AS THE LEADING CAUSE of job-related disability and

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1 ORIGINAL ARTICLE Therapeutic Use of Botulinum Toxin Type A in Treating Neck and Upper-Back Pain of Myofascial Origin: A Pilot Study Henry L. Lew, MD, PhD, Eun Ha Lee, MD, PhD, Annabel Castaneda, MD, MPH, Roger Klima, MD, Elaine Date, MD ABSTRACT. Lew HL, Lee EH, Castaneda A, Klima R, Date E. Therapeutic use of botulinum toxin type A in treating neck and upper-back pain of myofascial origin: a pilot study. Arch Phys Med Rehabil 2008;89: Objective: To determine the efficacy of botulinum toxin type A (BTX-A) in treating neck and upper-back pain of myofascial origin. Design: A randomized, double-blind, placebo-controlled pilot study. Setting: Outpatient physical medicine and rehabilitation clinic of a university-affiliated tertiary hospital. Participants: A total of 29 subjects enrolled from among 45 screened patients. No subject withdrawal due to serious adverse events occurred. Intervention: Subjects were evaluated at baseline, received a 1-time injection of either BTX-A (treatment group) or saline (control group), and were followed up at 2 weeks and at months 1, 2, 3, 4, and 6. Main Outcome Measures: Visual analog scale (VAS) for pain, the Neck Disability Index (NDI), and the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36). Results: Improvements in the VAS and NDI scores were seen in the treatment group but were not significant when compared with the controls. Statistically significant improvements for the treatment group were seen in the SF-36 bodily pain (at months 2 and 4) and mental health (at month 1) scales but not in the other scales, nor in the summary measures. No serious adverse events were reported. Conclusions: Trends toward improvements in VAS and NDI scores of the BTX-A group are encouraging, but they were possibly due to a placebo effect and were not statistically significant. The BTX-A subjects, at certain time points, showed statistically significant improvements in the bodily pain and mental health scales of the SF-36 compared with controls. Our study had limited power and population base, but the results could be used to properly power follow-up studies to further investigate this topic. Key Words: Back pain; Botulinum toxin type A; Myofascial pain syndromes; Rehabilitation by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation From the Physical Medicine and Rehabilitation Service, VA Palo Alto Health Care System, Palo Alto, CA; and Stanford University School of Medicine, Stanford, CA. Presented as a poster to the American Academy of Physical Medicine and Rehabilitation, November 2006, Honolulu, HI. Supported in part by Allergan Inc. 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 Henry L. Lew, MD, PhD, VA Palo Alto Health Care System, PM&R Service (117), 3801 Miranda Ave, Palo Alto CA, 94304, henry.lew@va.gov. or henrylew@stanford.edu /08/ $34.00/0 doi: /j.apmr AS THE LEADING CAUSE of job-related disability and the second leading cause for all disabilities in the United States, neck and back pain are major public health problems. 1 It has been estimated that neck and back pain affect up to 70% of adult Americans during their lifetimes. 1 The most common medications currently available to alleviate neck and back pain include muscle relaxants, nonsteroidal anti-inflammatory drugs, antidepressants, and opioids. In recent years, there has been a growing interest in the use of botulinum toxin type A (BTX-A) for the treatment of neck and back pain. Various clinical studies 2-4 suggest that BTX-A may provide effective analgesic effect for muscular pain conditions, particularly those due to myofascial pain syndrome (MPS), which is a common cause of muscular pain in the neck and back and is characterized by shortened muscle length, increased tone or tension, and trigger points. Prospective randomized studies have been conducted on the efficacy of BTX-A on neck and back pain of myofascial origin, but these are few in number. We found 3 randomized, placebocontrolled studies 5-7 regarding the effects of BTX-A on neck and upper-back myofascial pain and only 1 controlled study 8 concerning BTX-A effects on lower back pain that have been published to date. In a small randomized study of 6 subjects, Cheshire et al 5 reported that BTX-A treatment of myofascial neck pain resulted in improvement compared with saline. On the other hand, Ojala et al 6 did not find statistically significant results in neck pain and pressure pain threshold between the treatment and control groups in their study of 31 subjects. Gobel et al 7 conducted a larger, more recent study in 120 subjects with myofascial upper-back pain and reported that BTX-A injection resulted in significant pain reduction and significant pain-free days for the treatment group compared to those in the placebo group. Foster et al 8 studied the efficacy of BTX-A on chronic low back pain (CLBP) in 31 subjects who were randomly assigned to treatment or placebo groups. By using the visual analog scale (VAS) as a subjective measure of pain intensity, Foster showed that 73% of BTX-A subjects and 25% of placebo subjects had 50% or more pain relief. Foster s study likewise showed that more subjects in the treatment group (66.7%) experienced improvement (as measured by the Oswestry Disability Index [ODI]) compared with 18.8% among the placebo group. Other related studies have been mostly open-label trials, but these showed promising results. Vasan et al 9 injected BTX-A into the myofascial trigger points of 16 subjects with chronic neck pain. A significant reduction in pain was noted among patients in this prospective, open-label study. Jabbari et al 10 conducted an open-label prospective study on the short- and long-term effects of BTX-A injections on paraspinal muscles in 75 patients. They reported that BTX-A was beneficial in patients with CLBP. The findings of positive benefits with BTX-A for myofascial pain warrant further investigations using a randomized, placebo- 75

2 76 USING BOTULINUM TOXIN TO TREAT MYOFASCIAL PAIN, Lew controlled design that could yield valid clinical evidence to support the use of BTX-A for relief of neck and back pain. We report the results of a pilot study in which we used a randomized, double-blind, placebo-controlled design and set out to evaluate the therapeutic efficacy of BTX-A in the treatment of neck and upper-back pain of myofascial origin. The hypothesis was that the subjects treated with BTX-A would experience greater pain relief and clinical benefit than those who received placebo. METHODS Participants Twenty-nine adult subjects with diagnoses of cervical or upper-back pain of myofascial origin participated in the study. Through flyers and advertisements, subjects were recruited from the general population and the patient population of the physical medicine and rehabilitation clinic in a universityaffiliated tertiary hospital. The study was approved by the institutional review board of the hospital s affiliated university. Subjects were included if they (1) had been diagnosed as having neck or upper-back pain of myofascial origin within the past 2 to 6 months or had a previous diagnosis of neck or upper-back pain of myofascial origin but had experienced an exacerbation of pain symptoms within the same period, (2) were aged 18 to 70 years, and (3) had a VAS pain score of 5 or greater for the 4-week period before injection. The exclusion criteria were the following: (1) allergy to BTX-A; (2) any medical condition that put a subject at risk with exposure to BTX-A; (3) acute pathology such as infection, inflammation, cervical radiculopathy, or any operative pathology, as shown on physical examination or magnetic resonance imaging; (4) use of aminoglycoside antibiotics, curare-like agents, or other agents that may interfere with the neuromuscular junction; (5) history of gastroesophageal reflux disease (GERD); (6) abnormal swallowing test results on baseline; and (7) pregnancy, breastfeeding, or planned pregnancy. Use of concomitant pain medication and physical therapy was allowed, and no instructions were given to subjects to alter their current regimen. Subjects were referred by other physicians and their history, physical examinations, and pertinent laboratory and other examination results were reviewed during the screening visit. Initial screening included history taking to include medication and surgical history and duration of pain, as well as completion of preinjection assessments for the VAS for average and maximum pain, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) to assess functional status, and the Neck Disability Index (NDI). In addition to the screening review, a physical examination was performed to determine the most tender cervical or upper-back muscles and to rule out operative, radiculopathic, and other contraindicated conditions. Study Intervention Qualified, consenting subjects were randomized to the control group (injection with normal saline solution) or the treatment group (injection with BTX-A [Botox]). A computergenerated randomization scheme was used. Subjects were assigned a randomization number, which corresponded to a treatment allocation schedule and was stored by the hospital s research pharmacist. Hence, for each injection, both the subject and the investigator were blinded. Fourteen subjects were included in the treatment group, and 15 subjects participated in the control group (fig 1). Each vial of BTX-A (100U) or saline was reconstituted by 2mL of normal saline. The BTX-A or saline vials were prepared and reconstituted before receipt by the investigator, who received them in identically appearing syringes, which ensured that he remained blinded as to whether the syringe contained medication or placebo. The dose per injection site was 50U. The total dose did not exceed 200U per treatment and 100U per side. No more than 2 muscles were selected on each side, and only painful muscles were injected. Trigger points were determined before the injection procedure by deep finger pressure. Injections were performed without electromyographic guidance at the site of the trigger points. The muscles that were injected include the trapezius, levator scapulae, splenius capitis, and other posterior neck muscles. For the control group, the same determined volume was injected, but with normal saline. Injection sites were sterilized, and BTX-A or normal saline was administered by a disposable 27-gauge needle with disposable syringe. Each injection was performed slowly, over 15 seconds per location. The following outcome measures were used: (1) VAS for pain, (2) SF-36, and (3) NDI. Evaluations were performed at baseline, week 2, and months 1, 2, 3, 4, and 6. Subjects were monitored for possible adverse events after BTX-A injection by telephone follow-up at 3 and 10 days postinjection. Monitoring of adverse events continued throughout the entire study period. Outcome Assessment Subjects were evaluated at baseline, then at 2 weeks, and at 1, 2, 3, 4, and 6 months postinjection. For the baseline and second-week assessments, subjects were evaluated in person. For the succeeding evaluation periods, subjects were requested to complete the questionnaires for the outcome measures and to return them by mail to the study coordinator. The study used the following outcome measures to determine subjective pain relief as reported by each patient. VAS for pain. The VAS for pain measures the amount of pain experienced by a subject with a continuous range from none to extreme, using 0 for no pain and 10 for maximum pain. It has been validated as a reliable, generalizable and internally consistent measure of clinical and experimental pain. 11(p217) Subjects were asked to indicate the pain levels (average and maximum pain) which they experienced within the specified evaluation time periods. The SF-36. The SF-36 is a validated measure of health status widely used in clinical practice and research. 12 It has 36 items under 8 categories assessing general health concepts: physical functioning, role limitation due to physical health, bodily pain, general health perception, vitality, social functioning, role limitation due to emotional problems, and mental health. 12 Neck Disability Index. This is a modified pain index derived from the ODI and is designed to describe how much a subject s neck pain affected his/her ability to manage everyday activities. 13 Data Analysis The results of the study were analyzed by an independent data management group. SAS software a was used for statistical analysis. Patients were included in the analysis on the basis of intention to treat. The hypothesis, that the efficacy in pain relief would be better with BTX-A, was tested through between- and within-group comparisons in the average pain VAS, SF-36, and NDI scores. The normality of variables was tested using Shapiro-Wilk tests. According to the normality of variable, the 1-sided t test (Wilcoxon rank-sum test) and 2-sided paired t test (Wilcoxon signed-rank test) were used for between- and

3 USING BOTULINUM TOXIN TO TREAT MYOFASCIAL PAIN, Lew 77 Fig 1. Flow of participants in the study. within-group comparisons, respectively. Demographic variables were compared using the Fisher exact test and t test. Frequencies in adverse events were compared with the chisquare and Fisher exact tests. RESULTS Demographics Thirty subjects consented and were randomized to the study. One subject was excluded in the analysis because his age exceeded 70 years, which was a protocol deviation. There were 20 men and 9 women among the 29 subjects included in the analysis. An analysis of the group characteristics regarding age, sex, and race yielded no significant group differences between the treatment and control subjects (table 1). A comparison of the BTX-A and control groups showed no baseline differences in the outcome measures used in this study: NDI, VAS (average and maximum pain), and the summary measures for SF-36 (average total score, mental health, and physical health). Table 2 shows the efficacy results for between-group change (BTX-A vs control) from baseline comparisons for the outcome measures (NDI, VAS, and SF-36 bodily pain and mental health scales). A negative difference in NDI and VAS and a Table 1: Demographics and Baseline Characteristics of the BTX-A and Control Groups Characteristic BTX-A (n 14) Control (n 15) P Sex Male 8 (57.1) 12 (80.0).245* Female 6 (42.9) 3 (20.0) Age (y) VAS pain score (range, (0 10) Average pain Maximum pain SF-36 summary measures Average total score Physical health Mental health NDI (range, 0 50) NOTE. Values are n (%), mean standard deviation, and minimum and maximum. *Two-sided Fisher exact test. Two-sided t test.

4 78 USING BOTULINUM TOXIN TO TREAT MYOFASCIAL PAIN, Lew Table 2: Efficacy Outcomes of the BTX-A and Control Groups VAS SF-36 Follow-Up NDI Average Pain Maximum Pain Bodily Pain Mental Health Week 2 Mean % CI 4.67 to to to to to Cohen d P.824*.498*.787*.376*.640* Month 1 Mean % CI 4.14 to to to to to Cohen d P.765*.320*.337*.144*.010* Month 2 Mean % CI 7.16 to to to to to Cohen d P.502*.267*.703*.017*.582 Month 3 Mean % CI 6.34 to to to to to Cohen d P.918*.590*.828*.261*.801* Month 4 Mean % CI 4.09 to to to to to Cohen d P.619*.219*.936*.033*.408* Month 6 Mean % CI 2.71 to to to to to Cohen d P.276*.179*.405*.273*.265* Abbreviation: CI, confidence interval. *Two-sided t test. Two-sided Wilcoxon rank-sum test. positive difference in SF-36 summary measures indicate a more favorable result in BTX-A change from baseline. Although we found no significant between-group differences for most of the main outcomes (see table 2), we used the 95% confidence interval (CI) and Cohen d to describe treatment effects. An absolute value of the Cohen d effect size less than 0.2 was considered small, whereas 0.2 to 0.5 and greater than 0.5 were considered as moderate and large, respectively. A P value less than.025 was considered significant. VAS for Pain Between-group (BTX-A vs control) comparisons did not reach statistical significance. However, as shown in table 2, BTX-A treatment effect as determined by the Cohen d showed moderate to large effect sizes across all the evaluation periods Mean Scores (Changes from Baseline) VAS - Average Pain Scores Day 2 wk 1 mo 2 mo 3 mo 4 mo 6 mo Evaluation Periods BOTOX CONTROL Fig 2. Mean changes in pain scores on the VAS from baseline (BTX-A vs control). Negative change indicates improved outcome. Improvement in Mean Scores from Baseline Day SF-36: Bodily Pain * * 2 wk 1 mo 2 mo 3 mo 4 mo 6 mo Evaluation Periods BOTOX CONTROL Fig 3. Improvement in mean scores on the SF-36 bodily pain scale from baseline (BTX-A vs control). *Statistically significantly better outcome for the BTX-A group (P<.025).

5 USING BOTULINUM TOXIN TO TREAT MYOFASCIAL PAIN, Lew 79 Improvement in Mean Scores from Baseline SF-36: Mental Health * Day 2 wk 1 mo 2 mo 3 mo 4 mo 6 mo Evaluation Periods BOTOX CONTROL Fig 4. Improvement in mean scores on the SF-36 mental health scale from baseline (BTX-A vs control). *Statistically significantly better outcome for the BTX-A group (P<.025). from week 2 through month 6 in the average VAS scores. As shown in figure 2, the largest differences in mean changes between the BTX-A and control groups were seen at month 4 (BTX-A change from baseline, vs control group change from baseline, ; d.57) and at month 6 (BTX-A group change from baseline, vs control change from baseline, , d.59). The SF-36 We found statistically significant differences between the BTX-A and control groups only in the bodily pain and mental health scales of the SF-36 but not in the other scales nor in the summary measures. We found better outcomes in the BTX-A treatment group, compared with controls (fig 3), at months 2 and 4 for the bodily pain scale (2-sided, P.009, P.016, respectively). It should be noted that the BTX-A group showed improvements in the bodily pain scale compared with baseline across all the evaluation periods with the greatest improvement seen at the aforementioned months 2 and 4, in which the improvements reached statistical significance compared with the control group. In the mental health scale (fig 4), there was a statistically significant difference between the BTX-A and control groups only at the 1-month follow-up evaluation (2-sided, P.005). Neck Disability Index The highest effect of BTX-A on neck disability was detected at month 2 (BTX-A group change from baseline, vs control group change from baseline, ; d.30). The difference between the groups mean changes from baseline is within the 95% CI ( 7.16 to 3.46). The opposite effect on neck disability was detected at month 6, when the NDI score returned to the baseline value in the BTX-A group but we saw a strong reduction in neck disability in the control group (BTX-A group change from baseline, vs control group change from baseline, ; d.45). The insufficient number of values provided at both time points (powers of the tests were 10% and 18%, respectively) did not permit us to detect statistical significance. Moreover, the 2-point difference on the 50-point NDI scale could hardly be regarded as a clinically significant result. There was no serious adverse event noted during the study period. Likewise, there was no difference in the number of side effects between the BTX-A and control groups. DISCUSSION BTX-A inhibits acetylcholine release from motor nerve terminals at the neuromuscular junction, resulting in reversible chemical denervation and temporary (3 4mo) relief of muscle spasm. 2-4 But it has also been proposed that the pain relief resulting from BTX-A injection is due to mechanisms other than chemodenervation. Precisely what these mechanisms are remain unclear, but it has been postulated that BTX-A acts centrally on spinal interneurons, through antagonism with substance P, and directly on nociceptors functions. 2,14,15 Our study showed a general trend toward pain relief and clinical improvement in the BTX-A group. However, perhaps due to a placebo effect, changes in the VAS and NDI scores did not reach statistical significance when compared with the controls, although moderate to large Cohen d treatment effects were seen. Statistically significantly better outcomes for the BTX-A group compared with the control group were seen only in the bodily pain and mental health scales of the SF-36 but not in the other scales or in the summary measures. We compared our results with those of previous studies using BTX-A for chronic neck and back pain of myofascial origin. Foster et al s small randomized study 8 showed significant differences in the efficacy of BTX-A for lower back pain, when compared with a control, as measured by VAS. Likewise, Jabbari et al, 10 in an open-label study, showed significant improvement in low back pain as measured by the VAS. Although we observed significant changes in neck and upper back pain, as indicated by the improvements in the SF-36 bodily pain scale, our VAS findings were not significant. Using the Neck Pain and Disability Scale, SF-36, and Beck Depression Inventory, Wheeler et al 16 did not show significant differences between BTX-A and control in the treatment of neck pain. The study by Ojala et al 6 is similar to ours in that it was a randomized double-blind crossover study of neck and shoulder pain. Ojala failed to find significant differences as measured by a 10-point scale for severity of neck and shoulder pain and pressure pain thresholds. Unfortunately, there exist no other studies of the effects of BTX-A compared with a control on neck and upper back pain using the same scales used in our study. The injection of saline into the myofascial trigger points of patients with MPS has been shown to be effective in pain relief. 6,17 Some studies have shown that needling per se can be as effective as injection of a pain medication in the treatment of myofascial trigger points causing pain. 18 The effect of saline or needling effect could explain the analgesia that was experienced by the subjects in the control group. In fact, we found a placebo effect in our study, as shown by the reduction in VAS and NDI scores in both the BTX-A and control groups during the postinjection evaluations compared with baseline. The reduction in pain and neck disability experienced by the control group, which received only the saline injection, is a common clinical occurrence observed as placebo analgesia. 19 Study Limitations We realize that our pilot study had limited power and a limited population base. Further, a limitation of this study may be the injection paradigm used. Studies using a trigger point injections paradigm for administering BTX-A have reported variable success. 20 It has been suggested that targeting the belly of the muscle implicated in the pain may result in improved efficacy. 20,21 In fact, when looking at studies reporting positive outcomes, the majority have used injection paradigms other than targeting trigger points. 22 In addition, our choice to restrict the total dose to 200U, in 4 or fewer muscles, may have resulted in suboptimal efficacy in those patients in whom more than 4 muscles were implicated in the pain. Another limitation to the generalizability of our data is that we could not control for the concurrent treatments that the

6 80 USING BOTULINUM TOXIN TO TREAT MYOFASCIAL PAIN, Lew subjects received during the study period. We agree with Abram s recommendations 23 on the need to develop better criteria that could define the conditions in which BTX-A injections would yield the most benefit for patients suffering from chronic pain. To achieve this goal, there is a need to conduct larger-scale, well-powered multicenter studies and to do so with better-defined inclusion and exclusion criteria, injection technique, therapeutic regimen, and dosing schedule and perhaps a crossover design. The results of this doubleblind, placebo-controlled pilot study provide effect sizes that can be used to properly design and power future studies by our group and by others. CONCLUSIONS This study is among few randomized controlled investigations on the use of trigger point injections of BTX-A for the treatment of myofascial neck and upper back pain. Within the limitations of this pilot study, when compared with saline, BTX-A injections did not result in statistically significant changes in NDI and VAS measures. However, compared with controls, BTX-A injections produced significantly better outcomes in bodily pain (at 2 and 4 months postinjection) and mental health scales (at 1 month postinjection) as measured by the SF-36. These results may justify the need for larger, wellpowered, and similarly controlled studies of the use of BTX-A for the treatment of upper back and neck pain due to MPS. Acknowledgment: Research Inc. Data analysis conducted by ethica Clinical References 1. Strine TW, Hootman JM. US national prevalence and correlates of low back and neck pain among adults. Arthritis Rheum 2007;57: Jankovic J. Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 2004;75: Lew MF. Review of the FDA-approved uses of botulinum toxins, including data suggesting efficacy in pain reduction. Clin J Pain 2002;18:S Royal MA. Botulinum toxins in pain management. Phys Med Rehabil Clin N Am 2003;14: Cheshire WP, Abashian SW, Mann JD. Botulinum toxin in the treatment of myofascial pain syndrome. Pain 1994;59: Ojala T, Arokoski JP, Partanen J. The effect of small doses of botulinum toxin A on neck-shoulder myofascial pain syndrome: a double-blind, randomized, and controlled crossover trial. Clin J Pain 2006;22: Gobel H, Heinze A, Reichel G, Hefter H, Benecke R. Efficacy and safety of a single botulinum type A toxin complex treatment (Dysport) for the relief of upper back myofascial pain syndrome: results from a randomized double-blind placebo-controlled multicentre study. Pain 2006;125: Foster L, Clapp L, Erickson M, Jabbari B. Botulinum toxin A and chronic low back pain: a randomized, double-blind study. Neurology 2001;56: Vasan CW, Liu WC, Klussmann JP, Guntinas-Lichius O. Botulinum toxin type A for the treatment of chronic neck pain after neck dissection. Head Neck 2004;26: Jabbari B, Ney J, Sichani A, Monacci W, Foster L, Difazio M. Treatment of refractory, chronic low back pain with botulinum neurotoxin A: an open-label, pilot study. Pain Med 2006;7: Price DD, Bush FM, Long S, Harkins SW. A comparison of pain measurement characteristics of mechanical visual analogue and simple numerical rating scales. Pain 1994;56: Brazier JE, Harper R, Jones NM, et al. Validating the SF-36 health survey questionnaire: new outcome measure for primary care. BMJ 1992;305: Vernon H, Mior S. The Neck Disability Index: a study of reliability and validity. J Manipulative Physiol Ther 1991;14: Bhidayasiri R, Truong DD. Expanding use of botulinum toxin. J Neurol Sci 2005;235: Porta M, Maggioni G. Botulinum toxin (BoNT) and back pain. J Neurol 2004;251(Suppl 1):I Wheeler AH, Goolkasian P, Gretz SS. Botulinum toxin A for the treatment of chronic neck pain. Pain 2001;94: Wheeler AH, Goolkasian P, Gretz SS. A randomized, doubleblind, prospective pilot study of botulinum toxin injection for refractory, unilateral, cervicothoracic, paraspinal, myofascial pain syndrome. Spine 1998;23: Cummings TM, White AR. Needling therapies in the management of myofascial trigger point pain: a systematic review. Arch Phys Med Rehabil 2001;82: Cavanna A, Strigaro G, Monaco F. Brain mechanisms underlying the placebo effect in neurological disorders. Funct Neurol 2007; 22: Ho KY, Tan KH. Botulinum toxin A for myofascial trigger point injection: a qualitative systematic review. Eur J Pain 2007;11: Ferrante FM, Bearn L, Rothrock R, King L. Evidence against trigger point injection technique for the treatment of cervicothoracic myofascial pain with botulinum toxin type A. Anesthesiology 2005;103: Borodic GE, Pearce LB, Smith K, Joseph M. Botulinum A toxin for spasmodic torticollis: multiple vs single injection points per muscle. Head Neck 1992;14: Abram SE. Does botulinum toxin have a role in the management of myofascial pain? Anesthesiology 2005;103: Supplier a. SAS Institute Inc, 100 SAS Campus Dr, Cary, NC