therapeutic effects compared with oral administration.6. Intrathecal baclofen (ITB) therapy using programmable im- plantable pumps is widely acknowledged to ...
2165
ORIGINAL ARTICLE
A Clinical Study of Intrathecal Baclofen Using a Programmable Pump for Intractable Spasticity Daniel Guillaume, MD, PhD, Anthony Van Havenbergh, MD, PhD, Michael Vloeberghs, MD, PhD, Joan Vidal, MD, Geir Roeste, MD, PhD ABSTRACT. Guillaume D, Van Havenbergh A, Vloeberghs M, Vidal J, Roeste G. A clinical study of intrathecal baclofen using a programmable pump for intractable spasticity. Arch Phys Med Rehabil 2005;86:2165-71. Objective: To determine the impact of intrathecal baclofen (ITB) therapy on outcomes of functional independence, pain, subjective improvement, performance, and standard measures of spasticity. Design: A noncomparative, multicenter, prospective cohort trial of patients with implanted pumps followed up over a 12-month period for the assessment of spasticity, pain, and function. Setting: Twenty-four European centers of neurology or rehabilitation familiar with implantable pump technique participated. Participants: Patients with intractable spasticity (N⫽138) who responded positively to a trial dose of baclofen (n⫽133) and who began ITB therapy (n⫽129) were enrolled. Intervention: Implantation of a Medtronic SynchroMed Infusion System with the administration of ITB therapy. Main Outcome Measures: Ashworth Scale assessment, Penn Spasm Frequency Scale scores, pain assessment, FIM instrument scores or WeeFIM scores for children, Canadian Occupational Performance Measure (COPM), and subjective ratings of overall relief were the tools administered. Results: Muscle tone, spasm scores, and pain intensity reductions were observed. Overall FIM scores increased significantly in cognitive and motor function. COPM scores for both performance and satisfaction also improved significantly. Patients reported increased relief from pain and spasticity, supported by physician reports. Forty-three percent of patients reported adverse events, mostly related to patients’ underlying conditions (20%), the device implant surgery (10%), or complications with the catheter (9%). Conclusions: ITB therapy using a programmable pump is clinically effective and well tolerated, despite a seemingly high level of adverse events, in patients with intractable spasticity of spinal or cerebral origin and may offer improvements in pain relief and function.
From the Centre Neurologique et de Réadaptation Fonctionnelle, Fraiture-enCondroz, Belgium (Guillaume); University Hospital Antwerp, Antwerp, Belgium (Van Havenbergh); Queen’s Medical Centre, Nottingham, UK (Vloeberghs); Guttmann Institute, Barcelona, Spain (Vidal); and National Hospital, Oslo, Norway (Roeste). Supported by Medtronic Europe Sárl. 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 Daniel Guillaume, MD, PhD, Centre Neurologique et de Réadaptation Fonctionnelle, Champ des Alouettes 30, B-4557 Fraiture-en-Condroz, Belgium. 0003-9993/05/8611-9773$30.00/0 doi:10.1016/j.apmr.2005.05.018
Key Words: Baclofen; Infusion pumps, implantable; Muscle spasticity; Pain; Rehabilitation. © 2005 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation PASTICITY IS A CONDITION often occurring in patients S with cerebral palsy (CP), brain injury, and spinal cord injury (SCI). In a survey of adults with CP, 77% of respondents reported problems with spasticity.1 A U.S. study of patients with SCI reported that more than 25% of these patients experienced problems with spasticity or pain.2 Patients with spasticity are unable to make smooth voluntary muscle movements, which affects many aspects of day-to-day life.3 Roscigno4 reported that as many as 71% of children and 50% of adults with spasticity caused by CP have associated pain. Relief from spasticity, therefore, should lead to improvements in functioning and a reduction in pain among affected patients. Baclofen (4-amino-3[p-chlorophenyl] butyric acid) is a muscle relaxant, antispastic agent, and ␥-aminobutyric acid agonist that acts at the spinal cord level to inhibit the release of excitatory neurotransmitters (eg, glutamate, aspartate) by inhibiting Ca2⫹ influx into presynaptic terminals.5 Liquid baclofen can be administered directly into the intrathecal space, which requires much smaller amounts of the drug to achieve therapeutic effects compared with oral administration.6 Intrathecal baclofen (ITB) therapy using programmable implantable pumps is widely acknowledged to be clinically effective in the relief of intractable spasticity of either spinal or cerebral origin by reducting muscle tone and spasms, and it is generally well tolerated.7-15 In 2 studies of patients with spasticity of cerebral origin, significant improvements were seen in 76.5%16 and 100%17 of patients treated with ITB. A study of ITB therapy in patients with cerebral-based spasticity reported improved functioning in over half of the treated patients.7 Similar results have been reported for patients with spasticity of spinal origin, with 1 study showing a significant decrease in muscle tone and spasms in all patients treated with ITB therapy.18 However, published clinical trials involve relatively small sample sizes with limited outcome data relating to parameters other than spasticity. A multicenter, phase IV, noncomparative clinical trial of patients with intractable spinal or cerebral spasticity who received ITB therapy was conducted in Europe using programmable implanted pumps. Pain, motor function, cognitive function, occupational performance, and overall satisfaction data were analyzed in addition to muscle tone and spasms. METHODS Clinical outcome data were collected for patients with intractable spasticity of either spinal or cerebral origin who received ITB therapy at centers in Europe. Approval was obtained from the ethics committee at each center before paArch Phys Med Rehabil Vol 86, November 2005
2166
A PROGRAMMABLE PUMP FOR INTRACTABLE SPASTICITY, Guillaume
Fig 1. Average daily baclofen dose (mean ⴞ 2 standard errors [SEs]).
tient enrolment. Patients were expected to attend follow-up visits at 3, 6, 9, and 12 months postimplantation. Of the 138 patients enrolled, baclofen screening trials were performed on 136, of whom 133 had a positive response. The screening procedure was performed using a bolus injection for 85% of the patients, and the remaining patients were screened via a continuous infusion. A total of 129 patients underwent implantation of a programmable pump and provided 1387 device-months of experience (mean, 10.8⫾3.6mo; range, 1.0–19.2mo). Of this group, 118 patients completed the 3-month visit, 115 completed the 6-month visit, and 105 completed the 12-month visit. The mean starting dose of baclofen was 129g/d. At the 12-month visit, the mean baclofen dose had increased to 288g/d (fig 1). Patient Selection The study included patients between 5 and 75 years of age with intractable spasticity of spinal or cerebral origin. Witnessed or written consent was obtained before enrollment. It was essential that participants and their caregivers understood the mode of treatment and the requirements of the study. Patients were not enrolled if their condition did not meet the currently approved labeling for ITB therapy in the country in which they were treated. In some of the countries where the study was conducted, ITB therapy was approved for the treatment of spinal origin spasticity alone. Patients who were unsuitable for intrathecal pump use were also excluded from the study. Screening and Implantation Study participants underwent a screening trial to assess their responses to intrathecal baclofen, which was administered by either bolus or continuous infusion. Programmable pumps (SynchroMed Infusion Systema) were implanted in patients who responded positively to the ITB trial. We followed the screening trial and implantation procedures described by Ivanhoe et al.19 Baclofen was administered continuously throughout the follow-up period, with dosage changes when necessary. The pump reservoir was refilled percutaneously at least every 90 days. Clinical Assessments Spasticity in the lower and upper extremities was evaluated at study entry and at 3, 6, 9, and 12 months postimplantation using the Ashworth Scale assessment of muscle tone.20 Spasm scores, as measured by the Penn Spasm Frequency Scale Arch Phys Med Rehabil Vol 86, November 2005
(PSFS),6 were also measured at enrollment and at the 4 follow-up visits. In a pain assessment using a numeric rating scale (NRS), patients were asked to evaluate their pain using a numeric rating (0 [no pain] to 10 [the worst pain imaginable]) for 4 parameters: worst pain, least pain, average pain in the past week, and pain right now. Patients completed the NRS pain assessment at study entry and at 3, 6, 9, and 12 months postimplantation. Motor and cognitive functions were evaluated at baseline and at 3 and 12 months using the FIM instrument or WeeFIM for children.21 The WeeFIM and FIM total scores have been shown to have a high degree of correlation in monitoring functional status. The WeeFIM was used for children 7 years and younger, and the FIM was used for all patients over 7 years of age. The overall motor function score was the sum of 13 self-care, sphincter control, transfers, and locomotion activities, and the overall cognitive score was the sum of 5 communication and social cognition activities. The motor and cognitive scores were combined to give an overall function score. Patient performance and satisfaction with 1 to 5 tasks selected by themselves or their caregivers at study entry were measured on the Canadian Occupational Performance Measure (COPM).22 This instrument measures changes in a patient’s self-perception of personal performance of specific tasks over time. The COPM is rated on a scale where 1 is the worst score and 10 is the best score. This assessment was carried out at baseline and, for the same tasks, at the 3- and 12-month follow-up visits. Subjective ratings (very poor, poor, fair, good, very good) of overall relief from spasticity and pain with current treatments were obtained from patients and physicians at study entry. Spasticity and pain relief were then assessed at the 4 follow-up visits. Physicians were also asked for an overall satisfaction rating (very poor, poor, fair, good, very good) at the end of the study period for each patient. Safety Evaluation Adverse events were recorded at each visit throughout the study, regardless of whether the visit was scheduled or interim. An adverse event was defined as any untoward medical occurrence. The etiology of each adverse event and its relation to study procedures and medication were determined. Statistical Analysis Ashworth scores, PSFS scores, and NRS pain data at each of the 4 follow-up visits and FIM scores and COPM data at 3 and 12 months were compared with baseline values using 2-sided paired t tests. Ratings of overall pain and spasticity by both patients and physicians at each of the 4 time points were compared with baseline values using McNemar tests. A P value of less than .05 was considered significant and no adjustments to P values were made for multiple comparisons. All analyses were carried out using SAS software.b RESULTS A total of 138 patients were enrolled (intention-to-treat [ITT] population) in 24 centers in Austria, Belgium, Denmark, Germany, Luxembourg, Norway, Spain, Sweden, Switzerland, and the United Kingdom from December 1998 to December 2000. Demographic and baseline characteristics of the ITT population are given in table 1. The mean age was 35.2 years (range, 4 –74y); 37 patients were aged 18 years or younger. Sixty-four percent of patients were male. Multiple sclerosis (MS), SCI, and CP were the most frequently reported etiologies of spas-
2167
A PROGRAMMABLE PUMP FOR INTRACTABLE SPASTICITY, Guillaume Table 1: Demographic and Baseline Characteristics of the ITT Population (Nⴝ138)
Table 2: Ashworth Assessments and PSFS Scores Measures
Characteristic
Age (y) Mean ⫾ SD Range Sex (%) Male Female Etiology of spasticity (%) Multiple sclerosis SCI CP Traumatic brain injury Stroke Other Site of spasticity (%) Right lower extremities Left lower extremities Right upper extremities Left upper extremities Trunk Current antispasticity treatment (%) Baclofen Diazepam Dantrolene Nonsteroidal anti-inflammatory drugs Other medication Botulinum toxin injections
Values
35.2⫾18.8 4–74
Ashworth assessments Cerebral-origin spasticity Lower extremities Upper extremities
64 36 30 26 24 7 2 11 100 99 58 59 66 65 15 10 3 38 1
ticity. For analysis purposes, 8 of the 15 patients with an etiology of “other” were classified as having spasticity of spinal origin and the other 7 patients as having spasticity of cerebral origin. Spasticity occurred in the lower extremities in all patients, and most patients also experienced spasticity in the upper extremities or trunk. Ninety percent of patients also were currently receiving oral antispasmodic medications at the time of enrollment. Clinical Outcomes A significant (P⬍.001) improvement in muscle tone was observed in both lower and upper extremities at each follow-up visit for patients with spasticity of cerebral or spinal origin (table 2). For those patients with spasticity of spinal origin, the average lower-extremity Ashworth score decreased from 3.68⫾0.81 to 1.92⫾0.75 and the average upper-extremity score decreased from 1.65⫾0.78 to 1.34⫾0.50. In patients with spasticity of cerebral origin, the average lower-extremity Ashworth score decreased from 4.02⫾0.92 to 1.96⫾0.78 and the average upper-extremity score decreased from 3.58⫾1.25 to 2.07⫾0.86. ITB therapy also resulted in significant (P⬍.001) decreases from baseline to 12 months in spasm scores, from 2.70⫾1.24 to 0.97⫾0.95. Patients’ pain assessments during follow-up showed significant (P⬍.001) reductions in pain after implantation in all of the 4 categories at all 4 visits (fig 2). Pain relief increased steadily over the 12 months of follow-up for worst pain in the previous week, average pain in the previous week, and current pain, whereas the least-pain ratings remained at a similar level at the 4 time points after the initial decrease. Both motor and cognitive functions improved after initiation of ITB therapy (table 3). A significant improvement in motor function was observed at 12 months (P⬍.001) and in cognitive
Spinal-origin spasticity Lower extremities Upper extremities PSFS scores
Month
n
Mean ⫾ SD
Baseline Month 12 Baseline Month 12
52 39 52 39
4.02⫾0.92 1.96⫾0.78 3.58⫾1.25 2.07⫾0.86
Baseline 86 Month 12 65 Baseline 85 Month 12 65 Baseline 134 Month 12 102
3.68⫾0.81 1.92⫾0.75 1.65⫾0.78 1.34⫾0.50 2.70⫾1.24 0.97⫾0.95
P*
⬍.001 ⬍.001
⬍.001 ⬍.001 ⬍.001
Abbreviation: SD, standard deviation. *For 2-sided paired t test for patients with data at baseline and month 12.
function at 3 months (P⫽.01) postimplantation. The mean change in combined function score was significant at both the 3-month (P⫽.034) and 12-month (P⬍.001) visits. The COPM assessments at 3 and 12 months postimplantation showed significant (P⬍.001) improvements in performance and satisfaction in selected occupational tasks as perceived by the patients (fig 3). Patients reported significantly (P⬍.001) improved ratings of spasticity and pain relief after initiation of ITB therapy compared with pretherapy ratings. Physicians reported similar results (fig 4). At baseline, 6% of patients rated spasticity relief as good or very good. After initiation of baclofen therapy, spasticity relief was rated as good or very good by 69% of patients at 3 months and by 84% at 12 months. At baseline, 2% of physicians rated their patients’ spasticity relief as good or very good. After 12 months of therapy, physicians rated spasticity relief as good or very good in 89% of those patients. Similarly, patients and their physicians reported improvement in their pain relief. At baseline, 12% of the patients rated pain relief as good or very good compared with 70% after 12 months of ITB therapy. At baseline, 9% of patients were rated by their physicians as having pain relief that was good or very good. At 12 months, physicians rated pain relief as good or very good in 72% of those patients.
Fig 2. Average pain scores (mean ⴙ 2 SEs). All changes from baseline are significant (P
