Trial of Amitriptyline for Relief of Pain in Amputees: Results of a Randomized Controlled Study

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1 ARTICLES Trial of Amitriptyline for Relief of Pain in Amputees: Results of a Randomized Controlled Study Lawrence R. Robinson, MD, Joseph M. Czerniecki, MD, Dawn M. Ehde, PhD, W. Thomas Edwards, MD, PhD, David A. Judish, MD, Myron L. Goldberg, PhD, Kellye M. Campbell, RN, Douglas G. Smith, MD, Mark P. Jensen, PhD 1 ABSTRACT. Robinson LR, Czerniecki JM, Ehde DM, Edwards WT, Judish DA, Goldberg ML, Campbell KM, Smith DG, Jensen MP. Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study. Arch Phys Med Rehabil 2004;85:1-6. Objective: To evaluate whether amitriptyline is more effective than placebo in improving phantom limb pain or residual limb pain. Design: Randomized controlled trial of amitriptyline for 6 weeks. Setting: University hospital. Participants: Thirty-nine persons with amputation-related pain lasting more than 6 months. Intervention: Six-week trial of amitriptyline (titrated up to 125mg/d) or an active placebo (benztropine mesylate). Main Outcome Measures: Analyses were conducted to examine whether there was a medication group effect on the primary outcomes (average pain intensity) and secondary outcome measures (disability, satisfaction with life, handicap). Results: No significant differences were found between the treatment groups in outcome variables when controlling for initial pain scores. Conclusions: Our findings do not support the use of amitriptyline in the treatment of postamputation pain. Key Words: Amitriptyline; Amputation; Pain; Phantom; Rehabilitation by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation BOTH PHANTOM LIMB PAIN (PLP) and residual limb pain (RLP) are frequent problems after amputation. Population-based studies, 1-3 have found that most persons who undergo limb amputation will experience PLP. For example, in a recent study 4 of 255 amputees, we reported that 72% of lower-limb amputees experience PLP and 74% reported RLP. In addition, 79% reported nonpainful phantom limb sensations. For most, the pain was episodic and not particularly disabling. From the Departments of Rehabilitation Medicine (Robinson, Czerniecki, Ehde, Campbell, Jensen), Anesthesiology (Edwards), and Orthopaedic Surgery and Sports Medicine (Smith), University of Washington, Seattle, WA; and Good Samaritan Hospital, Puyallup, WA (Judish, Goldberg). Supported by the National Institutes of Health, National Institute of Child Health and Human Development, National Institute of Neurological Disorders and Stroke (grant no. 1PO1 HD/NS33988). 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 authors(s) or upon any organization with which the author(s) is/are associated. Reprint requests to Lawrence R. Robinson, MD, Dept of Rehabilitation Medicine, Box , Harborview Medical Center, 325 Ninth Ave, Seattle, WA 98104, lorenzo@u.washington.edu /04/ $30.00/0 doi: /s (03) However, for a notable subset (14%), the pain was severely limiting. 4 Tricyclic antidepressants (TCAs) have long been used to treat PLP. Studies testing the efficacy of TCAs for PLP, however, are essentially nonexistent. In a meta-analysis of 39 controlled trials, 5 antidepressants were found to be beneficial in the treatment of a variety of types of chronic pain; however, none of the clinical trials focused on pain after amputation. Some studies 6-13 suggest a beneficial effect of TCAs in patients with painful peripheral polyneuropathy. Given that amputation usually includes severing multiple peripheral nerves, it is plausible to hypothesize that these medications may be helpful in treating PLP or, possibly, RLP. However, a rigorous clinical trial in persons with postamputation pain has been lacking. The objectives of our study were to address the following questions: (1) Does amitriptyline produce better relief for PLP than placebo? (2) Does amitriptyline produce better relief for RLP than placebo? and (3) Does amitriptyline reduce handicap or improve function or satisfaction with life more than placebo? METHODS Participants Study participants were recruited from several sources, including lists of patients treated for amputation at Harborview Medical Center, Seattle, WA (a regional trauma center) during the last 10 years, patients recruited for a survey on pain after amputation, 4 flyers sent to local prosthetists offices, the Veterans Administration Puget Sound Health Care System, and regional amputee clinics including Good Samaritan Hospital in Puyallup, WA. Potential study participants were asked to contact the investigators if they were interested in learning more about the study. Study inclusion criteria were amputation more than 6 months before enrollment, pain for at least 3 months, and average pain rating in the last month of at least 2 on a scale of 0 to 10. Each subject gave written informed consent. Individuals were excluded if they were less than 18 years or more than 65 years of age, had a history of cardiovascular disease or seizures, were pregnant, were on any type of antidepressant medication (because of medication interaction or because they might produce pain relief), or reported consuming more than 2 alcoholic drinks per day. Those 50 years or older had a screening electrocardiogram (ECG) and were excluded if they had conduction abnormalities. The University of Washington Human Subjects Review Committee and the Institutional Review Board of Good Samaritan Hospital approved the study. We screened 457 persons for potential participation. Of these, 239 (52%) were ineligible, most commonly because they were outside the age range (n 100), pain rating was less than 2 out of 10 (n 67), or they were currently on antidepressants (n 33). In addition to the 239 excluded, 108 people (24% of the 457) declined to participate. The most common reasons for declining were not wanting to take the study medication

2 2 AMPUTATION PAIN, Robinson (n 34), previous negative experience with the study drug (n 30), and too many visits required (n 12). An additional 71 people were not contacted because they lived too far away, did not have telephones, or did not return messages. A total of 39 subjects (18% of those eligible) were enrolled in the study. Study Design and Treatment We used a double-blind, randomized, active placebo-controlled study design. Max 13 has cautioned that without an active placebo an agent that mimics some of the side effects of the antidepressant drug studied subjects in randomized clinical trials (RCTs) may not be truly blind to the antidepressant drug, and their beliefs may affect the results. 14 Thus, in this double-blind RCT we compared amitriptyline to an active placebo, benztropine mesylate. Benztropine mesylate was chosen as an active placebo for its ability to produce dry mouth, a common side effect of amitriptyline. After subjects were enrolled, they were randomly assigned to either amitriptyline or the active placebo. Twenty subjects were randomized to amitriptyline and 19 to active placebo. All research personnel were blind to the drug assignment. Procedures Potential participants were screened in an interview conducted by the research nurse and one of the physician investigators, to determine whether they met the inclusion and exclusion criteria. Subjects were interviewed regarding their pain, and the physician classified their pain into PLP, RLP, or both. Based on description of the patient s pain and the physical examination, RLP was further classified by the physicians as neuropathic or mechanical. Patients with either PLP or RLP (mechanical or neuropathic) were included in the study. A physical examination was also conducted to look for any obvious pain sources, such as skin lesions, poorly fitting prostheses, or other causes. If patients were in the process of obtaining a new prosthesis or other interventions that might change their pain level, they were advised to wait to enroll until the intervention had been completed. Individuals 50 years or older were also given an ECG to screen for cardiac abnormalities and were excluded if abnormalities were found. Eligible subjects completed baseline study measures in a telephone interview before randomization. Random assignment to the treatment group and provision of medication was done by the Harborview Medical Center Pharmacy Investigational Drug Services. Medication was provided to each participant on a weekly basis by the study nurse or by mail for participants who lived far from the study center. A 7-day supply of medication was provided to each participant each week in identical gelatin capsules placed in a plastic holder (Mediset), so that study personnel and participants were blind to medication assignment. Participants were instructed to take a single daily dose of medication 1 to 2 hours before bedtime. The number of doses missed was recorded for local participants by counting the number of pills left in each week s pill container and by verbal report for those receiving their medications by mail. During the last week of the 6-week trial, before unblinding and while subjects were taking their maximal dose of study medication, subjects completed the posttreatment measures in another telephone interview. All pre- and posttreatment measures were administered by a research assistant blinded to the subject assignment, not by the study physician or nurse. After unblinding at the end of the 6-week trial, subjects who wanted to stay on the study medication were given a prescription for a 1-week supply of medication and were advised to discuss continuing the medication with their regular health care provider. Those who took placebo were so informed. Four months after the posttreatment assessment, subjects were telephoned again about medication use after the posttreatment interview. Each subject was paid $100 for completing the study. TCAs and Active Placebo The amitriptyline dosage started at 10mg/d and was gradually increased each week to a maximum of 125mg/d by mouth, whereas the dosage of benztropine mesylate was held constant at 0.5mg/d by mouth. The amitriptyline dose schedule was as follows: week 1, 10mg/d; week 2, 25mg/d; week 3, 50mg/d; week 4, 75mg/d; week 5, 100mg/d; and week 6, 125mg/d. Medication dosage was increased by the study nurse each week until there was complete pain relief or until the subject reached either the maximal dose tolerated during the 6-week trial or 125mg/d. If side effects were intolerable, the dose was decreased to a lower level or discontinued if the subject was on the lowest dose level. The study nurse contacted subjects on day 4 or 5 of each week to assess pain and medication side effects. For local subjects in the amitriptyline group, serum amitriptyline levels were determined from blood drawn immediately after unblinding at the end of week 6. Because many subjects were not local, only 6 subjects had their levels drawn. Measures The primary outcome measure for this study was patientreported average pain intensity, rated on a 0- to 10-point numerical rating scale with anchors of 0 (no pain) and 10 (pain as bad as could be). Subjects rated their average pain during the past 24 hours on this scale 3 times during the baseline week (before receiving any medication) and 3 times during week 6, as well as once a week during weeks 1 to 5 of the treatment phase. The 3 baseline week ratings were averaged for a single measure of pretreatment pain intensity, and the 3 week 6 ratings were also averaged for a single measure of posttreatment pain intensity. Secondary outcome measures are described later. Short-Form McGill Pain Questionnaire The Short-Form McGill Pain Questionnaire (SF-MPQ) has 15 pain descriptions, rated from 0 (none) to 3 (severe). These individual scores are added to produce a summary score. The SF-MPQ correlates highly with the original McGill Pain Questionnaire and is sensitive to the effects of pain treatments. 15 Modified Brief Pain Inventory All subjects were administered the Pain Interference Scale of the Modified Brief Pain Inventory 16,17 (BPI). The interference scale assesses the degree to which pain interferes with 7 daily activities (general activity, mood, normal work, walking, relations with other people, sleep, enjoyment of life). We also added 3 items (pain interference with self-care, recreational activities, social activities) to provide a more broad-based assessment of the extent to which pain interfered with important activities. Center for Epidemiologic Studies Depression Scale We used the Center for Epidemiologic Studies Depression Scale (CES-D) to measure symptoms of depression. FIM Instrument Functional abilities were assessed by using the FIM instrument. 22 This 18-item measure is a commonly used functional measure for patients undergoing rehabilitation. The FIM assesses independent functioning in self-care, sphincter control, mobility, transfers, locomotion, communication, and so-

3 AMPUTATION PAIN, Robinson 3 cial cognition. An interview version of the FIM 23 was used in this study. Satisfaction With Life Scale The Satisfaction With Life Scale 24 (SWLS) is a 5-item scale designed to measure global life satisfaction. Diener et al 24 showed that the SWLS assesses a single factor and that it shows excellent test-retest stability and internal consistency. Craig Handicap Assessment and Reporting Technique Handicap, which reflects how disabled persons function in societal contexts, was measured by using an interview version of the Craig Handicap Assessment and Reporting Technique 25 (CHART). The CHART is a 27-item measure that assesses orientation, physical independence, mobility, occupation, social integration, and economic self-sufficiency. Statistical Analysis Baseline characteristics of subjects in the amitriptyline and placebo groups were compared by using t tests and nonparametric (Wilcoxon rank-sum) tests. Multiple regression analyses were conducted to assess whether subjects in the amitriptyline and placebo groups differed on the outcome measures at the end of the 6-week trial, when controlling for initial pain levels. Intention-to-treat analysis was used. The chi-square test was used to compare symptoms or side effects in the amitriptyline and placebo groups at weeks zero and 6 as well as to compare side-effect frequency between medication groups. Side-effect symptom severity ratings of medication groups were compared using t tests. RESULTS Participant Characteristics Characteristics for the 39 participants are shown in table 1. There were no significant baseline differences between the amitriptyline and placebo groups for age, sex, education, or duration of amputation. Cause and level of amputation were also similar between groups. The type of pain, assigned by the physician examining the subject, is shown in table 2; most subjects had both RLP and PLP. Attrition Two subjects (10%) in the amitriptyline group discontinued medication compared with none in the active placebo group. Reasons for discontinuing medication in the amitriptyline group were related to side effects. Dosing and Protocol Adherence Eleven (61%) subjects on amitriptyline and 6 (32%) of those on placebo did not miss any drug doses. There was no difference in posttreatment average pain intensity for those who missed more than 20% of total doses as compared with those who missed less than 20% of total doses in each medication group. Table 1: Sociodemographic and Injury Characteristics of Study Participants Characteristic Amitriptyline (n 20) Medication Group Active Placebo (n 19) Age (y) Mean SD Range Sex (%) Male Level of amputation (%) Hip disarticulation 5 11 Transfemoral Knee disarticulation 5 Transtibial Ankle 5 Foot 5 Toes 10 Transhumeral 5 11 Hand 5 Causes of amputation (%) Trauma Vascular disease Tumor 5 5 Diabetes 11 Infection 5 Duration of amputation (y) Mean SD Ethnic group (%) White Hispanic/Chicano 0 11 African American 15 5 Asian/Pacific Islander 0 0 Native American 5 5 Other 5 0 Marital status (%) Married Living with partner 15 5 Never married Separated/divorced Widowed 0 5 Education (%) grade HS graduate Voc/tech/some college College graduate Grad/prof school 0 5 Employment status (%) Employed full-time Employed part-time 5 21 School/vocational training 0 5 Retired Homemaker 0 5 Unemployed Abbreviations: HS, high school; Grad/prof, graduate/professional; SD, standard deviation; Voc/tech, vocational/technical. Outcomes There were no significant baseline differences between groups for any measures except the SWLS, which was higher in the placebo group (t 2.96, P.004; see table 3). Regression analyses were conducted to examine whether there was a medication group effect on the primary (average pain intensity) and secondary (SF-MPQ, BPI Pain Interference, CES-D, FIM, SWLS, CHART) outcome measures. Intent-totreat analyses were conducted, including all subjects randomized in the study (except 1 for whom no posttreatment data were available). Separate regression analyses were performed to predict each dependent variable at posttreatment, adjusting for pretreatment scores on the variable. In each case, the pretreatment scores explained a large and statistically significant proportion of the variance in the posttreatment scores, and

4 4 AMPUTATION PAIN, Robinson Pain Type Table 2: Pain Type Amitriptyline (n 20) n (%) Medication Group Placebo (n 19) n (%) PLP 4 (20) 3 (16) RLP 2 (10) 4 (21) Both RLP and PLP 13 (65) 11 (58) Other* 1 (5) 1 (5) *Muscle contraction pain for the amitriptyline group and vascular claudication for the placebo group. the medication group (placebo, amitriptyline) did not make a significant additional contribution. Exploratory analyses were conducted to examine whether age, sex, level of injury, pretreatment CES-D scores, and pretreatment CES-D by medication group interactions predicted posttreatment scores on each measure, but none of these variables explained a statistically significant proportion of the variance in posttreatment scores after adjusting for pretreatment scores. When subjects who received amitriptyline were grouped into those with less than 3 years since amputation (n 6) or more than 3 years since amputation (n 12), there was no significant difference in change in pain (pre- to posttreatment) between the 2 groups. Mean serum level of amitriptyline at the end of the study in the 6 participants of the amitriptyline group who had the serum levels drawn was 80.3ng/mL (n 6; range, ng/mL). There was no significant correlation between the blood level of amitriptyline and posttreatment pain, when controlling for pretreatment pain (P.45). At the 4-month follow-up interview, 7 of 18 subjects were still taking the amitriptyline, prescribed by their health care provider. However, the reduction in pain scores (pre- to posttreatment) reported by the group still taking the medication (.17) was no greater than that for those who chose not to take the medication (.91) (P.42). Adverse Effects The most common side effects or symptoms reported among those on amitriptyline and placebo were dry mouth and dizziness. Dry mouth was significantly more severe in the amitriptyline group than in the placebo group. Other side effects were similar in the 2 groups (table 4). DISCUSSION To our knowledge, this is the first placebo-controlled trial to examine the efficacy of a TCA in the treatment of pain after amputation. Our results indicate that amitriptyline was not effective in reducing PLP or RLP. It was also not effective in changing satisfaction with life, functional independence, or handicap. At the same time, amitriptyline did produce more dry mouth than the active placebo group. We chose amitriptyline for our study because of its common use in postamputation pain and the studies that have shown efficacy in other clinical scenarios. In the meta-analysis of placebo-controlled studies of the analgesic effect of antidepressants by Onghena and Van Hondenhove, 5 the mean effect size of amitriptyline was.73 in chronic nonmalignant pain. In our study, the 95% confidence interval for the difference in pain between the 2 groups was ; hence, we ruled out an effect size of.73. Although amitriptyline was found helpful by almost half the subjects (7/18) who continued on the drug after unblinding, these subjects did not indicate a greater improvement in pain during the drug trial than did those who chose to discontinue amitriptyline after the trial. Limitations of this trial need to be considered when interpreting these results. As noted earlier, the sample size was of sufficient power to detect moderate or large effect sizes; it could, however, have missed a small treatment effect. On the other hand, if the effect size was present but small, it would be much lower than the mean effect size of amitriptyline in other studies. This argues against the efficacy of amitriptyline for PLP or RLP specifically. One might argue that the subjects did not receive the drug for a sufficient length of time (ie, 6wk); however, most studies of antidepressants for chronic back pain have shown pain improvement in 1 to 3 weeks. 26 Given that our sample was 18% of those eligible to participate, it is possible that the sample does not accurately reflect the amputee population at large. We had a high percentage of persons with traumatic amputations, compared with vascular amputations. Additionally, the study may have selected for patients who had pain refractory to standard interventions that had been previously tried by their clinicians. Hence it is possible that there is a subset of individuals with postamputation pain who might benefit from amitriptyline more than others. Moreover, although there was no difference in those more than or less than 3 years since amputation, our sample size was too small to analyze those with more brief duration of pain. Hence, there may be some benefit to further studies testing those with recent onset of pain. However, our study does likely reflect that segment of the amputee population willing to try this medication intervention. Measure Table 3: Pre- and Posttreatment Outcome Measure Scores in Amitriptyline and Placebo Groups Amitriptyline Group (n 18)* Placebo Group (n 19) Pre (mean SD) Post (mean SD) Pre (mean SD) Post (mean SD) APLPI ARLPI SF-MPQ CES-D SWLS BPI FIM CHART Abbreviations: APLPI, average PLP intensity; ARLPI, average RLP intensity. *Two subjects did not complete posttreatment measures.

5 AMPUTATION PAIN, Robinson 5 Table 4: Subjects With New Symptoms or Increased Severity of Existing Symptoms Symptom n (%) Amitriptyline Group (n 18) Severity* (mean SD) No. of Weeks (mean SD) n (%) Placebo Group (n 19) Severity* (mean SD) No. of Weeks (mean SD) Dry mouth 13 (72.2) (68.4) Drowsiness/tiredness/fatigue 9 (50.0) (47.4) Blurred vision 1 (5.6) (26.3) Constipation 4 (3.1) (15.8) Dizziness 2 (1.1) (15.8) Heartburn 0 (0.0) (15.8) Poor sleep 2 (1.1) (10.5) Palpitations 0 (0.0) (10.5) Nausea/vomiting 2 (1.1) (0.0) Better sleep 2 (1.1) (0.0) Urinary retention 1 (5.6) (5.3) Diarrhea 1 (5.6) (5.3) Tinnitus 1 (5.6) (5.3) Tremor 0 (0.0) (5.3) Sweating 0 (0.0) (5.3) Headache 0 (0.0) (5.3) *Severity rating scale of 1 to 3 (1, mild; 2, moderate; 3, severe) averaged over the weeks that symptom were reported. Number of weeks symptom were reported by those with symptoms. Not on symptom checklist, mentioned spontaneously. Statistically significant difference between the 2 groups (t , P.05). There was no significant difference in depression scores between those taking amitriptyline and active placebo, although there was a nonsignificant trend (P.18) to lower scores in those on the active drug. Although the exact mechanism of the analgesic effect of TCAs is still unclear, their effect on pain does not appear to be because of their effect on mood. Doses as low as 25mg of amitriptyline, which is well below antidepressant doses, were efficacious in patients with chronic nonmalignant pain, compared with placebo. 27 Furthermore, TCAs have been found efficacious in painful diabetic neuropathy in nondepressed patients compared with placebo. 7,10 CONCLUSION The results do not support the use of amitriptyline for the treatment of postamputation pain syndrome. Given the severity and seriousness of PLP and RLP among persons with amputation, 4 there is a need for additional clinical studies to develop and test the efficacy of other possible treatments for these pain problems. Acknowledgments: We gratefully acknowledge the contributions by Amy Hoffman in database management. References 1. Jensen TS, Krebs B, Nielsen J, Rasmussen P. Immediate and long-term phantom limb pain in amputees: incidence, clinical characteristics, and relationship to pre-amputation pain. Pain 1985;21: Sherman RA, Sherman CJ. Prevalence and characteristics of chronic phantom limb pain among American veterans. Am J Phys Med 1983;62: Jensen TS, Krebs B, Nielsen J, Rasmussen P. Phantom limb, phantom pain, and stump pain in amputees during the first six months following limb amputations. Pain 1983;17: Ehde DM, Czerniecki JM, Smith DG, et al. Chronic phantom sensations, phantom pain, residual limb pain, and other regional pain after lower limb amputation. Arch Phys Med Rehabil 2000; 81: Onghena P, Van Houdenhove B. Antidepressant-induced analgesia in chronic non-malignant pain: a meta-analysis of 39 placebocontrolled studies. Pain 1992;49: Kishore-Kumar R, Max MB, Schafer SC, et al. Desipramine relieves postherpetic neuralgia. Clin Pharmacol Ther 1990;47: Kvinesdal B, Molin J, Froland A, Gram LF. Imipramine treatment of painful diabetic neuropathy. JAMA 1984;251: Langohr HD, Stohr M, Petruch F. An open and double-blind cross-over study on the efficacy of clomipramine (Anafranil) in patients with painful mono- and polyneuropathies. Eur Neurol 1982;21: Lynch SD, Max MB, Muir J, Smoller B, Dubner R. Efficacy of antidepressants in relieving diabetic neuropathy pain: amitriptyline versus desipramine, and fluoxetine versus placebo [abstract]. Neurology 1990;40: Max MB, Culnane M, Schafer SC, et al. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 1987;37: Max MB, Schafer SC, Culnane M, Smoller B, Dubner R, Gracely RH. Amitriptyline, but not lorazepam, relieves postherpetic neuralgia. Neurology 1988;38: Sindrup SH, Gram LF, Brosen K, Eshoy O, Morgensen EF. The selective serotonin reuptake inhibitor paraxetine is effective in the treatment of diabetic neuropathy symptoms. Pain 1990;42: Max MB. Antidepressant drugs as treatments for chronic pain: efficacy and mechanisms. In: Bromm B, Desmedt JE, editors. Advances in pain research and therapy: issue on pain and the brain: from nociception to cognition. Vol 22. New York: Raven Pr; p Max MB, Byas-Smith MG, Gracely RH, Bennett GJ. Intravenous infusion of the NMDA antagonist, ketamine, in chronic posttraumatic pain with allodynia: a double-blind comparison to alfentanil and placebo. Clin Neuropharmacol 1995;18: Melzack R. The short-form McGill Pain Questionnaire. Pain 1987;30: Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med 1994;23: Daut RL, Cleeland CS, Flannery RC. Development of the Wisconsin Brief Pain Questionnaire to assess pain in cancer and other diseases. Pain 1983;17: Geisser ME, Roth RS, Robinson ME. Assessing depression among persons with chronic pain using the Center for Epide-

6 6 AMPUTATION PAIN, Robinson miological Studies Depression Scale and the Beck Depression Inventory: a comparative analysis. Clin J Pain 1997;13: Radloff LS. The CES-D Scale: a self-report depression scale for research in general population. Appl Psychol Meas 1977;1: Turk DC, Okifuji A. Detecting depression in chronic pain patients: adequacy of self-reports. Behav Res Ther 1994;32: Weissman MM, Sholomskas D, Pottenger M, Prusoff BA, Locke BZ. Assessing depressive symptoms in five psychiatric populations: a validation study. Am J Epidemiol 1977;106: Granger CV, Hamilton BB, Linacre JM, Heinemann AW, Wright BD. Performance profiles of the functional independence measure. Am J Phys Med Rehabil 1993;72: Hamilton BB, Granger CV. Guide for the use of the uniform data set for medical rehabilitation. Buffalo: Research Foundation of State Univ New York; Diener E, Emmons RA, Larsen RJ, Griffin S. The satisfaction with life scale. J Pers Assess 1985;49: Whiteneck GG, Charlifue SW, Gerhart KA, Overholser JD, Richardson GN. Quantifying handicap: a new measure of longterm rehabilitation outcomes. Arch Phys Med Rehabil 1992; 73: Egbunike IG, Chaffee BJ. Antidepressants in the management of chronic pain syndrome. Pharmacotherapy 1990;10: McQuay HJ, Carroll D, Glynn CJ. Low dose amitriptyline in the treatment of chronic pain. Anaesthesia 1992;47: