The lack of efficacy of different infusion rates of intrathecal baclofen in complex regional pain syndrome: a randomized, doubleblind, crossover study

Pain Medicine 2011; 12: 459–465Wiley Periodicals, Inc. NEUROPATHIC PAIN SECTION
Original Research Article
The Lack of Efficacy of Different Infusion Rates
of Intrathecal Baclofen in Complex Regional
Pain Syndrome: A Randomized, Double-Blind,
Crossover Studypme_1065459.465

Anton Adriaan van der Plas, MD,* Johan Marinus,
Results. There were no significant differences
PhD,* Sam Eldabe, MD,† Eric Buchser, MD,‡ and
between the FIRD and the SIRD groups for the
Jacobus Johannes van Hilten, MD, PhD*
median change of numeric rating scale dystonia
(–0.3 [interquartile range {IQR}
-1.1–0.5]), pain (0.1
*Department of Neurology, Leiden University Medical [IQR –0.8–1.3]), and secondary outcomes, except for
the frequency of adverse events, which was signifi-
cantly higher during FIRD (12 vs 2). FIRD was pre-

ferred only by patients who were included because
Department of Pain and Anaesthesia, James Cook side effects to ITB prevented dose escalation.
University Hospital, Middlesbrough, England, UK; Conclusions. Increasing the IR at a fixed daily dose
‡Pain Clinic, Morges Hospital, Morges, Switzerland is not associated with improvement of dystonia or
pain but warrants further investigation in patients in

Reprint requests to: Anton A. van der Plas, MD, whom side effects prevent further dose escalation.
Department of Neurology, Leiden University MedicalCenter, P.O. Box 9600, 2300 RC Leiden, The Key Words. Infusion; Rate; Intrathecal; Baclofen;
+31-71-524-8253; E-mail: [email protected].
Complex regional pain syndrome type I (CRPS I) is com- Objective. Intrathecal baclofen (ITB) is effective in
monly preceded by injury, usually to a limb, and is char- the treatment of dystonia related to complex
acterized by pain, disturbed blood flow, temperature regional pain syndrome (CRPS). In a previous study,
regulation, and motor control of the affected area [1–3].
we noted that the responsiveness to ITB declined in
Approximately 20% of patients with CRPS develop dys- 30% of patients once drug delivery was switched
tonia, which is characterized by fixed flexion postures from an external to an implanted device associated
[1,4–7]. Because dystonia in CRPS tends to spread to with a reduction of the infusion rate (IR).
other limbs, the syndrome may evolve into a disablingdisorder with a marked impact on quality of life [4,6,8].
Design. In a double-blind study, we investigated the
Impaired inhibitory control of sensorimotor circuits is a key effect of varying the IR at a fixed daily dose on the
pathophysiological finding in dystonia of CRPS [9].
efficacy and safety of ITB in patients with CRPS-
Baclofen stimulates pre- and postsynaptic gamma- related dystonia. Patients were randomized to either
aminobutyric acid B receptors, which enhances central slower infusion rate delivery (SIRD) or four-times
inhibitory activity [10,11]. However, dystonia in CRPS is faster infusion rate delivery (FIRD) for 2 weeks and
rarely controlled by oral baclofen, probably because of the were crossed over after a 1-week washout period.
drug’s poor ability to pass the blood–brain barrier [12,13];although in some patients, beneficial effects are reported Patients. Patients were eligible if they experienced
with dosages as high as 90–120 mg/day [4]. Epidural no beneficial response to ITB on dystonia despite a
administration of baclofen was shown to be beneficial in minimum dose of 600 mg/day, or because side
intractable spasticity likely because the drug is lipid effects limited dose escalation.
soluble and may cross the dura to act on the spinal canal[14]. Intrathecal delivery of baclofen overcomes the Outcome Measures. Primary outcome measures
obstacle of the blood–brain barrier and results in greater were changes in global dystonia and pain severity.
therapeutic efficacy concentrated at the spinal site of van der Plas et al.
Drug delivery characteristics during screening procedure and post-pump implantation [16] IQR = interquartile range; ITB = intrathecal baclofen.
action [15,16]. However, not all patients may respond to and the study was approved by the local Ethics Commit- this mode of drug delivery, which is expensive and tee. The trial was registered in The Netherlands National requires an invasive implantation procedure. Hence, a Trial Register (NTR 1269). All patients were followed in our screening procedure with an external pump is frequently outpatient clinic and had CRPS-related dystonia in at least used to evaluate the responsiveness to intrathecal one extremity for which continuous ITB was administered.
baclofen (ITB) to help select those patients that are most The patients fulfilled the CRPS criteria of the International suitable for continuous ITB delivery through an implanted Association for the Study of Pain including continuing pump. Against this background, we screened patients pain; allodynia or hyperalgesia disproportionate to any using a 2-day placebo run-in dose escalation (200– inciting event; evidence at some time of edema; changes 800 mg ITB) design [16]. The responder criterion for pump in skin blood flow or abnormal sudomotor activity in the implantation was set at a Ն25% improvement of global area of pain; and the absence of any condition that would dystonia severity on two consecutive baclofen days as otherwise account for the degree of pain and dysfunction compared with placebo. However, after pump implanta- [2]. Patients had received an internal programmable Syn- tion, 30% of patients on ITB surprisingly failed to meet the chromed EL or II® pump (Medtronic, Minneapolis, MN, responder criterion of the screening despite the use of a USA) for continuous infusion of ITB after oral baclofen up minimum daily dose of 600 mg or because side effects to a minimal daily dose of 60 mg failed to provide benefi- limited dose escalation. In an attempt to find an explana- cial response or side effects limited escalation of the daily tion for this finding, we reviewed the procedures of our dose [16]. Patients were eligible for the IR study if they study [16]. We found that the infusion rates (IRs) applied experienced no beneficial response to ITB on dystonia at during the screening and postimplantation period differed a minimum daily dose of 600 mg, or dose-limiting side because of the use of different baclofen concentrations effects prohibited dose escalation of ITB. Furthermore, (0.5 mg/mL vs 3 mg/mL) (Table 1). The IRs decreased patients had to rate their global dystonia severity as at once patients were switched to 3 mg/mL concentration in least 5 on a numeric rating scale (NRS) ranging from 0 the postimplantation period. Two different concentrations (absent) to 10 (most severe) in order to be eligible for the were used because of the utilization of two pumps with study. Exclusion criteria were identical to those used in a different requirements for effective drug delivery. Could the previous study examining the efficacy of ITB in CRPS- lack of response to ITB in some patients, after the switch related dystonia [16]. In 11 patients, a screening proce- to the higher baclofen concentration, be explained by the dure was performed using an external microinfusion pump use of lower IRs? In an animal model, higher IRs of before pump implantation [16]. The remaining three baclofen and bupivacaine increased the drug’s cere- patients participated in a trial with intrathecal glycine, after brospinal fluid distribution; although experiments were which they were switched to ITB without a screening performed in a nonphysiological setting [17] and pain procedure [19]. These three patients were included in this severity was reduced by increasing the IR of intrathecally study because they failed to improve Ն25% in dystonia delivered bupivacaine in patients with intractable pain [18].
severity as a result of dose-limiting side effects to ITB.
To our knowledge, the influence of the IR on the clinical Pump-catheter system integrity was verified in all patients efficacy of ITB, independent of the daily dose, has not prior to the study, and other conditions potentially influ- been described to date. In this study, we compared the encing dystonia severity were ruled out. At baseline, the efficacy and safety of two ITB IRs at a fixed daily dose in administered daily dose varied between patients, and all patients with CRPS-related dystonia and hypothesized patients used a baclofen solution of 3 mg/mL.
that the clinical efficacy may improve by increasing the IRwithout affecting safety as the daily dose was fixed.
In a double-blind, randomized, two-period, crossoverdesign, solutions of 3 and 0.75 mg/mL baclofen were administered in a randomized sequence. A computermethod was used to randomly allocate patients to one of The study was conducted in an ambulatory setting the two sequences of different IRs. Prior to the start of the between April and December 2008. Patient consent was study, all patients received ITB at a simple continuous rate obtained in accordance with the declaration of Helsinki, with a 3 mg/mL concentration. To obtain two IRs at a 4:1 Intrathecal Baclofen Delivery in CRPS
ratio with a fixed daily dose, concentrations of 3 mg/mL (slower infusion rate delivery [SIRD]) and 0.75 mg/mL(faster infusion rate delivery [FIRD]) were used. A physician The results are expressed as median (interquartile range who was not involved in the assessments of the patients [IQR]). For all variables, a Wilcoxon signed rank test or carried out the switch procedure at the start of each Mann–Whitney U test was used to examine differences sequence, filling the pump reservoir with baclofen concen- within and between patients, respectively. A chi-square trations of 0.75 or 3 mg/mL. Notably, reservoir fillings were test was conducted to compare the amount of adverse always changed, regardless of the assigned new concen- events between the FIRD and the SIRD groups. Signifi- tration to guarantee maintenance of blinding. When the cance was assumed at the 0.05 level. Assuming an alpha baclofen concentration is changed, a bridge bolus can be of 0.05, beta of 0.2, a standard deviation of the NRS of 2, used to empty the internal pump tubing and external and a correlation between measures of 0.6, we calculated catheter with the old baclofen concentration with the origi- that 14 patients would be required to detect a statistically nal IR. With a fixed daily administered dose, the replace- significant difference of Ն25% in the reduction of NRS ment of the 3 mg/mL concentration will result in a substantial delay before the new concentration reachesthe tip of the catheter. As this concentration-dependent delay may potentially contribute to deblinding, we usedthe side port to carry out a procedure that included aspi- Demographic and Baseline Characteristics ration of the content of the external catheter followed bymultiple boluses to replace the removed volume. As a Fourteen CRPS patients (13 women) aged 45.5 years result of this approach, the new concentration would (IQR 37.3–56.0) with a median disease duration of 12.5 always reach the tip of the catheter within an hour regard- years (IQR 8.0–16.3) were found eligible and participated less of the old concentration. During the first 2 weeks of in the study (Table 2). The median daily dose of ITB was the study, the first assigned IR was used. This was fol- 695 mg (IQR 393–838), with the median thoracic level of lowed by a 1-week open administration of the 3 mg/mL the catheter tip at T7 (range T2–T11). Seven patients (six concentration of baclofen to minimize potential conse- women) were allocated to the FIRD–SIRD sequence; quences of any carryover effect. Subsequently, over the seven patients (all women) were allocated to the SIRD– following 2 weeks, patients received the other IR.
FIRD sequence. All patients completed the study. A Wil-coxon signed rank test indicated there were no significant Patients were asked to rate the global severity of pain and dystonia using an NRS ranging from 0 (absent) to 10 (mostsevere) once every day starting 1 week before the first switch procedure until the end of the second treatmentperiod. At the start and end of each treatment period prior to changing the IR, a blinded clinical assessor rated the dystonia severity using the Burke–Fahn–Marsden (BFM) scale, which is the sum of the scores of the individual body regions [20]. The same rater assessed the change of CRPS signs and symptoms from baseline on a global impression scale (GIS) at the end of each treatment, ranging from -3 (much worse) to +3 (much better) with 0 for “no change.” At the end of the study, patients were asked to compare both treatment periods using a patient preference questionnaire (PPQ). The PPQ consists of a 10-cm horizontal line ranging from -5 to +5. A score of 0 reflects no preference, whereas -5 or +5 expresses maximal preference for the first or second treatment period, respectively. In addition, patients were asked to indicate the reasons for their preference. At the end of each study the clinical assessor was asked to guess treat- ment assignment to evaluate the integrity of blinding. The primary outcome measure was the difference in change in global severity of pain and dystonia between baseline and end of each IR period. The secondary outcome measures were defined as the difference in change in BFM score between baseline and end of each IR period, the differ-ence in GIS between both treatment periods, the PPQ score, and the frequency and severity of adverse events CRPS = complex regional pain syndrome; ITB = intrathecal assessed at the end of each IR period.
van der Plas et al.
Baseline scores for primary and secondary outcome measures NS = not significant; FIRD = faster infusion rate delivery; SIRD = slower infusion rate delivery; NRS = numeric rating scale.
differences between baseline measures (NRS for dystonia sion headache and likely resulted from aspiration of cath- and pain and BFM) of the first and second treatment eter content during the switch procedure. Two patients period for each sequence, indicating a successful reported one adverse event (both mild) while on SIRD washout (Table 3). Additionally, a Mann–Whitney U test including one patient with intracranial hypotension head- indicated that there were no significant differences ache. There were significantly more adverse events on between these baseline measures of patients assigned to FIRD compared with SIRD (c2 = 6.78, df = 1, P = 0.01), each treatment sequence (FIRD–SIRD or SIRD–FIRD).
even after the removal of events due to intracranialhypotension (c2 = 6.97, df = 1, P = 0.01).
There were no significant differences between the FIRD and the SIRD group in median change of NRS score fordystonia (–0.3 [IQR -1.1–0.5]) and pain (0.1 [IQR –0.8– None of the demographics or clinical characteristics pre- 1.3]) and BFM score (2 [IQR -4–13]) (Table 4). Six patients dicted any outcome measures except for the reason of preferred FIRD with a median PPQ score of 3.0 (IQR inclusion in the study, which was related to the preference 1.6–4.3), and seven patients favored the SIRD with a median PPQ score of 3.0 (IQR 1.0–3.0). One patient hadno preference for any of the IRs. The difference between Six out of eight patients, who entered the study because both groups in PPQ score was not significant. After FIRD, side effects prohibited dose escalation of ITB, reported six patients showed an improvement on the GIS (+1 in four preference for FIRD because dystonia and pain improved and +2 in two patients), three patients deteriorated (–1 in (median PPQ score 2.5 [IQR -1.4–3.8]). All six patients, two and -2 in one patient), and five patients showed no who entered the study because they did not respond to a change. After SIRD, four patients showed an improvement minimum daily dose of 600 mg ITB without baclofen- on the GIS (+1 in three and +3 in one patient), three related side effects, preferred SIRD, except one patient patients deteriorated (–1 in one and -2 in two patients), who reported no preference for any of the IRs (median and seven patients showed no change. There was no PPQ score 2.0 [IQR 0.8–3.5]). Mann–Whitney U test significant difference in change found on the GIS score revealed a significant difference in patient’s preference between both IRs (z = –1.66). There was no significant (P = 0.03) between groups, stratified according to “reason effect of IR sequence on any of the outcome measures.
of participation.” No significant difference was found for Twelve adverse events (five moderate, seven mild) were any of the other primary and secondary outcomes as well reported in eight patients on FIRD (Table 5). Headache as the rate or severity of adverse events between both was the most frequently reported adverse event (N = 5), groups (P > 0.05). The clinical assessor’s guess of which which in three patients was typical of intracranial hypoten- IR was administered was correct in 57%.
Difference in change for primary and secondary outcome measures Negative values represent improvement in outcome measures. P values were derived from a Wilcoxon signed rank test.
NS = not significant; FIRD = faster infusion rate delivery; SIRD = slower infusion rate delivery; IQR = interquartile range;NRS = numeric rating scale.
Intrathecal Baclofen Delivery in CRPS
implanted pump [16]. These poor responders includedpatients who failed to improve Ն25% in global dystonia severity in spite of repeated dose escalations (up to600 mg/24 hours) and patients in whom dose escalation was limited because of the occurrence of side effects.
Interestingly, the intrathecal IR applied during the screen- ing period exceeded the IR of the postimplantation period as much as seven times because a lower concentration (0.5 mg/mL) was used. Additionally, the daily dose at the time patients qualified for the responder criterion of the screening procedure was lower in the majority of patients compared with the daily dose administered during the postimplantation period (Table 1). Triggered by these find-ings, we evaluated if different IRs at a fixed daily dose influence the efficacy and safety of ITB in patients with SIRD = slower infusion rate delivery; FIRD = faster infusion rate CRPS-related dystonia. In addition to dystonia, we evalu- ated the influence of ITB on pain because baclofen mayexert an analgesic effect [22]. Prior to the start of this study Discussion
none of the patients experienced a beneficial response inpain to ITB. Both for the total group as well as the sub- Intrathecal drug delivery has opened new avenues for the groups defined by reason of inclusion, we found no differ- administration of drugs like baclofen that have difficulty ences between FIRD and SIRD on any of the primary passing the blood–brain barrier. However, once the drug is outcome measures. Blinding was adequately maintained, in the intrathecal space, many aspects may influence its as the sequence of IRs was correctly guessed in approxi- profile of efficacy and safety [21]. One of these aspects is mately half of the cases. Our findings may indicate that IR the IR of a drug, which surprisingly has barely been differences up to a factor four do not account for the lack explored [17,18]. In a recent study on long-term effects of of response to ITB in implanted patients. Although we ITB in CRPS-related dystonia, we noted that a substantial cannot exclude that the difference between the two IRs percentage of patients, who responded to ITB during a was too small to detect a clinically relevant difference, the screening procedure using an external pump, subse- use of a four-times higher IR seemed appropriate. The use quently failed to respond to continuous ITB with an of a concentration below 0.75 mg/mL would have implied Figure 1 Box plot illustrating patient’s preference for patients with a poor response with and without
van der Plas et al.
an extra refilling of the pump during the FIRD period in headache during FIRD and consequently preferred SIRD.
some patients, which may have caused deblinding. The However, it deserves emphasis that the aforementioned majority of patients displayed dystonia in all extremities findings are the result of post hoc subgroup analyses and reflecting the referral of more severely affected patients to hence warrant further investigation in future studies.
our tertiary center. One could argue the severity of dysto- During the FIRD, patients reported significantly more nia may account for the lack of response to ITB. However, adverse events of a supraspinal origin. As the daily dose of only patients who had demonstrated responsiveness to ITB was fixed for both IRs, this finding likely suggests a ITB at an earlier stage were included in this study. Another more extended intrathecal distribution of baclofen with limitation of this study could be the large variability in the daily administered dose of ITB across the patients, whichreflects individual differences with respect to the dose ofITB at which patients perceived some albeit insufficient Conclusions
benefit (<25%) or the highest tolerated dose that did notcause unacceptable side effects. Consequently, it was not In conclusion under a fixed daily dose, a four-times higher possible to equalize the daily administered dose of ITB. On IR enhances the intrathecal distribution of baclofen as the other hand, using a crossover design, patients served evident from the significantly higher number of adverse as their own controls with the daily dose fixed for each events. However, in CRPS a fourfold higher IR is not patient. Contrary to the primary outcomes, patient’s pref- associated with clinically overt improvement of dystonia or erences indicated significant differences with respect to pain. Patients in whom side effects restricted further dose the preferred IR. Except for one case, all patients who escalations of ITB favored FIRD because of subjective were included because they failed to respond to sequen- improvement of dystonia and pain. In these patients, FIRD tial dose escalations of ITB (without baclofen-related side did not cause more side effects than in patients who failed effects) favored SIRD. Surprisingly, the majority of patients, to respond to ITB after subsequent dose escalations but who were included in the study because side effects who had not experienced side effects. Consequently, in restricted further dose escalation of ITB, reported a pref- the subgroup of patients in whom side effects prevent ITB erence for FIRD. In a written statement delineating their dose escalation, the effect of increasing the IR of ITB at a preference, all but one patient in both subgroups revealed fixed daily dose should be further investigated.
that their preference was based on the influence of the IRon dystonia and pain, which apparently outweighed the Disclosure of Funding
There was no funding or financial support received from Of note is that patients’ preferences were paralleled any funding agency, individual, organization, or other kind neither by changes in primary and secondary outcome measures of dystonia nor by the clinical impression ofchange, which may question the responsiveness of theapplied assessment scales to subtle changes. Possibly, Conflicts of Interest
increasing the IR under a fixed daily dose reduces theseverity of side effects as compared with increasing the IR All authors report no financial interest on the subject by raising the daily dose. In 11 patients, a screening matter or any competing materials. Sam Eldabe currently procedure was performed prior to pump implantation.
receives research funding from Medtronic and has also Interestingly, patients who participated in the study received honoraria for lectures given on Medtronic’s because ITB-related side effects limited dose escalation behalf in the last year. Eric Buchser’s employer, EHC had a significantly larger difference between the IRs of the Hospital of Morges, has received research and educa- screening and postimplantation, compared with patients tional grants from Medtronic sàrl, Tolochenaz Switzerland.
with a poor response without side effects (Table 6). All Jacobus Johannes van Hilten has been a consultant for patients of the first category favored FIRD, except for one Medtronic and has received an unconditional research patient, who suffered from severe intracranial hypotension Ratios of drug delivery characteristics for screening vs postimplantation period The screening to postimplantation period ratio for infusion rate and daily dose for patients with a poor response with and without sideeffects to intrathecal baclofen [16].
P values were derived from a Mann–Whitney U test.
IQR = interquartile range.
Intrathecal Baclofen Delivery in CRPS
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