PERSONS WITH SPINAL CORD injury (SCI) frequently

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1 1547 ORIGINAL ARTICLE Comparison of the Effectiveness of Amitriptyline and Gabapentin on Chronic Neuropathic Pain in Persons With Spinal Cord Injury Diana H. Rintala, PhD, Sally Ann Holmes, MD, Daisy Courtade, MA, Richard Neil Fiess, Luz Viviana Tastard, MD, Paul G. Loubser, MD ABSTRACT. Rintala DH, Holmes SA, Courtade D, Fiess RN, Tastard LV, Loubser PG. Comparison of the effectiveness of amitriptyline and gabapentin on chronic neuropathic pain in persons with spinal cord injury. Arch Phys Med Rehabil 2007; 88: Objective: To test the hypotheses that both amitriptyline and gabapentin are more effective in relieving neuropathic pain than an active placebo, diphenhydramine. Design: Randomized, controlled, double blind, triple crossover 8-week trial. Setting: Veterans Affairs medical center. Participants: Community dwelling adults with spinal cord injury (N 38) were recruited by telephone, letters, and flyers. Intervention: Eight-week trial each of amitriptyline, gabapentin, and diphenhydramine. Main Outcome Measures: Pain intensity measured with a 10-cm visual analog scale (VAS) and an 11-point (0 10) numeric rating scale (NRS) and depressive symptomatology measured with the Center for Epidemiologic Studies Depression Scale Short Form (CESD-SF). Results: Baseline VAS scores for participants with low ( 10) CESD-SF scores was 4.61 and for those with high scores ( 10) it was At week 8, in participants with high baseline CESD-SF scores, amitriptyline (mean, 4.21) was more effective than diphenhydramine (mean, 6.67; P.035), and there was a nonsignificant trend suggesting that amitriptyline may be more effective than gabapentin (mean, 6.68; P.061). Gabapentin was no more effective than diphenhydramine (P.97). There was no significant difference among the medications for those with lower CESD-SF scores. Results could not be attributed to dropout rates, order or dose of medications, amount of medication taken for breakthrough pain, or side effects. Conclusions: Amitriptyline is more efficacious in relieving neuropathic pain than diphenhydramine at or below the level of spinal cord injury in people who have considerable depressive symptomatology. From the Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX (Rintala, Holmes, Courtade, Fiess, Tastard); Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX (Rintala, Holmes, Courtade, Fiess, Tastard); and Bayshore Medical Center, Pasadena, TX (Loubser). Presented to the American Pain Society, May 2006, San Antonio, TX, and the American Association of Spinal Cord Injury Psychologists and Social Workers, September 2006, Las Vegas, NV. Supported by the Department of Veterans Affairs, Veterans Health Administration, Rehabilitation Research and Development Service (grant no. B2573R). No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the author(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Diana H. Rintala, PhD, MEDVAMC (153), 2002 Holcombe Blvd, Houston, TX 77030, drintala@bcm.tmc.edu /07/ $32.00/0 doi: /j.apmr Key Words: Amitriptyline; Depression; Diphenhydramine; Pain, intractable; Rehabilitation; Spinal cord injuries by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation PERSONS WITH SPINAL CORD injury (SCI) frequently have chronic pain; estimates put the numbers from 65% to 81% Neuropathic pain at or below the level of the injury is a particularly intractable type of pain experienced by an estimated 29% to 75% of persons with SCI. 2,11-15 The prevalence of chronic neuropathic pain varies, based on time since injury 2,13,14,16 and by whether the pain is at or below the level of injury. 2,13,14,17 For example, Siddall et al 2,13,14 reported an approximate 38% prevalence of at-level pain at 2 weeks and 6 months postinjury and a prevalence of 41% at 5 years. The prevalence of below-level pain was 14% at 2 weeks, 19% at 6 months, and 34% at 5 years. Chronic pain is associated with depressive symptomatology in participants with SCI. Higher levels of depressive symptoms are related to (1) having chronic pain compared with not having chronic pain, 7,18 (2) greater pain intensity, 19,20 (3) more painful days a month, 18 (4) more hours of daily pain, 18 and pain interference with daily activities. 21 Various treatments for chronic neuropathic pain have included increased activity levels, provision of psychosocial support, management of concomitant health problems, electric stimulation, nerve blocks, surgery, use or stopping use of chemicals including nicotine, cannabis, alcohol, caffeine, herbs, and prescription medications (antidepressants [eg, amitriptyline], anticonvulsants [eg, carbamazepine, gabapentin], narcotic drugs [eg, morphine, codeine]). 22 These treatments are often ineffective and have undesirable side effects. 23 Amitriptyline (Elavil) is a tricyclic antidepressant that has been associated with significant analgesia in different animal models, 24 including neuropathy and deafferentation-induced autotomy. 25 It has been a drug of choice for treating pain in people with SCI, but to our knowledge, only a few studies have described the effect of amitriptyline on chronic pain syndromes in the SCI population. These include several surveys and a randomized controlled trial (RCT). 30 Gabapentin (Neurontin) is an anticonvulsant. RCTs of gabapentin for postherpetic neuralgia 31 and painful neuropathy in patients with diabetes mellitus 32 found the medication to be effective and to have tolerable side effects. Preclinical studies in rat models with SCI indicated that gabapentin reduced allodynia, 33 reduced paw withdrawal to mechanic and thermal stimuli, 34 and ameliorated changes in spontaneous exploratory activity. 35 There have been several studies of the effectiveness of gabapentin on pain in participants with SCI, including surveys, retrospective studies, 36,37 uncontrolled open-label trials, 38,39 and RCTs. 40,41

2 1548 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala In light of our previous work, 7,18 and the works of others that have highlighted the prevalence of depressive symptomatology in conjunction with chronic pain in the SCI population, we conducted a clinical trial to directly compare the effectiveness of an antidepressant (amitriptyline) and an anticonvulsant (gabapentin) with an active control substance, diphenhydramine (Benadryl). We used an active control to maintain the double blind, placebo-controlled design. Our hypotheses were that in participants with SCI: (1) amitriptyline will be more effective than diphenhydramine in relieving chronic neuropathic pain at or below the level of injury; (2) gabapentin will be more effective than diphenhydramine in relieving chronic neuropathic pain at or below the level of injury; and (3) amitriptyline will differentially affect pain, depending on the baseline level of depressive symptomatology. Although we did not state it as an a priori hypothesis, because there was no previous evidence comparing the 2, we expected gabapentin to be more effective than amitriptyline, based on the limited evidence available when we designed the study. METHODS Study Design We used a randomized, controlled, double blind, triplecrossover design to compare the effectiveness and safety of gabapentin and amitriptyline with an active control medication, diphenhydramine, for the relief of chronic neuropathic pain at and/or below the level of injury in people with SCI. We used a crossover design to control for the effect of individual differences in the perception and reporting of pain. We began a baseline week after all medications being used for pain control at time of entry to the study were discontinued. During the baseline week, participants were instructed not to take any pain medications except the medication for breakthrough pain that we provided. Mercadante et al 42 define breakthrough pain as transitory exacerbation of pain that occurs in addition to otherwise stable persistent pain. At the end of the baseline week, eligible participants were randomized into 1 of 6 groups. The groups differed only in regard to the order in which the participants would receive the 3 study medications. The groups were: (1) gabapentin-amitriptyline-diphenhydramine (GAD), (2) GDA, (3) AGD, (4) ADG, (5) DGA, and (6) DAG. For each consecutive set of 6 participants, 1 was assigned to each of the 6 groups. The order of this assignment within the sets of 6 was based on a table of random numbers, and varied from set to set. Each study drug was administered for 9 weeks. During each of the 3 medication phases, the daily dose of medication was gradually increased in the first 4 weeks. Daily dosage was kept constant to the extent possible for weeks 5 through 8; however, if side effects became too severe, dosages or the number of doses a day were decreased. The medication was gradually decreased and then discontinued during the ninth week. The tenth week of each medication phase was a washout week similar to the baseline week. Participants were instructed not to take any pain medications other than those we provided at any time during the study. Participant Recruitment From November 2001 to April 2004, participants were recruited primarily from lists of persons with SCI who had participated in previous research studies and had given permission to be contacted for future studies, and through word of mouth. Inclusion criteria were: (1) 18 to 70 years of age, (2) with an SCI at any level and any degree of completeness, (3) the SCI occurred at least 12 months before entering the study, (4) at least 1 chronic ( 6mo) pain component characteristic of neuropathic pain, (5) at least 1 neuropathic pain component rated as at least 5 on a0to10scale when initially contacted about participating, and (6) lived within 160km (100 miles) of the Michael E. DeBakey Veterans Affairs Medical Center (MEDVAMC). Exclusion criteria were: (1) evidence of significant cardiac conduction disturbance, (2) history of seizures, (3) evidence of liver dysfunction indicative of an infectious process or hepaticellular injury, (4) evidence of renal insufficiency, (5) taking any contraindicated medications such as maximum acid output (MAO) inhibitors, (6) current or recent substance abuse problem, (7) evidence of a previous allergic reaction to any of the study medications, (8) evidence of a serious psychologic disorder that would prevent giving informed consent or hinder one s ability to follow through with the study based on the attending physician s clinical judgment, (9) evidence of psychologic or psychosomatic chronic pain based on clinical judgment (no one was excluded based on this criterion), and (10) pregnancy. In planning this study, we based our required sample size calculation on an RCT by Rowbotham et al 31 of the use of gabapentin to treat neuropathic pain after herpes zoster. At the time we designed this study, there were no published RCTs of gabapentin to treat neuropathic pain in persons with SCI. A parallel arm design, rather than a crossover design, was used in the Rowbotham study. The sample size requirement for a parallel study would be 31 participants in each group in order to detect a difference as large as 1.8 on the visual analog scale (VAS). Our planned sample size for each of the 6 assignment groups was based on the formula n * [n(1 ICC)]/2, where n is the sample size needed for each group in an equivalent 3-arm parallel study and ICC is the intraclass correlation coefficient. 43 Thus, using data from Rowbotham, n * [31(1.55)]/2 7. Because there were 6 randomly assigned sequence groups we estimated that we would need 42 (6 7) participants to complete all 3 arms of the study. Procedure The Institutional Review Board for Human Subject Research for Baylor College of Medicine and Affiliated Hospitals approved all procedures. After prescreening by telephone, potential candidates were invited to the MEDVAMC SCI outpatient clinic to provide their written informed consent and establish their eligibility. A research assistant (RNF) administered several questionnaires concerning pain, daily activities, and the participants well being (see the Measures section). The candidates vital signs were obtained and their medical records reviewed to identify any contraindications for participating in the study. The following were verified for each participant within a 6-month window prior to study entry: complete blood count, electrolyte panel, liver function studies, and electrocardiogram (ECG). Women of childbearing potential were given a serum pregnancy test. A physician reviewed the results of all tests and interviewed candidates to assess whether they had chronic neuropathic pain at and/or below the level of injury. Identification of pain as being neuropathic depended on (1) the location of pain with respect to the level of injury (at or below the level of injury), (2) its qualitative nature (burning, stinging, or stabbing), (3) its pattern (diffuse, nonradicular), and (4) what worsens the pain (eg, movement, certain activities, spasticity). If a participant had more than 1 pain site, 1 site of neuropathic pain at and/or below the level of injury was specified as the pain site of

3 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala 1549 interest for the study. Eligible candidates were randomized as described in the study design section. Participants were evaluated on 8 occasions in the clinic and on 9 occasions in their homes during the 31 weeks they were in the study. After their eligibility was established, the participants were evaluated at the end of the baseline week and at weeks 2, 4, 8, and 10 during each of the 3 medication phases. Beginning in January 2003, we began evaluating participants at the end of week 6 to better ensure their safety and compliance. During each visit, the research assistant again administered questionnaires regarding pain at the specified study site, daily activities, and subjective well-being, took vital signs, and obtained information about medication intake, side effects, and adverse events, if any. The study coordinator (DC) provided the medications and instructions for the next study period, and also set each participant s next clinic appointment. Participants were paid $50 for each clinic visit and $25 for each home visit. The payments covered the costs of transportation, arranging for an attendant, childcare, or other incurred expenses. The first visit lasted approximately 1 hour and all subsequent visits lasted approximately 30 minutes. In addition to the clinic and home visits every 1 to 4 weeks, the research assistant contacted the participants by telephone once or twice a week. During these contacts, the research assistant obtained the participants numeric pain ratings, as well as information about medication usage, side effects, and adverse events since the last contact. These interviews lasted approximately 5 to 10 minutes. Medications Participants were provided tablets containing a combination of 5mg of oxycodone and 325mg of acetaminophen for breakthrough pain in packets of 8 tablets, 1 packet for each day of the study, from the beginning of the baseline week through the washout week after the third medication (maximum, 217d; 1736 tablets). Participants were instructed to take the tablets only if necessary and to start a new packet each day. They were told to leave any remaining tablets for that day in the packet so that we could monitor the amount of breakthrough medication used each day. The maximum doses in this study were 50mg, 3 times daily for amitriptyline and 1200mg, 3 times daily for gabapentin. We chose these dosages because they are widely accepted by practitioners as the standards for treating neuropathic pain in persons with SCI. 44 Smaller dosages of amitriptyline may have been effective, however. For example, Max et al 45 found that 105mg of amitriptyline was equally effective in depressed and nondepressed patients with diabetic neuropathic pain. In our study, amitriptyline was provided in 3 daily doses rather than 1 dose at bedtime because gabapentin was taken 3 times daily and we wanted to keep the treatments as similar as possible. Table 1 shows the daily maximum dose schedules for amitriptyline and gabapentin. Lower doses were taken if necessary due to unacceptable side effects or if pain relief was achieved. During week 9 of each medication phase, the daily dose of the study medication was gradually decreased (table 1). We considered a 1-week washout period after each medication was discontinued to be sufficient to avoid carry-over effects, because gabapentin has a half-life of 6 to 8 hours and amitriptyline has a half-life of 24 to 70 hours. Our control medication, diphenhydramine, is an antihistamine. Its maximum individual dose was 25mg, 3 times daily, and that dose was kept constant for the entire 9-week phase. Participants received 1 dose a day for the first 3 days, 2 doses a day for the next 2 days, and 3 a day thereafter through week 8. During week 9 they received 2 doses a day for 2 days and 1 dose a day for 2 days, to gradually discontinue the medication. We used diphenhydramine as the control medication because it is not a pain reliever but does have some side effects, such as drowsiness and dry mouth, which are similar to side effects of the other 2 medications. This fact helped maintain the double blind design. The half-life of diphenhydramine is 3 to 12 hours. All 3 medications were prepared by a commercial compounding pharmacy and placed in identical capsules according to the dosing schedule. Inactive filler, sodium bicarbonate, was used for 1 or 2 doses a day while gradually increasing or decreasing the total daily dose (see table 1). They were packaged in blister packs, which were labeled with the day and the Table 1: Daily Maximum Dose Schedule for Gabapentin and Amitriptyline Gabapentin Amitriptyline Week Day Morning Afternoon Evening Morning Afternoon Evening 0 7 to 0 Baseline week: no study medication except breakthrough medication IC IC 300 IC IC IC IC IC IC IC IC 100 IC IC IC 9 63 IC IC 100 IC IC IC Washout week: no study medication except breakthrough medication NOTE. Values are in milligrams. Inactive capsules contained sodium bicarbonate as filler. Abbreviation: IC, inactive capsule.

4 1550 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala time for each dose to be taken. We used labeled blister packaging to facilitate adherence to the dosing schedule. Measures Demographic and injury-related information was obtained from questionnaires and medical records and included age, sex, race and ethnicity, marital status, whether the participant was a military veteran, age at onset of SCI, time since onset, and level and completeness of the injury. The VAS is a 10cm line anchored on the left with the words no pain and on the right with worst possible pain. 46 A participant draws a mark across the line at a point representing the severity of his/her pain. The distance from the left end to the participant s mark is the VAS pain intensity score. Huskisson 46 and other researchers have found the VAS to be reliable and valid. The VAS was obtained at each visit to the clinic or to the home. For participants who were unable to accurately draw a line across the appropriate point on the VAS (ie, persons with tetraplegia), the research assistant slowly moved the pen along the VAS line until the participant indicated that the pen was at the correct point. The research assistant then drew the line across the VAS at that point. The numeric rating scale (NRS) is a simple 0 to 10 rating scale. Only the 2 ends are designated by words (0, no pain; 10, worst possible pain). It is similar to the VAS, but can be used during a telephone contact. Downie et al 47 found that a similar 11-point scale was more sensitive than a 4-point descriptive scale and was more easily understood than the VAS. We used the NRS at intake, during each telephone call, and at each clinic and home visit. We used it in addition to the VAS because we wanted to assess pain intensity during telephone contacts. NRS ratings could thus be obtained more frequently than VAS ratings. Weekly averages of the NRS obtained by phone and/or in person are likely to be more stable than single ratings. An additional advantage in using both the NRS and VAS is that by using 2 methods of obtaining the data, the study conclusions are strengthened if similar effects are indicated. The Center for Epidemiologic Studies Depression Scale Short Form (CESD-SF) is a 10-item, self-report scale designed to measure symptoms of depression in the general population. 48 Each item is rated on a0to3scale according to how often the person experienced certain feelings (eg, depression and hopefulness) in the past week ( 1d, 1 2d, 3 4d, 5 7d). Scores for positive feelings are reversed. It has good predictive accuracy (.97) compared with the original 20-item CES-D. 49 The CESD-SF was found by the developers to have a test-retest correlation of r equal to The CESD-SF was administered at baseline and at weeks 4, 8, and 10 of each medication phase. The Cronbach was.80 in this study. Side-effects checklist. During each telephone contact, clinic visit, and home visit, participants were asked if they had experienced any of 17 possible side effects. The list included common and serious side effects for each medication. Participants were also encouraged to report any other side effects they experienced that were not on the list. Medication costs. The cost of amitriptyline and gabapentin at the maximum dosing for 1 month at the schedule used in this study was obtained from the MEDVAMC pharmacy department in January Data Analysis Descriptive analyses were performed on all study variables. Means, medians, standard deviations, and ranges were obtained for continuous variables and number and percentage were obtained for categoric variables. All NRS ratings were averaged for each participant for each week. CESD-SF scores were recoded into 2 groups: less depressive symptomatology (CESD-SF score 10) and more depressive symptomatology (CESD-SF score 10). This cutpoint was recommended by the developers of the short-form of the CES-D. 48 Side effects were tallied for each medication arm. Differences between participants who completed all 3 phases (completers) and those who did not (noncompleters) were assessed with t tests for continuous variables and chi-square tests for categoric variables. The primary outcome variable was the final pain rating (pain on average for week 8 for each medication) as measured by the VAS. We did a repeated-measures analysis of variance (ANOVA) to compare the effectiveness of the 3 medications. Because amitriptyline is an antidepressant, the analysis was repeated with the dichotomous depressive symptomatology variable (CESD-SF scores 10 or 10) as a between-subjects factor. We did a similar analysis using the week 8 NRS average score. We calculated the change in average pain intensity as measured by the VAS and the percentage change from baseline to week 8 of each medication. The proportion of participants whose pain intensity decreased at least 30% was calculated for each medication within the 2 depressive symptomatology groups. A change of 30% or better is considered to be a minimal clinically important difference. 50 We determined the dropout rates across time for each medication. A dropout was defined as a participant who was unable to complete at least the first 8 weeks of a given medication phase. A participant could drop out of the entire study or could drop out of a particular medication phase because of intolerable side effects, then after a washout week, begin the next scheduled medication phase. The effect of dropping out was assessed by comparing VAS data for those who completed all 3 phases of the study with all available data at baseline and weeks 2, 4, and 8 for each medication. The effect of the order in which the medications were taken was assessed with separate 1-way ANOVAs for each medication for the VAS score at week 8. Similarly, we compared the percentage of the maximum dose of the 3 medications taken during weeks 2, 4, and 8. The amount of breakthrough medication taken during the 3 medication phases was compared within the 2 depressive symptomatology groups by using nonparametric Friedman tests because the distribution was highly skewed. Finally, we calculated the 1-month costs for 50mg of amitriptyline taken 3 times a day and 1200mg of gabapentin taken 3 times a day. We calculated an efficacy factor by dividing the percentage change in average pain intensity by the cost for 1 month. Separate calculations were conducted for the 2 depressive symptomatology groups. RESULTS Participants and Profile of the Study Figure 1 shows the study s flowchart. People excluded from the study included: 3 who had elevated liver enzymes, 1 who had an abnormal ECG, 1 who was already taking higher doses of the study medications than the maximum allowed in this study, 1 who was allergic to 1 of the study medications, 1 with a recent history of drug abuse, and 1 who did not have chronic neuropathic pain. One person died from unrelated causes before being randomized. One person was excluded because his laboratory findings were outdated and he was unable to have them updated before the end of recruitment. Of the 38 participants randomized, 22 (58%) completed all 3 phases of the medication regimen. A total of 26 participants completed the gabapentin phase, 28 completed the amitriptyline phase, and 25

5 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala 1551 Consented (N=50) Not Randomized (n=12) Reasons: 8 ineligible, 2 withdrew, 1 died before randomization, 1 lab results unattainable Randomized (n=38) Randomized to Group 1 GAD (n=7) Randomized to Group 2 GDA (n=6) Randomized to Group 3 AGD (n=6) Randomized to Group 4 ADG (n=6) Randomized to Group 5 DGA (n=7) Randomized to Group 6 DAG (n=6) Gabapentin: 1 withdrew due to adverse effects 1 crossed over early due to adverse effects Gabapentin: 1 crossed over early due to adverse effects Amitriptyline: 1 withdrew due to adverse effects 1 withdrew due to medical problems Amitriptyline: 1 withdrew after completing all of this arm due to moving out of state Diphenhydramine: 2 lost to contact 2 early crossover due to adverse effects Diphenhydramine: No withdrawals or early crossovers amitriptyline (n=6): 1 withdrew due to adverse effects 1 withdrew due to medical problems 1 crossed over early due to adverse effects diphenhydramine (n=4): No withdrawals diphenhydramine (n=6): 1 withdrawn due to protocol violation amitriptyline (n=5): No withdrawals gabapentin (n=4): 1 withdrew due to medical problems diphenhydramine (n=3): No withdrawals diphenhydramine (n=5): 1 withdrew due to medical problems gabapentin (n=4): No withdrawals gabapentin (n=5): 1 early crossover due to adverse effects amitriptyline (n=5): No withdrawals amitriptyline (n=6): 1 early crossover due to adverse effects, no outcome data available gabapentin (n=6): 1 withdrew due to adverse effects, no outcome data available Attempted all 3 arms including early crossover (n=4) Attempted all 3 arms including early crossover (n=5) No early crossovers No early crossovers Attempted all 3 arms including early crossover (n=5) Attempted all 3 arms including early crossover (n=6) Completed all 3 arms (n=3) Completed all 3 arms (n=4) Completed all 3 arms (n=3) Completed all 3 arms (n=4) Completed all 3 arms (n=3) Completed all 3 arms (n=5) Fig 1. Profile of the study. There were 6 random assignment groups that differed only with respect to the order in which the medications were received. Twenty-two completed all 3 phases; 26 completed the gabapentin phase, 28 the amitriptyline phase, and 25 the diphenhydramine phase. Abbreviations: A, amitriptyline; D, diphenhydramine; G, gabapentin. completed the diphenhydramine phase. Five persons attempted all 3 phases, but had to crossover to the next medication early in at least 1 phase because of unacceptable side effects. Tables 2 and 3 show the continuous and categorical variables of the study sample. More than one third of the participants had high CESD-SF scores ( 10). The mean for pain intensity on average during the baseline week fell in the moderate range while the mean for worst pain at both intake and during the baseline week was in the severe intensity range. 51 There was no significant difference between the completers and the noncompleters on any of the variables listed in tables 2 and 3. Effectiveness of the Medications Mean VAS ratings for pain on average during week 8 for all 22 completers were: amitriptyline, ; gabapentin, ; and diphenhydramine, A repeatedmeasures ANOVA indicated a main effect of medication (F 4.61, P.016). Follow-up paired t tests with Bonferroni adjustment for multiple comparisons indicated that average pain intensity in week 8 with amitriptyline therapy was significantly lower than with gabapentin therapy (t 2.32, P.03; effect size, Cohen d.55), or diphenhydramine therapy (t 2.76, P.012; Cohen d.71). There was no significant difference between gabapentin and diphenhydramine therapy. A similar repeated-measures ANOVA was performed in which the dichotomous depressive symptomatology variable was entered as a between-subjects factor. The main effect of medication was significant (F 5.48, P.008), as was the main effect of the depressive symptomatology variable (F 8.48, P.008). The interaction term was not significant, indicating that the pattern of relative effects among the 3 medications is similar in the high and low CESD-SF groups. Figure 2 shows the means and error bars ( 2 standard errors) for the VAS scores for each of the 3 medications within the high and low CESD-SF groups. When follow-up paired t tests were performed separately for the high (n 8) and low (n 14) CESD-SF participants, pain intensity during amitriptyline therapy (mean, ) was significantly lower than during diphenhydramine therapy (mean, ) within the high CESD-SF group only (t 2.61, P.035). Additionally, when the effect of amitriptyline and gabapentin therapy on pain intensity was compared within the high CESD-SF group, there was a nonsignificant trend toward lower pain intensity during amitriptyline therapy

6 1552 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala Table 2: Characteristics of the Sample for Continuous Variables Characteristics Completers (n 22) Noncompleters (n 16) Age (y) Mean SD Median Range Age at onset (y) Mean SD Median Range Time since onset (y) Mean SD Median Range Duration of pain (y) Mean SD Median 5 5 Range Intake pain intensity at its worst Mean SD Median Range Pain intensity on average baseline week Mean SD Median 6 6 Range Pain intensity at its worst baseline week Mean SD Median Range No. of oxycodoneacetaminophen tablets taken during baseline week Mean SD Median Range Baseline CESD-SF Mean SD Median Range Abbreviation: SD, standard deviation. (t 2.23, P.061). There was no significant difference in pain intensity among the 3 medications in the low CESD-SF group. Results for pain intensity at its worst during week 8 were similar to those for pain intensity on average during week 8. Means for worst pain intensity (n 22) were: amitriptyline, ; gabapentin, ; and diphenhydramine, In a repeatedmeasures ANOVA in which the CESD-SF variable was entered as a between-subjects factor, the main effect for medication (F 5.7, P.007) and the depressive symptomatology variable (F 14.41, P.001) were both significant, but the interaction was not. Figures 3 and 4 show the longitudinal results for the VAS and the NRS. Week 0 refers to the pain intensity rating just before each medication was started. For the first medication, this was the baseline rating. For the second and third medications, it was the rating at the end of week 10 (end of washout) of the previous medication. There was no significant difference in the week 0 VAS pain ratings among the 3 medications, whether they were analyzed with the CESD-SF variable as a covariate (main effect of medication, F.77, P.472; main effect of CESD-SF group, F 11.85, P.003; interaction, F.40, P.671) or not (effect of medication, F.85, P.437). In both figures (VAS and NRS), with 1 exception in the high CESD-SF group at week 2 for VAS, pain intensity during amitriptyline therapy was consistently lower (but not always significantly) than during therapy with either of the other 2 medications at weeks 2 through 8 for both the high and low CESD-SF groups. Figure 5 shows the decrease in average pain from baseline to week 8 of each medication for the high and low CESD-SF groups. In both groups, the decrease was greater during the amitriptyline phase; however, the differences in pain intensity among the medications was significant only in the high CESD-SF group (F 4.02, P.042). Figure 6 shows the mean percentage change from baseline for each medication within each depressive symptomatology group. Amitriptyline had the greatest percentage of change from baseline in both CESD-SF groups; however, the differences among the medications was not significant in either group, but there was a nonsignificant trend in the high CESD-SF group (F 3.2, P.072). Among the participants in the low CESD-SF group, the percentages with at least a 30% decrease from baseline in pain intensity were 50% with amitriptyline, 42.9% with gabapentin, and 35.7% diphenhydramine. Among participants in the high CESD-SF group, the percentages were 62.5, 12.5, and 25, respectively. Table 3: Characteristics of the Sample for Categorical Variables Completers (n 22) Noncompleters (n 16) Characteristics N % N % Sex Men Women Race and ethnicity White (non-hispanic) Black Hispanic Marital status Married Not married Military veteran Yes No Level and completeness of SCI Tetraplegia (AIS grade A, B, or C) Paraplegia (AIS grade A, B, or C) Any level (AIS grade D) Baseline depressive symptomatology CESD-SF score * 28.6 CESD-SF score * 71.4 Abbreviation: AIS, American Spinal Injury Association Impairment Scale. *Baseline CESD-SF scores were not available for 2 noncompleters.

7 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala 1553 Fig 2. Means and error bars ( 2 standard error) of VAS ratings of pain intensity on average during week 8 of each medication by the 22 participants who completed all 3 phases of the study (completers) within the depressive symptomatology groups. Fig 4. Mean pain intensity ratings on the NRS across time for each study medication within the depressive symptomatology groups. Figure 7 shows the CESD-SF scores across time. There was no significant difference among the 3 medications at any given time point and no significant change in CESD-SF scores across time for any medication. Dropout Rate and Its Effect on Pain Intensity Ratings Figure 8 displays the percentage of the 38 participants who dropped out across time during each medication phase. There was no significant difference in dropout rate among the medications. Four persons withdrew or crossed over early due to medical problems not thought to be study related: urinary tract infection, autonomic dysreflexia, onset of diabetes, and pneumonia (see fig 1). Two people quit for unknown reasons before completing their first medication. One person was withdrawn because he twice claimed that he had lost his breakthrough medication and a study physician considered this to be excessive. That person then obtained a nonstudy pain medication from his primary care physician, which was a protocol violation. Because some participants attempted 1 or 2 medication phases but not all 3, and/or withdrew early from 1 or more of the phases, mean VAS scores for all participants with data for any medication at any measurement point (ie, 2, 4, and 8wk) were calculated using all available data; the scores are shown in figures 9, 10, and 11. There was almost no difference between the pain intensity ratings for those who completed at least 8 weeks of all 3 phases of the study (completers, n 22) and the total number (from 25 to 29 participants) who had data for a particular medication at a particular time point. This suggests a minimal effect of dropouts on the findings regarding pain intensity. Order and Dose of Medication Figure 12 shows the VAS mean scores of the 22 completers for average pain during week 8 by the 6 random assignment groups. Amitriptyline had the lowest mean ratings in 5 of the 6 groups. A repeated-measures ANOVA with group assignment entered as a covariate revealed a significant main effect of medication (F 3.41, P.045), no effect of group assignment (F.21, P.956), and no interaction effect (F.42, P.929). At any given measurement point (2, 4, or 8wk), the majority of participants (85% 97% [from 25 to 30]) who were receiving a given medication at a given time point were able to tolerate the maximum dose of whichever medication they were receiving. It should be noted, however, that participants who withdrew from a particular phase of the study before a given time Fig 3. Mean pain intensity ratings on the VAS across time for each study medication within the depressive symptomatology groups. Fig 5. Mean decrease in average pain intensity ratings on the VAS from baseline to week 8 of each medication within the depressive symptomatology groups.

8 1554 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala Fig 6. Mean percent change in average pain intensity ratings on the VAS from baseline to week 8 of each medication within depressive symptomatology groups. point because of intolerable side effects were not included in the analyses for that particular medication for that or for later time points. For the 22 completers, there was no significant difference in the percentage of the maximum dose received among the 3 medications. For example, at week 8, on average, they received 94% of the maximum dose of amitriptyline, 91% of the maximum dose of gabapentin, and 95% of the maximum dose of diphenhydramine. Breakthrough Medication Figure 13 shows the number of tablets of breakthrough medication taken during week 8 for each medication within the 2 CESD-SF groups. For all 3 medications, regardless of the CESD-SF group, at least 50% of the participants who completed the study received no breakthrough medication during week 8. The majority of the other participants received no more than an average of 2 tablets a day (ie, 14/wk). Nonparametric Friedman tests revealed no significant difference in ranks for the low CESD-SF group (amitriptyline, 1.73; gabapentin, 2.23; diphenhydramine, 2.04; 2 test 2.69; P.261), the high CESD-SF group (amitriptyline, 2.13; gabapentin, 1.88; diphenhydramine, 2; 2 test.38, P.827), or the 2 groups combined (amitriptyline, Fig 8. Dropout rate across time for each medication. 1.88; gabapentin, 2.1; diphenhydramine, 2.02; 2 test.79, P.673). Side Effects The side effects reported by the participants throughout each medication phase are listed in table 4 for the completers and table 5 for the noncompleters. The side effects checklist was completed 210 times by the completers during amitriptyline therapy, 201 times during gabapentin therapy, and 205 times during diphenhydramine therapy. We divided the number of times a given side effect was reported during therapy with a certain medication by the number of reports for that medication. For example, dry mouth was reported 134 times out of the 210 reports, or 62.5% of the time during amitriptyline therapy. Dry mouth was by far the most frequent complaint, with 21 of 22 completers reporting having had it at least once. Among the completers during amitriptyline therapy, 5 side effects dry mouth, constipation, difficulty emptying the bowel, nausea, and difficulty emptying the bladder were significantly more frequently reported than during therapy with the other 2 medications. Not surprisingly, increased spasticity was reported significantly less often during gabapentin therapy than with the other 2 medications. Gabapentin reduces spasticity in persons Fig 7. Mean CESD-SF scores across time for each medication within the depressive symptomatology groups. Fig 9. Average pain intensity ratings on the VAS during amitriptyline treatment by the 22 completers and by all available ratings for amitriptyline at each time point. Sample sizes for the All points varied depending on dropout and early withdrawal rates.

9 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala 1555 Fig 10. Average pain intensity ratings on the VAS during gabapentin treatment by the 22 completers and by all available ratings for gabapentin at each time point. Sample sizes for the All points varied depending on dropout and early withdrawal rates. Fig 12. Average pain intensity ratings on the VAS for week 8 by the order in which each medication was received according to randomly assigned group. with SCI. 52,53 Spasticity was not listed on the side effects checklist but was mentioned frequently when the participants were asked about other side effects. For the noncompleters, dry mouth, drowsiness, and fatigue were more frequently reported during amitriptyline therapy. It is important to identify possible adverse side effects that were so intolerable that in spite of dose reductions, participants withdrew or crossed over early to the next medication. This happened 4 times during the amitriptyline phase. Complaints included (1) light-headedness, drowsiness, pain in the lower abdomen, flushing, rapid heart beat, and chills (week 1); (2) allodynia and pins and needles feeling in extremities (week 4); (3) suicide ideation (week 1); and (4) drowsiness, dizziness, and falling out of a wheelchair (week 1). Withdrawal because of possible side effects occurred 5 times during the gabapentin phase: (1) shortness of breath (week 1); (2) dizziness, fatigue, and nausea (week 4); (3) increased spasticity and pain (week 6); (4) fatigue, drowsiness, constipation, and dry mouth (week 3); and (5) severe itching (week 1). Possible side effects caused an early crossover twice during the diphenhydramine phase: (1) palpitations (first dose) and (2) fatigue, dizziness, and drowsiness (week 7). Cost of Medication At the MEDVAMC as of January 25, 2007, the monthly (30d) cost of taking 50mg of amitriptyline, 3 times a day was $1.76 ($.020/tablet) and for taking 1200mg of gabapentin (400mg tablets, $.117/tablet, or $.351/dose) 3 times a day it was $ Costs in the private sector vary, but are likely to be much higher. For the group with less depressive symptomatology, which had a 31.5% change in average pain intensity while receiving amitriptyline, the efficacy factor (percentage change/ cost for a month) was This means that for every dollar spent, there was a decrease in pain of nearly 18%. For gabapentin in the low CESD-SF group, the efficacy factor was.44. The efficacy factors for the high CESD-SF group were for amitriptyline and.36 for gabapentin. Fig 11. Average pain intensity ratings on the VAS during diphenhydramine treatment by the 22 completers and by all available ratings for diphenhydramine at each time point. Sample sizes for the All points varied depending on dropout and early withdrawal rates. Fig 13. Frequency distribution of the number of oxycodoneacetaminophen tablets taken for breakthrough pain during week 8 for each medication within the depressive symptomatology groups.

10 1556 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala Side Effects Table 4: Reported Side Effects for Each 8-Week Medication Phase for Completers Amitriptyline Percentage of Side-Effect Reports (n 210) Gabapentin Percentage of Side-Effect Reports (n 201) Diphenhydramine Percentage of Side-Effect Reports (n 205) 2 Dry mouth * Drowsiness Fatigue Constipation * Increased spasticity Dizziness Difficulty emptying bowel Nausea Edema Itching Difficulty emptying bladder Low blood pressure Uncoordinated muscles Vomiting Abnormal heart rhythms Skin rash Weight gain Seizure NA Abbreviation: NA, not applicable. *P.001; P.05. DISCUSSION To our knowledge, this is the first head-to-head, randomized, controlled, double blind, triple crossover comparison of the effectiveness of amitriptyline and gabapentin in the treatment of neuropathic pain at or below the level of injury in persons with SCI. Contrary to previous findings reported in the literature, we found amitriptyline to be effective in relieving pain. In this study, amitriptyline was even more effective than gabapentin, which other studies 40,41 have shown to be effective. Our results could not be attributed to the effects of dropout rates, the order in which the medications were taken, the dosage of the medications, amount of medication taken for breakthrough pain, or the number of side effects. The effectiveness of amitriptyline was greatest in participants who had many depressive symptoms at baseline; they had more than a 3-point decrease on a scale of 0 to 10. Amitriptyline was the most effective medication even among those with fewer depressive symptoms at baseline; they had an average decrease in pain intensity of more than 1.5 points, but the difference between the medications was not statistically significant. Most participants experienced a clinically meaningful decrease (ie, 30% of baseline) in pain when taking amitriptyline. Not only was it more effective than gabapentin, the monthly cost for amitriptyline is far less than it is for gabapentin. There has been considerable research into the effects of pharmacologic agents on chronic pain after SCI. Studies that focused on amitriptyline and gabapentin are briefly reviewed here. Side Effects Table 5: Reported Side Effects for Each 8-Week Medication Phase for Noncompleters Amitriptyline Percentage of Side-Effect Reports (n 67) Gabapentin Percentage of Side-Effect Reports (n 57) Diphenhydramine Percentage of Side-Effect Reports (n 43) 2 Dry mouth * Drowsiness Fatigue Constipation Increased spasticity Dizziness Difficulty emptying bowel Nausea Edema Itching Difficulty emptying bladder Low blood pressure Uncoordinated muscles Vomiting Abnormal heart rhythms Skin rash Weight gain Seizure NA *P.001; P.01; P.05.

11 COMPARING AMITRIPTYLINE AND GABAPENTIN, Rintala 1557 Amitriptyline Survey studies. Survey studies in which the respondents evaluated the effectiveness of amitriptyline to reduce pain in general found amitriptyline to be relatively ineffective. Warms et al 26 reported survey responses from 2 separate samples. On average, the helpfulness of amitriptyline was rated as 2.08 and 2.06 on a scale of 1 (not at all helpful) to 5 (extremely helpful). Widerström-Noga and Turk 27 reported the results of a postal survey in which three fourths of those who used unspecified antidepressants indicated that there was no effect on pain, or that their pain worsened. Cardenas and Jensen 28 reported that the average rating for amitriptyline was 2.9 on a scale of 0 (no relief) to 10 (complete relief). We 29 have reported that the success of amitriptyline in relieving pain in veterans with SCI was rated as 3.22 on a scale of 0 (no relief) to 5 (total relief). Although the results varied to some extent among the survey studies, in all of them amitriptyline was not perceived as being very effective, on average, for pain relief in the SCI population. Randomized controlled trial. Cardenas et al 30 conducted the first randomized controlled trial of the effectiveness of amitriptyline in relieving pain in persons with SCI. They used a parallel group design with 44 participants randomly assigned to receive amitriptyline (maximum of 125mg once a day), and 40 assigned to receive an active control, benztropine mesylate (Cogentin) (0.5mg once a day). Benztropine mesylate was selected because it causes side effects similar to those caused by amitriptyline. Randomization was stratified according to depressive symptomatology (20-item CES-D 49 score of 15 vs 16) to control for baseline depressive symptomatology. The participants had a variety of pain types, including SCI pain (pain below the level of injury), transition zone pain (pain at the level of injury), radicular pain, visceral pain, mechanical spine pain, and overuse pain. There was no significant difference between the groups in the primary outcome measure of a rating of pain intensity on a numeric scale of 0 (no pain) to 10 (pain as bad as could be) during week 6 of the trial after controlling for baseline pain intensity ratings. Cardenas concluded that amitriptyline was not efficacious in relieving pain or improving the quality of life of participants with SCI. The question arises as to why our results differ from those of the study of amitriptyline by Cardenas and colleagues. Differences between that study and our study include the fact that they used a parallel group design rather than a crossover design. The advantage of a crossover design is that each person is his/her own control, which accounts for possible individual differences. Cardenas included participants with different pain types rather than limiting participation to people with neuropathic pain at and/or below the level of injury, as we did in this study. They did a post hoc analysis with a subset of participants who had at- or below-level pain, but they included only a small number of people (15 in the amitriptyline group, 17 in the placebo); consequently, its statistical power was reduced. The maximum dose of amitriptyline in their study was 125mg once a day, with the median dose taken at week 6 (their end point) being 50mg per day. This suggests that some of their participants were unable to tolerate the maximum dose when taken once a day. Others may not have reached the maximum dose, however, because of pain relief at a lower dose. In our study, the maximum and median doses at week 8 (our end point) were 150mg a day taken as 50mg, 3 times a day. Perhaps receiving several smaller doses of amitriptyline throughout the day results in increased effectiveness and/or a reduction in unwanted side effects, thus permitting a larger total dose a day. Another difference was that the 2 studies used different active control medications. Cardenas used benztropine mesylate, a drug often used to treat symptoms of Parkinson s disease, and we used diphenhydramine, which is an antihistamine. To what extent this could have had an impact on the results is unknown. Gabapentin Survey studies. In the surveys by Warms 26 and Cardenas and Jensen, 28 gabapentin was rated somewhat better than amitriptyline but it was not reported to be very effective. In the Warms samples, the helpfulness of gabapentin was rated as 3.21 and 2.9, respectively, on a scale of 1 (not at all helpful) to 5 (extremely helpful), compared with 2.08 and 2.06 for amitriptyline. In the survey by Cardenas, 28 the efficacy of gabapentin was rated as 3.32, on average on a scale of 0 (no relief) to 10 (complete relief), compared with 2.9 for amitriptyline. In the survey by Widerström-Noga and Turk, 27 one third of those who used anticonvulsants reported there was no effect, compared with three fourths for those who used antidepressants. In our survey, 29 the effectiveness of gabapentin (2.89/5) was rated lower than amitriptyline (3.22). Retrospective studies. In a retrospective chart review, To et al 36 found that 58% of people with SCI who received gabapentin for neuropathic pain (maximum dose, 4800mg/d) had some improvement. The mean pain intensity score decreased by nearly 5 points from baseline to the 6-month follow-up on a 10cm VAS. Putzke et al 37 retrospectively contacted persons with traumatic SCI who had been in a trial of gabapentin as an analgesic. At 6 months, 22% had discontinued use because of unacceptable side effects. Fifty-two percent had experienced at least a 2-point decrease in pain intensity, on a scale of 0 to 10. Three years later, 91% of those contacted still experienced a benefit from the gabapentin; however, their pain intensity scores had risen. Doses of gabapentin ranged from 300mg to 3600mg a day at the follow-up contacts. Open-label, uncontrolled studies. Attal et al 38 conducted a pilot study to assess the effects of gabapentin on peripheral and central neuropathic pain syndromes. The maximum dose of gabapentin was 2400mg a day. Gabapentin significantly reduced spontaneous pain, especially paroxysmal pain, by the end of week 6. There was no difference in the effects of gabapentin between participants who had central pain and those who had peripheral pain. Ahn et al 39 evaluated the effect of gabapentin on intractable neuropathic pain in persons with SCI, with the maximum dose at 1800mg a day. They had significant reductions in pain and sleep interference from baseline to the end of 8 weeks. The majority had at least a 2-point decrease in pain intensity, on a scale of 0 to 10. The effects of gabapentin were evident by week 2, and by week 4, pain and sleep interference reached a plateau. Randomized controlled trials. Tai et al 40 conducted a prospective, randomized, double blind, crossover trial of the effects of gabapentin on neuropathic pain in participants with SCI. Seven (50%) of the 14 persons enrolled completed the study. Participants were assigned to receive either gabapentin (maximum dose, 1800mg/d) or a placebo for 4 weeks, and then to receive the alternate medication for 4 weeks after a 2-week washout period. Effects were assessed with the Neuropathic Pain Scale (NPS), which evaluates 10 aspects of pain. 54 The rating for unpleasant feeling was significantly lower at the end of week 4 during the gabapentin phase than during the placebo phase and there was a tendency for lower pain intensity and burning sensation during the gabapentin phase. Levendoglu et al 41 also conducted a prospective, randomized, double-blind, crossover study to determine the efficacy of gabapentin to treat chronic neuropathic pain in 20 people with paraplegia. Participants were randomly assigned to which medication they would receive for the first 8 weeks; after a 2-week washout period they received