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Efficacy of Intrathecal Baclofen on Different Pain Qualities in Complex Regional Pain Syndrome

van der Plas, Anton A. MD*; van Rijn, Monique A. MD, PhD*; Marinus, Johan PhD*; Putter, Hein PhD; van Hilten, Jacobus J. MD, PhD*

doi: 10.1213/ANE.0b013e31826f0a2e
Pain Medicine: Research Reports
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BACKGROUND: Complex regional pain syndrome (CRPS) is characterized by severe debilitating chronic pain. Patients with CRPS may experience various pain sensations, which likely embody different pathophysiologic mechanisms. In this study, we evaluated the differential effects of central γ-aminobutyric acid (B) receptor stimulation on the different pain qualities in CRPS patients with dystonia.

METHODS: The 10 pain qualities of the neuropathic pain scale, dystonia severity, and changes in use of antinociceptive drugs were evaluated every 3 months for a period of 1 year in 42 CRPS patients with dystonia receiving titrated doses of intrathecal baclofen (ITB) treatment in an open design.

RESULTS: Using a linear mixed model analysis and controlling for global dystonia severity and the use of supplemental analgesics, we found a significant improvement in global intense pain, sharp pain, dull pain, and deep pain during the first 6 months. After this period, the scores leveled off despite further improvement of dystonia and continued ITB dose escalation.

CONCLUSIONS: γ-Aminobutyric acid (B) receptor stimulation by ITB exerts differential antinociceptive effects on specific pain qualities in CRPS patients with dystonia.

Published ahead of print December 7, 2012 Supplemental Digital Content is available in the text.

From the Departments of *Neurology and Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.

Accepted for publication August 7, 2012.

Published ahead of print December 7, 2012

Study Funding: Funding information is provided at the end of the article.

This report was previously presented, in part, at the Meeting of the TREND Consortium in 2010.

Monique A. van Rijn, MD, PhD, is currently affiliated with Department of Neurology, Albert Schweizer Hospital, Dordrecht, the Netherlands.

Conflicts of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Anton A. van der Plas, MD, Department of Neurology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands. Address e-mail to A.A.van_der_Plas@lumc.nl.

Complex regional pain syndrome (CRPS) is a multifactorial disorder that is associated with an aberrant host response to tissue injury of a limb.1 The clinical spectrum of CRPS is heterogeneous and includes sensory, autonomic, trophic, and motor changes of the affected limb, which reflects the involvement of biological pathways that underlie exaggerated inflammation, vasomotor dysfunction, and maladaptive neuroplasticity.1 The key symptom of CRPS is spontaneous continuous pain, which is disproportionate to the inciting event.2 However, patients with CRPS exhibit various qualities of pain3 depending on the presence of allodynia, hyperalgesia, vascular involvement, and fixed dystonia.4–8 Analgesics are often used in the management of pain in CRPS, but evidence supporting these treatments is limited.9 Different qualities of pain may have different underlying mechanisms. Studying the modifying effects of drugs with a known action on the different pain qualities in homogeneous groups of patients may contribute to the development of future pain management strategies.4 γ-Aminobutyric acid (GABA)ergic circuits play a major role in the processing of different types of pain, especially at the spinal level.10–12 In a previous study, we found that continuous delivery of intrathecal baclofen (ITB), a presynaptic and postsynaptic GABAB agonist, significantly improved the global severity of pain in patients with CRPS and dystonia.13 It is interesting to note that this improvement of pain was only partly explained by a decrease of dystonia, suggesting a direct antinociceptive effect of baclofen. This study therefore explored whether GABAB receptor stimulation by ITB exerted a differential effect on pain qualities in CRPS patients with dystonia.

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METHODS

Patients

Patients with a diagnosis of CRPS-1 and dystonia in at least one extremity who were participating in a trial of ITB administration were included in this study (Table 1).13 Written informed consent was obtained from patients in accordance with the Declaration of Helsinki, and the local ethics committee approved the study. The trial was registered in the Dutch Trial Register (NTR403) on September 12, 2005, with van Hilten serving as the principal investigator. Patients were assessed for eligibility between January 2002 and January 2007. Inclusion criteria were as follows: CRPS-1 according to the diagnostic criteria of the International Associat ion for the Study of Pain (IASP)2 and symptoms for at least 1 year. The IASP criteria include a combination of the following: (1) the presence of an initiating noxious event or a cause of immobilization; (2) continuing pain, allodynia, or hyperalgesia disproportionate to the inciting event; (3) evidence at some time of edema, changes in skin blood flow, or abnormal sudomotor activity in the area of pain; and (4) the absence of a condition that would otherwise account for the degree of pain and dysfunction. Criteria 2 to 4 are required for the diagnosis of CRPS. In contrast to the previously reported study, this study also included patients who developed CRPS spontaneously because recent evidence emerged showing that the clinical presentation of these patients does not differ from those in whom the syndrome developed after a trauma.14 All patients were subjected to the same study design, including a single-blind placebo run-in, dose escalation screening procedure, followed by open-label continuous ITB administration for 12 months for patients who met the responder criteria.13 The procedure for the implantation of a pump (SynchroMed infusion system; Medtronic Inc., Minneapolis, MN) and the verification of pump–catheter system integrity as well as the ITB dose escalation scheme were identical to those used in the previous study.13 The administration of ITB was started at a rate of 150 μg/d and increased in 10% to 20% steps until patients experienced a satisfactory improvement of dystonia (the patient’s experience of dystonia relief) or dose-limiting side effects occurred.15,16 Changes of supplemental analgesics were allowed and monitored throughout the study.

Table 1

Table 1

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Measures

In this open-label study, we performed a post hoc analysis of data from a study that was designed (1) to investigate the effectiveness of ITB in a dose escalation study in a large group of patients with CRPS-related dystonia and (2) to evaluate whether ITB is effective and safe in this population over a 12-month period.13

This study was performed in an outpatient setting. Patients were evaluated at the start of continuous ITB administration and every 3 months for the following year.

To study the effect of ITB on the different pain qualities, we used the neuropathic pain scale (NPS), which includes 2 global ratings (intensity and unpleasantness) and 8 specific ratings (sharp, hot, dull, cold, sensitive, itchy, deep, and surface).4 This scale uses a numeric rating scale (NRS) ranging from 0 (absent) to 10 (most severe) to rate each pain quality item. Preceding each 3-month visit, patients rated their global dystonia severity (GDS) at hourly intervals for 5 consecutive days using the same NRS.13 A mean NRS score was calculated from all ratings in these 5 consecutive days.13 A medication quantification scale (MQS) was used to quantify the use of analgesics based on the number of medications used, the pharmacologic class of the drug, and the dosage level.17 The MQS score was calculated by multiplying the dosage level and a detriment weight, which was assigned for 8 classes of medication. The MQS scores of all drugs of each patient were summed to obtain a total MQS score per patient.

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Statistical Analysis

We used a longitudinal linear mixed effects model with a heterogeneous first-order autoregressive covariance structure to test the hypothesis of change in NPS over time for each of the NPS qualities including time as a categorical variable. We analyzed the effect at each time point (3, 6, 9, and 12 months) compared with baseline and were not interested in a linear or quadratic change.

In this model, patients are treated as random effects, so the analysis can be adjusted to the pain level of each single subject. Furthermore, it adjusts for correlation between repeated measures from the same patient (assuming stronger correlations between scores that are closer in time) and allows missing data and analysis of repeated data with a variable number of measurements per subject. Because we used a linear mixed model, we examined the distribution of the residuals for all components of the NPS. An inspection of the normal probability plots showed that the distribution of the residuals was normal for all pain qualities. The analysis was controlled for the potential confounding effect of other analgesic medication (MQS), GDS, and the absence or presence of an inciting event triggering CRPS. All statistical tests were 2-sided, with α = 0.05. The Cronbach α for internal consistency in our study was 0.93, and interitem correlations ranged from 0.27 to 0.90 with an average of 0.57. Because items are clearly not uncorrelated, we believe that correcting for multiple comparisons may not be necessary. The results are expressed as mean (standard deviation [SD]). Given that the present study concerns a post hoc analysis of a study that was primarily aimed at reducing dystonia,13 no sample size calculations with respect to pain relief were performed. Analyses were performed using SPSS software (version 17.0; SPSS Inc., Chicago, IL).

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RESULTS

Forty-two patients with a mean (SD) age of 37.3 (12.4) years and a mean (SD) disease duration of 8.8 (6.4) years were found to be eligible and participated in this study (Figure 1). Forty patients (95%) were female, and in 31 patients (74%) the onset of CRPS was triggered by a noxious stimulus. The number of affected extremities was 2 (24%) in 10 patients, 3 (17%) in 7 patients, and 4 (60%) in 25 patients. Four patients failed to complete the 1-year follow-up period (Fig. 1) but were included in the linear mixed model analysis. A complete list of adverse events is illustrated in Table 2.

Table 2

Table 2

Figure 1

Figure 1

After correction for the use of supplemental analgesics and GDS, a significant time effect was found for global intense pain (P = 0.009), sharp pain (P < 0.0001), dull pain (P = 0.003), and deep pain (P < 0.0001; Table 1). This effect was characterized by a decline of scores for the first 6 months, after which the scores leveled off. We compared the course of the scores between each pair of these 4 pain qualities for the first 6 months within persons and considered the course to be similar if both pain qualities improved, worsened, or remained the same, and dissimilar if otherwise. Following this definition, a similar course of pain was found in 71% of cases for the combination of global intense and sharp pain, in 67% of cases for the combination of global intense and dull pain, in 74% of cases for the combination of global intense and deep pain, in 68% of cases for the combination of sharp and dull pain, in 66% of cases for the combination of sharp and deep pain, and in 63% of cases for the combination of deep and dull pain. The time effect for GDS was also significant (P = 0.003) with a continuous decline all through the 1-year follow-up (Table 1). The mean daily dose of ITB increased every 3 months during the year (Table 1). The absence or presence of an inciting event triggering CRPS did not significantly influence the time effect for any pain quality, GDS, MQS, or daily dose of ITB.

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DISCUSSION

CRPS is associated with severe debilitating pain, which may involve different pain qualities across patients.4,6 These various pain qualities may result from different pain mechanisms.4 This study focused on patients with CRPS characterized by dystonia. Homogeneous groups enhance the clinical, pathophysiologic, and genetic coherence, which in turn may benefit research aiming to study or influence specific biological pathways. Patients in this study received baclofen, a presynaptic and postsynaptic GABAB agonist, which possesses analgesic properties.18–20 The intrathecal delivery of baclofen is used to overcome the obstacle of the blood–brain barrier and thus results in greater therapeutic effectiveness concentrated at the spinal site of action.13,21

In this study, we found a significant time effect with a reduction of pain scores during the first 6 months of follow-up for global intense, sharp, dull, and deep pain. These reductions can be interpreted as clinically significant (reduction in NRS scores ≥2) for global intense, sharp, and deep pain and to a lesser extent for dull pain.22 Notably, the time effect was independent of the course of GDS and the use of supplemental analgesics, supporting the notion of baclofen’s antinociceptive effect on these pain qualities in these patients. This assumption is further supported by the significant decrease of supplemental analgesic consumption during the first 3 months. Oral administration of baclofen proved to be effective in the management of neuropathic pain in both peripheral neuropathy and central pain syndromes.18–20 Notably, the add-on of ITB to spinal cord stimulation improved neuropathic pain over a prolonged period in patients who experienced insufficient benefit from spinal cord stimulation alone.23 However, this improvement was based on a reduction of the global pain ratings. Findings of our study show that a targeted stimulation of the central GABAB receptor may have differential effects on various pain qualities, which to our knowledge has not been described previously. The scores for the different pain qualities leveled off after 6 months whereas GDS continued a declining course, and the dose of ITB was further escalated. The differential effects of these variables over time further support an independent role of GABAergic mechanisms on global intense, sharp, dull, and deep pain qualities. Furthermore, patients were informed that the purpose of ITB was to improve dystonia severity. The continued decrease of GDS with further ITB dose escalations when improvement of different pain qualities had stabilized additionally highlights the differential roles of GABAB receptors in mechanisms underlying pain and dystonia in CRPS.

The onset of CRPS is generally thought to result from a noxious stimulus, although this is not an obligatory criterion for the diagnosis following the IASP criteria.2 A previous study showed no significant difference in clinical characteristics between patients who developed CRPS spontaneously or after an inciting event.14 Also in this study, we found no differences in outcomes between CRPS patients with and without an initiating trauma.

Although most studies on CRPS report a female-to-male ratio of 3 to 4, the high percentage of female patients in this study (95%) is in line with other studies on CRPS patients with dystonia.7,24,25

One limitation of our study is the open-label design, which hampers the identification of a potential placebo effect due to the absence of a control group. Ideally, a placebo-controlled, randomized design would have been performed. Because this would involve the follow-up of patients with an implanted pump without medication for 1 year, this was considered unethical. However, we believe that the somewhat differential effect of ITB on particular pain qualities over time as compared with dystonia makes a substantial role of a placebo effect on the outcomes of this study less likely. We cannot, however, exclude a placebo effect or natural progression of the disease affecting the pattern of the different pain qualities over time.

Another limitation of the study could be the lack of homogeneity in dose escalation of ITB. However, this was inevitable because the occurrence of side effects limited dose escalation in some patients and the daily dose was maintained once a satisfactory result was achieved. Nonetheless, we noticed a trend of continuous increase of the daily dose of ITB throughout the whole 1-year follow-up period.

In conclusion, ITB proved beneficial in reducing global intense, sharp, dull, and deep pain and highlights the differential antinociceptive effects of central GABAB receptor stimulation on specific pain qualities in CRPS.

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STUDY FUNDING

This study is part of the Trauma Related Neuronal Dysfunction (TREND), a Dutch consortium that integrates research on epidemiology, assessment technology, pharmacotherapeutics, biomarkers, and genetics on complex regional pain syndrome type 1. The consortium aims to develop concepts on disease mechanisms that occur in response to tissue injury, its assessment, and treatment. TREND is supported by the Dutch Ministry of Economic Affairs (grant no. BSIK03016).

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DISLCOSURES

Name: Anton A. van der Plas, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Anton A. van der Plas has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Monique A. van Rijn, MD, PhD.

Contribution: This author helped design the study and conduct the study.

Attestation: Monique A. van Rijn has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Johan Marinus, PhD.

Contribution: This author helped designthe study, conduct the study, and write the manuscript.

Attestation: Johan Marinus has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Hein Putter, PhD.

Contribution: This author helped design the study and conduct the study.

Attestation: Hein Putter has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: The author has no conflicts of interest to declare.

Name: Jacobus J. van Hilten, MD, PhD.

Contribution: This author helped designthe study, conduct the study, and write the manuscript.

Attestation: Jacobus J. van Hilten has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Conflicts of Interest: Jacobus J. van Hilten has been a consultant for Medtronic and has received an unconditional research grant from Medtronic. He reports no financial interest on the subject matter or any competing materials.

This manuscript was handled by: Spencer S. Liu, MD.

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