the dosage was not increased up to the maximum in the GBP-treated patients nos. 2 and 3, because of the occurrence of intolerable dizziness. The occurrence of side effects (somnolence, dry mouth, dizziness, constipation, orthostatic hypotension, and dysuria) prevented further dose increases in all four AMI patients (nos. 1, 3, 4, and 12) who could not attain the therapy goal. Paresthesia Score Paresthesia s are shown in Tables 1, 2, and 4. In the GBP group, mean final was 1.2 (1.8 below baseline value, Wilcoxon test, P 0.01). This was 1.6 in the AMI group (0.9 below baseline, Wilcoxon test, P 0.01). Again, there was a significant difference between improvements (Mann-Whitney, P 0.004). The efficacy of GBP in reducing was markedly greater than AMI: nine GBPtreated patients achieved a of 1 or less (two reached 0), in comparison with four AMItreated patients (none reached 0). Group Table 4 and End-Point Paresthesia Scores for Gabapentin and Amitriptyline Variable Change in P value vs. baseline P value between treatments Gabapentin Mean 3.0 1.2 1.8 0.01 Standard deviation 0.7 0.8 0.7 0.04 Amitriptyline Mean 2.5 1.6 0.9 0.01 Standard deviation 0.8 0.7 0.5

Vol. 20 No. 4 October 2000 GBP vs. AMI in Painful Diabetic Neuropathy 285 Side Effects Four patients in the GBP group reported side effects (two dizziness, one somnolence, and one ataxia) compared with 11 patients in the AMI group (somnolence, dizziness, and dry mouth were the most common). The difference in frequency of side effects between the two therapies was statistically significant (Fisher s exact test: P 0.003). use of randomization. Moreover, the trial was performed in 1997, when GBP had been available in Italy for the treatment of epilepsy just for 1 year and neurologists had not yet used the new drug for. Therefore, neither physicians nor patients had biases toward which drug might be better. Regardless, the results from this study are preliminary and need to be confirmed in a larger, double-blind trial. Discussion In this open-label comparison between GBP and AMI in the treatment of patients with ful diabetic neuropathy, both drugs were shown to be effective, but GBP was statistically better than AMI in relieving and. In addition, AMI caused statistically more side effects than GBP. Side effects of AMI, such as dry mouth and orthostatic hypotension, are particularly poorly tolerated by elderly patients, who often would rather accept a residual than continue taking AMI. In a controlled trial of GBP in postherpetic neuralgia, a disorder also characterized by an elderly patient population, the reported incidence of side effects was higher than in the present study. 13 However, this could be explained by the fact that all patients dosages were titrated up to 3,600 mg/day in that study, compared with the mean dose of less than 1,800 mg/day in this trial. TCAs are considered as a first-line therapy for ful diabetic neuropathy. Among TCAs, AMI is the most effective, even if probably the least-tolerated one. Therefore, the results of the present study should not be generalized to all TCAs, because it cannot be excluded that choosing a TCA with less anticholinergic side effects, such as imipramine, would result in a substantial equivalence of the two treatments. Nonetheless, clinical experience, along with the results of the placebo-controlled trial, 1 suggest that GBP is a well-tolerated treatment for ful diabetic neuropathy, and perhaps it should be considered as a first-line therapy for this condition. Potential advantages of GBP over a TCA include its apparently better tolerability, safety profile, and lack of drug interactions. The results of this trial cannot be considered conclusive because of the small sample size and lack of blinding. However, possible biases due to lack of blinding were reduced by the References 1. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V, et al. Gabapentin for the symptomatic treatment of ful neuropathy in patients with diabetes mellitus, a randomized controlled study. JAMA 1998;280:1831 1836. 2. Low PA and Dotson RM. Symptomatic treatment of ful neuropathy. JAMA 1998;280:1863 1864. 3. McQuay HJ, Tramèr M, Nye BA, Carroll D, Wiffen PJ, et al. A systematic review of antidepressants in neuropathic. Pain 1996;68:217 227. 4. Young RJ, Clarke BP. Pain relief in diabetic neuropathy: The effectiveness of imipramine and related drugs. Diabetic Med 1985;2:363 366. 5. Max MB, Culnane M, Schafer SC, Gracely RH, Walther DJ, et al. Amitriptyline relieves diabetic neuropathy in patients with normal and depressed mood. Neurology 1987;37:589 596. 6. Bryson HM, Wilde MI. Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic states. Drugs & Aging 1996;8:459 476. 7. Biesbroeck R, Bril V, Hollander P, Kabadi U, Schwartz S, et al. A double-blind comparison of topical capsaicin and oral amitriptyline in ful diabetic neuropathy. Adv Ther 1995;12(2):111 120. 8. Max MB, Kishore-Kumar R, Schafer SC, Meister B, Gracely RH, et al. Efficacy of desipramine in ful diabetic neuropathy: A placebo-controlled trial. Pain 1991;45:3 9. 9. Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment of ful diabetic neuropathy. JAMA 1984;251:1727 1730. 10. Atkinson JH, Slater MA, Williams RA, Zisook S, Patterson TL, et al. A placebo-controlled randomized clinical trial of nortriptyline for chronic low back. Pain 1998;76:287 296. 11. Richeimer SH, Bajwa ZH, Kahraman SS, Ransil BJ, Warfield CA. Utilization patterns of tricyclic antidepressants in a multidisciplinary clinic: A survey. Clin J Pain 1997;13:324 329. 12. Joss JD. Tricyclics antidepressant use in diabetic neuropathy. Ann Pharmacother 1999;33(9):996 1000. 13. Rowbotham M, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for the treatment of postherpetic neuralgia, a randomized controlled study. JAMA 1998;280:1837 1842.