Clinical Care/Education/Nutrition/Psychosocial Research ORIGINALDiabetes ARTICLE Care Publish Ahead of Print, published online February 25, 2011

A Comparative Trial to Evaluate and Duloxetine in Painful A randomized, double-blind, cross-over

1 2 HARJOT KAUR, MD PINAKI DUTTA, MD, DM literature did not reveal any head-to- 1 3 DEBASISH HOTA, MD, DM DIPIKA BANSAL, MD, DM 2 1 head comparison of duloxetine with ANIL BHANSALI, MD AMITAVA CHAKRABARTI, MD, DM amitriptyline, an established first-line therapy for PDN (1). Thus, the current study was planned to compare the effi- OBJECTIVE— fi To compare the ef cacy and safety of duloxetine and amitriptyline in painful cacy and safety of duloxetine with ami- diabetic neuropathy (PDN). triptyline in PDN. RESEARCH DESIGN AND METHODS—In this randomized, double-blind, cross-over, active-control trial, 58 patients received amitriptyline and duloxetine orally once daily at bed- RESEARCH DESIGN AND time, each for 6 weeks with optional dose uptitration fortnightly. Single-blinded wash- METHODS—Patients of either sex out was given for 2 weeks between the two treatments and a single-blinded placebo run-out with type 2 diabetes, aged between 18 phase of 4 weeks was given at the end of the treatment period. Pain relief was measured by the and 75 years, who were on stable glucose- patient’s global assessment of efficacy, using a visual analog scale (0–100) as a primary end point, lowering during the preced- and overall improvement and adverse events were assessed as secondary outcome measures. . – , ing month and who had PDN for at least 1 Median pain score reductions of 50%, 25 50%, and 25% were considered good, moderate, month were considered for the study. and mild responses, respectively. Patients who had a pain score of .50%, RESULTS—There was a significant improvement in pain with both treatments compared with as assessed by visual analog scale (VAS), their baseline values (P , 0.001 for both). Good, moderate, and mild pain relief was achieved in were enrolled in the study. Those previ- 55, 24, and 15% of patients, respectively, on amitriptyline and 59, 21, and 9% of patients, ously exposed to medications for PDN, respectively, on duloxetine. There were no significant differences in various other outcome regardless of dose and duration, were measures between the groups. Of the reported adverse events, dry mouth was significantly more considered after 2 weeks of placebo wash- common with amitriptyline than duloxetine (55 vs. 24%; P , 0.01). Although, numerically, fi P out in a single-blind manner. The study more patients preferred duloxetine, overall this was not statistically signi cant (48 vs. 36%; = was initiated after approval by the institu- 0.18). tional ethics committee and was con- CONCLUSIONS—Both duloxetine and amitriptyline demonstrated similar efficacy in PDN. ducted following the principles of the A large, multicentric clinical trial in other populations could possibly demonstrate the superiority Declaration of Helsinki. Written informed of either drug. consent was obtained from each subject prior to enrollment. PDN was confirmed by 1) the pa- tient’s medical history, 2) a diabetic neu- he management of painful diabetic Administration for the treatment of ropathy symptom (DNS) score of .1 neuropathy (PDN) includes inten- PDN. It attenuates persistent pain mech- point (7), 3) a diabetic neuropathy exam- T . 4 sive glycemic control and drugs for anisms, including the central sensitiza- ination (DNE) score of 3points(8), )a pain relief. The American Diabetes Asso- tion and hyperexcitability of the spinal modified neuropathy symptom score ciation recommends amitriptyline, a tri- and supraspinal pain-transmitting path- (NSS) (9,10), and 5) increased thresholds cyclic , as the first choice; ways. Duloxetine has been evaluated in on the vibration perception test and however, titration to higher doses is placebo-controlled trials for a variety of monofilament test. Patients were ex- limited by its anticholinergic adverse ef- , including PDN (2–6). It cluded if they had any clinically signifi- fects (1). The selective serotonin norepi- not only relieves pain but also improves cant or unstable medical or psychiatric nephrine , duloxetine, functionality and quality of life in patients illnesses. Patients with other causes of is approved by the Food and Drug with PDN. An extensive search of neuropathy; renal dysfunction (serum creatinine .132 mmol/L); disease ccccccccccccccccccccccccccccccccccccccccccccccccc (alanine aminotransferase and aspartate From the 1Department of Pharmacology, Postgraduate Institute of Medical Education and Research, Chan- aminotransferase more than three time digarh, India; the 2Department of Endocrinology, Postgraduate Institute of Medical Education and Re- 3 times the normal level); epilepsy; psychi- search, Chandigarh, India; and the Department of Pharmacy Practice, National Institute of Pharmaceutical atric illness; uncontrolled hypertension; Education and Research, S.A.S. Nagar, India. Corresponding author: Anil Bhansali, [email protected]. malignancy; substance abuse; those tak- Received 17 September 2010 and accepted 28 January 2011. ing , , lo- DOI: 10.2337/dc10-1793 cal anesthetics, or ; those who © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly were pregnant; lactating women; or those cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ licenses/by-nc-nd/3.0/ for details. being treated with any investigational

care.diabetesjournals.org DIABETES CARE 1 Copyright American Diabetes Association, Inc., 2011 Amitriptyline or duloxetine in PDN drug within the last 30 days were ex- by an independent person unrelated to washout was given and the next sched- cluded from the study. the study. The drug packets were admin- uled drug was started. Patients were not A 14-week, randomized (computer- istered to patients serially according to the allowed any pain other than generated randomization of blocks of patient’s reporting sequence. A median up to 3 g per day paracetamol as a rescue four), double-blind, cross-over, active- pain score reduction on the basis of the medication during the trial period, except control with optional dose titration, VAS of .50%, between 25 and 50%, and 24 h prior to assessment. Compliance was equivalence clinical trial was conducted. ,25% were considered as good, moder- assessed by direct questioning and pill All patients underwent an initial 2-week ate, and mild responses, respectively. counting. Success of blinding was as- run-in period in order to achieve a base- Overall improvement in pain intensity of sessed by the accuracy of the physician’s line state (during which the patients were $30 and $50% also was assessed. As- prediction at the end of the study. withdrawn from any existing medication sessments for depression and change in for PDN), followed by 6 weeks of treat- sleep pattern were performed at the be- Statistical analysis ment with each drug and a washout ginning and end of each of the treatments, The sample size calculation was based on period of 2 weeks between the two ther- PGIC was assessed at the end of each the means and SDs observed for pain apies. At the end of 14 weeks, patients treatment period, and patient preference scores in previous trials of duloxetine entered a 4-week run-out phase, during of treatment was carried out fortnightly versus placebo and amitriptyline versus which placebo response was evaluated after beginning the second treatment, placebo in PDN. The efficacy of both in a single-blind manner. whereas all other assessments were per- drugs was estimated to be 70%. To prove Three doses each of amitriptyline (10, formed at each of the 2-weekly follow- that there is no difference in efficacy 25, or 50 mg once daily at bed time) and up visits. The investigator administered between the two treatments, with two- duloxetine (20, 40, of 60 mg once daily at the drug and performed assessment for sided significance levels of 2.5% and bed time) were used in the study. Wock- the efficacy and safety at each visit and power of 80%, a within-subject SD of hardt Limited (Mumbai, India) and Sun was accessible by telephone to all patients 20%, and a maximum-allowable differ- pharmaceutical Industries Limited throughout the study. No additional dose ence of 10%, the total number of patients (Mumbai, India) provided amitriptyline escalation was carried out in the case of to be included was 44. Because of its and duloxetine, respectively, as free sam- appearance of adverse events, lack of ben- cross-over design, with 40% noncompli- ples. Treatment was started with the low- efit with the initial two doses (no benefit ance and loss to follow-up, we decided to est dose of either drug, with fortnightly on patient VAS), patient’s satisfaction include a total of 60 patients in the study. assessments with optional uptitration. with pain relief, the highest dose was The primary and secondary efficacy anal- The primary end point of the study reached, or patient’s noncompliance. Pa- yses were performed on the intention-to- was the reduction in the median pain tients were reminded by telephone calls treat population, defined as patients who score from baseline, as assessed by the for the due visits and also were traced for received at least one dose of randomized patient’s global assessment of efficacy by missed visits. In case of a missed visit, the study medication and had at least one the VAS (0–100 points). Secondary end patient was given the scheduled dose if postbaseline efficacy assessment. Values points included the assessment of pain by he/she turned up during the stipulated are expressed as means 6 SD, median the short-form McGill Pain Questionnaire time of 2 weeks or else the placebo (11); an 11-point Likert scale for pain (0 = no pain and 10 = excruciating pain); over- all improvement by DNE score, DNS Table 1—Baseline demographic parameters of patients who completed the study score, modified NSS, and the 24-point Hamilton Rating Scale for Depression Characteristics Values (12); change in sleep pattern (increased, unchanged, or decreased); and patient Age (years) 52.5 (48.2–62) self-evaluation of overall change on the Sex basis of a 7-point patient global impres- Male 27 (47) sion of change (PGIC) scale. Treatment- Female 33 (53) emergent adverse events (TEAEs) were Height (cm) 158.8 (153.6–166.7) assessed by clinical and laboratory evalu- Weight (kg) 69 (64.0–77.7) ation of fasting and postprandial plasma Waist circumference (cm) 93.1 (88.2–99.1) glucose, A1C levels, lipid profile, urea, BMI (kg/m2)26.8(24.7–29.3) creatinine, aspartate aminotransferase/al- Duration of diabetes (years) 7 (2–12) anine aminotransferase, and alkaline Duration of pain (months) 18 (6–36) phosphatase. The patient’spreferenceof Site of pain treatment was assessed by direct ques- Foot 45 (78) tionnaire. Demographic characteristics Foot and hand 13 (22) were noted and all the parameters were Hypertension 43 (74) measured before and after treatment Vibration perception threshold score 25 (14–33.8) with both drugs and compared. DNS (.1 point abnormal) 58 (100) Uptitration was done after assessment DNE (.3 points abnormal) 58 (100) of the therapeutic response and tolerabil- NSS (1–9) 7 6 1.8 ity by the above-mentioned scores. Blind- A1C (g %) 8.2 6 1.7 ing and randomization were carried out Data are median (IQR), means 6 SD, or n (%). n = 58 patients.

2 DIABETES CARE care.diabetesjournals.org Kaur and Associates with interquartile range (IQR), and num- bers and percentages. The median pain scores, the patient VAS, the Likert pain scale, and the McGill Pain Questionnaire were compared using the Wilcoxon matched-pair test. In addi- tion, data from all visits were compared with baseline scores using the Friedman test for intragroup comparison. PGIC was compared by the McNemar Bowker test. The Hamilton Depression Rating Scale, altered sleep pattern, percentage of pa- tients showing improvement, treatment preference, and incidence of adverse events were compared using the x2 test or Fisher exact test. Baseline parameters were compared by the Student paired or unpaired t test, x2 test, or Fisher exact test. A P value ,0.05 was considered sig- nificant. SPSS (version 12.0) was used to perform analysis.

RESULTS—The study was conducted between March 2009 and April 2010. Patient demography, clinical character- istics, and disposition through the study period are summarized in Table 1 and Fig. 1, respectively. Of 203 patients screened, 86 were found to be eligible and 65 pa- tients reported for randomization follow- ing the run-in period. Of a total of 58 patients, 53 (91%) completed the study with .80% compliance. The reasons for noncompliance included frequent follow- up visits and long distance from home to the hospital. Scores at baseline both be- fore and after the crossover were similar in the two groups, and, thus, the data were pooled. No patient suffered from depres- sion as per the Hamilton Depression Rat- ing Scale. Previously tried treatments for included the use of pre- gabalin in 20%, amitriptyline in 8%, and duloxetine and in 2% of pa- tients each. n With duloxetine, 59% ( = 34) of pa- Figure 1—CONSORT statement. tients showed good improvement, 22% (n = 13) showed moderate improvement, and 9% (n =5)showedmildimprove- ment. With amitriptyline, 55% (n = 32) on other scales as well (McGill Pain Ques- cohort, 48% (n = 28) of patients preferred of patients showed good improvement, tionnaire and Likert scale), and both duloxetine and 36% (n = 21) of patients 24% (n = 14) showed moderate improve- drugs significantly relieved pain at 6 preferred amitriptyline, but it was not sta- ment, and 16% (n =9)showedmildim- weeks (P , 0.001 for both). Significant tistically significant (P = 0.18). In addition, provement (Fig. 2). improvement in sleep and overall well be- 16% of patients had no preference, out of Overall pain relief of .30% was ob- ing was observed with both drugs (P , which 9% were equally satisfied and 7% served in 64 and 62% of patients with 0.001 for both). were equally dissatisfied with either treat- duloxetine and amitriptyline, respec- Of the total study population 5, 14, ment options. Forty-eight percent (n = 28) tively, and .50% improvement was and 30% preferred 20, 40, and 60 mg of patients with amitriptyline and 65% seen in 59 and 55% of patients with du- duloxetine, respectively, whereas 5, 22, (n = 38) with duloxetine were uptitrated loxetine and amitriptyline, respectively. and 9% preferred 10, 25, and 50 mg of to their highest doses of 50 and 60 mg, No significant difference in the efficacy amitriptyline, respectively, based on pain respectively. Significantly more patients between the two treatments was observed relief and tolerability. In the whole preferred a higher dose of duloxetine care.diabetesjournals.org DIABETES CARE 3 Amitriptyline or duloxetine in PDN

significantly with either of the drugs over the treatment period. The investiga- tor was able to identify the prescribed drug correctly in 34% of the patients at the run-out phase. The median VAS (IQR) score increased from 26 (10–40) to 40 (20–54) at the end of run-out phase (P , 0.001), and the average run-out duration was 21 6 12 days.

CONCLUSIONS—The current study compared the efficacy and safety of du- loxetine with amitriptyline head to head in patients with PDN. Both drugs demon- strated comparable efficacy and safety as per the established pain-rating scales for PDN. Although, numerically, more patients preferred duloxetine over amitriptyline, this did not reach the level of significance. In the present trial, both duloxetine and amitriptyline demonstrated similar efficacy (.30% pain relief). More than 50% improvement in pain score was ob- Figure 2—Median VAS pain scores of patients. served in 59% of patients with duloxe- tine, compared with 49–52% in various placebo-controlled trials (4,5,13), and 55% with amitriptyline, compared with n n common with amitriptyline compared ( = 17) compared with amitriptyline ( = 51–58% in other placebo-controlled and 5; P , 0.02). with duloxetine (51 vs. 24% of patients; active-control trials (14–16). Improve- Table 2 depicts TEAEs with the two P , 0.01). Of all the events, dry mouth ment in pain was significant with both drugs. The events were similar between was significantly more common with am- drugs as per patient assessment by the amitriptyline (n = 111) and duloxetine itriptyline (P , 0.01). The more common VAS, the 11-point Likert scale, and the (n = 112). The number of mild TEAEs adverse events reported with duloxetine McGill Pain Questionnaire. These find- with duloxetine was higher compared were constipation and . No ings are in concordance with previous with amitriptyline (P , 0.02), whereas significant change in weight was noticed studies (17,18) where pain evaluation the number of moderate to severe TEAEs, with either therapy. The mean A1C levels was confirmed by similar well-established limiting dose uptitration and requiring in- improved from 8.2 to 7.8% (P , 0.01). pain-evaluation scores. In addition, neu- tervention or discontinuation of the drug, The fasting and postprandial plasma glu- ropathy status was evaluated using well- was higher with amitriptyline (P , 0.01). cose levels, lipid profile, and renal and established scales like the DNS score, Moderate to severe TEAEs were more liver function tests did not change DNE score, and modified NSS, which also demonstrated significant improve- Table 2—Adverse events observed ment. The pain scores demonstrated pain resurgence during the washout and P run-out phase (Fig. 2). This suggests that Adverse events Duloxetine Amitriptyline the drugs do not affect the basic patho- Somnolence 18 (31) 21 (36) 0.89 physiology of PDN; however, it also is too Dry mouth 14 (24) 32 (55) ,0.001 short a duration of therapy to comment Constipation 22 (37) 10 (17) 0.06 on the same. There was comparable im- Lethargy 14 (24) 19 (33) 0.30 provement in sleep with both drugs, as 9 (15) 6 (10) 0.71 per the sleep score. There was a significant Uneasiness 11 (19) 6 (10) 0.40 improvement in A1C over the trial period, 7 (12) 8 (14) 0.86 and thus the reduction in cumulative gly- 6 (10) 3 (5) 0.58 cemic burden can be expected to contrib- Anorexia 5 (8) 1 (2) 0.25 ute to the pain relief and may have a 4 (7) 3 (5) 0.78 confounding effect on the efficacy assess- Pain abdomen 1 (2) 1 (2) 0.95 ment (13,19). However, this is negated Itching 1 (2) 1 (2) 0.95 because of the cross-over study design Total adverse events (n) 112 111 and demonstration of pain resurgence Mild events* 98 82 ,0.02 during the washout and run-out phases. Moderate to severe events† 14 29 ,0.01 The various published placebo-con- Data are n (%). n = 58 in each group. *Mild: not requiring any intervention or discontinuation. †Moderate to trolled studies on duloxetine for treating severe: limiting dose uptitration, requiring intervention or discontinuation of the drug. PDN have parallel designs for efficacy and

4 DIABETES CARE care.diabetesjournals.org Kaur and Associates safety evaluation (3,20). The current and Sun Pharmaceutical Industries Limited, fructose, and myo- related to sural study has a cross-over design and dose Mumbai, India, for providing amitriptyline nerve morphometry. Ann Neurol 1980;8: titration was gradual, from a low 20–60 and duloxetine, respectively, as free samples. 590–596 No potential conflicts of interest relevant to 11. Melzack R. The short-form McGill Pain mg daily compared with trials evaluating – 20–120 mg fixed daily doses. It was con- this study were reported. Questionnaire. Pain 1987;30:191 197 H.K. helped conduct the study, researched 12. Snaith RP. Hamilton rating scale for de- sidered appropriate to plan two weekly and analyzed data, and drafted the manu- pression. Br J Psychiatry 1977;131:431–432 evaluations because previous trials have fi script. D.H. contributed to the study concept 13. Ziegler D. Treatment of diabetic neurop- demonstrated ef cacy within 2 weeks of and design and discussion of the study results athy and neuropathic pain: how far have the onset of therapy. Therefore, the study and reviewed the final manuscript. A.B., P.D., we come? Diabetes Care 2008;31(Suppl. was planned to be of shorter duration D.B., and A.C. helped conduct the study and 2):S255–S261 (i.e., 6 weeks of active drug therapy com- reviewed and edited the manuscript. D.B. was 14. Morello CM, Leckband SG, Stoner CP, pared with a duration of 12–52 weeks, as working as a resident during the study in Moorhouse DF, Sahagian GA. Random- in other trials [5,21]). The most preferred Pgimer, Chandigarh. ized double-blind study comparing the fi effective doses were 60 mg duloxetine Parts of this study were presented in abstract ef cacy of gabapentin with amitriptyline and 25 mg amitriptyline, which are lower form at the 13th World Congress of Pain, on diabetic pain. Montreal, Canada, 29 August to 2 September Arch Intern Med 1999;159:1931–1937 than the recommended dose range of ’ – – 2010. 15. Zin CS, Nissen LM, Smith MT, O Callaghan 60 120 mg and 25 150 mg for duloxe- The authors thank R. Walia, Department of JP, Moore BJ. An update on the pharma- tine and amitriptyline, respectively Endocrinology, for revising the final draft of cological management of post-herpetic (1,22,23). Even at these doses, moderate the manuscript. and painful diabetic neuropathy. pain relief was achieved, and as conferred CNS Drugs 2008;22:417–442 in the previous studies the lower doses of 16. Max MB, Lynch SA, Muir J, Shoaf SE, amitriptyline are effective because of the References Smoller B, Dubner R. Effects of de- possible lower body size and weight of the 1. American Diabetes Association. Standards sipramine, amitriptyline, and fluoxetine Indian population (17,18,24). of medical care in diabetes: 2009. Diabetes on pain in diabetic neuropathy. 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