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Accepted Manuscript
Thoracic Sympathetic Block for the Treatment of Complex Regional Pain Syn-drome Type I: A double-blind randomized controlled study
Roberto de Oliveira Rocha, Manoel Jacobsen Teixeira, Lin Tchia Yeng, MirleneGardin Cantara, Viviane Gentil Faria, Victor Liggieri, Adrianna Loduca,Barbara Maria Müller, Andrea Cristina Matheus da Silveira Souza, DanielCiampi de Andrade
PII: S0304-3959(14)00374-1DOI: http://dx.doi.org/10.1016/j.pain.2014.08.015Reference: PAIN 9298
To appear in: PAIN
Received Date: 18 March 2014Revised Date: 12 August 2014Accepted Date: 13 August 2014
Please cite this article as: R. de Oliveira Rocha, M.J. Teixeira, L.T. Yeng, M.G. Cantara, V.G. Faria, V. Liggieri,A. Loduca, B.M. Müller, A.C.M. da Silveira Souza, D.C. de Andrade, Thoracic Sympathetic Block for the Treatmentof Complex Regional Pain Syndrome Type I: A double-blind randomized controlled study, PAIN (2014), doi: http://dx.doi.org/10.1016/j.pain.2014.08.015
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Thoracic Sympathetic Block for the Treatment of Complex Regional Pain Syndrome
Type I: A double-blind randomized controlled study
Roberto de Oliveira Rocha, MD, PhD1; Manoel Jacobsen Teixeira, MD, PhD
1,3; Lin
Tchia Yeng MD, PhD1,2
; Mirlene Gardin Cantara1,2
; Viviane Gentil Faria1,2
; Victor
Liggieri1,2
; Adrianna Loduca, MD, PhD1; Barbara Maria Müller
1; Andrea Cristina
Matheus da Silveira Souza1, Daniel Ciampi de Andrade, MD, PhD
1,4
1 Pain Center, Department of Neurology, School of Medicine, University of São Paulo,
São Paulo, Brazil
2 Physical Medicine, Department of Orthopedy, School of Medicine, University of São
Paulo, São Paulo, Brazil
3 Neurosurgery Division, Department of Neurology, School of Medicine, University of
São Paulo, São Paulo, Brazil
4 Instituto do Câncer do Estado de São Paulo Octávio Frias de Oliveira, university of São
Paulo, Brazil
Corresponding author:
Dr. Roberto de Oliveira Rocha
Divisão de Clínica Neurocirúrgica do Hospital das Clínicas da FMUSP
Secretaria da Neurologia, Instituto Central
Av. Dr. Enéas de Carvalho Aguiar, 255, 5º andar, sala 5084 – Cerqueira César
05403-900 – São Paulo – SP - Brazil
2
Phone/ Fax: +55 11 26 61 71 52
Email addresses:
LT Yeng: [email protected]
MJ Teixeira: [email protected]
M G Cantara: [email protected]
V Gentil: [email protected]
Victor Liggieri: [email protected]
Adriana Loduca: [email protected]
B M Müller: [email protected]
A C M S Souza: [email protected]
D Ciampi de Andrade: [email protected]
Contents of the manuscript: 31 pages, 2 tables and 3 figures, Supplementary Data: 2
tables, 1 figure.
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1. Introduction
Complex Regional Pain Syndrome (CRPS) type-I arises following trauma to a limb
and is characterized by functional impairment in the affected body segment. It is
associated with intense sensory, autonomic, motor and trophic changes, which are
disproportionate to the inciting event and cannot be accounted for by other causes of
chronic pain [25]. Despite recent advances in the understanding of its pathophysiology,
pain relief in CRPS remains a major challenge. This is partly due to the complexity of the
mechanisms underlying the maintenance of pain and the functional impairment present in
this syndrome, but it is also related to the lack of evidence-based treatment trials specific
for this condition [22]. Most interventions used for CRPS relief are not supported by high
quality evidence-based data [39].
Sympathetic nerve blocks have been used for the treatment of CRPS since the
beginning of the 20th
century [6]. Despite the paucity of evidence-based information on
its efficacy, it is commonly utilized in patients with CRPS, leading to variable analgesia
when used in combination with physical therapy [4, 17, 49].
Different techniques of sympathetic blocks are frequently grouped together in
efficacy analyses and CRPS reviews [51]. However, these procedures are not all similar,
and their clinical efficacy may depend on variables such as the target anatomical
structures, the medication injected during the procedure, and the number of blocks
performed [12, 14]. For instance, the technique that is most commonly used to target
sympathetic innervation of the upper limbs is the stellate ganglion block (SGB) [14, 17,
36]. Anatomical and clinical studies have suggested that this may not be the most
effective technique for upper limb sympathetic block [6, 26, 27].
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Second order neuron cell bodies that supply the upper limbs are located in the
intermediolateral horn of the thoracic spinal cord. Preganglionic fibers ascend cephalad
and synapse on postganglionic fibers, primarily in the 2nd
(and to a lesser extent in the
3rd
) thoracic sympathetic ganglia, before ascending and passing through the stellate and
the middle cervical ganglia en route to the upper limbs [44, 46]. However, in 20% of the
individuals, nerves from these two thoracic sympathetic ganglia project directly to the
brachial plexus, bypassing the upper stellate and middle cervical ganglia [31, 44, 46].
Thus, different from SGB, which only influences nerve fibers that actually pass through
this structure before reaching the upper limbs, thoracic sympathetic blocks (TSB) act
directly on the main synapse site of most sympathetic fibers innervating this body
segment [44, 46]. Despite this potentially relevant anatomical information, TSB has
rarely been evaluated in CRPS patients (1, 53).
Given the lack of conclusive studies on the validity of the sympathetic block of the
upper limb as a treatment for CRPS as well as the reported limitations of the SGB
technique and the lack of controlled long-term studies on sympathetic blocks in general
for CRPS, we performed a twelve-month, randomized, double-blinded active-control
study to evaluate the efficacy of TSB for upper limb type-I CRPS.
2. Methods
2.1. Clinical trial
The study was approved by our Institution’s Ethics Review Board (#0465/09) and
is registered at www.clinicaltrials.org under (NCT01612364). Data were collected from
October 2009 to October 2013.
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2.2. Patients
Patients from our own institution and related outpatient clinics in our district area
were screened for eligibility. All assessments and procedures were performed in our
Institution’s Pain Center. The IASP 1994 diagnostic criteria for type I CRPS were used
during the first months of the study during the screening phase and before any patient
underwent the blocking procedure. After the publication of validation of the new criteria
(Harden et al. 2010), an addendum was added to the project (approved by the Ethics
Review Board) and since then, only the Budapest criteria were used for screening and
inclusion in the protocol [50, 24]. To be eligible, adult patients (18-70 years) needed to
have CRPS I for at least six months and have failed to obtain pain relief [numeric rating
scale (NRS) >4] after conventional treatment. Patients needed to be on a stable dose of
CRPS medications for at least 28 days prior to study entry. The exclusion criteria were
pregnancy/lactation, substance abuse issues, history of serious brain trauma, epilepsy or
stroke, presence of a serious systemic illness (e.g., cancer), and serious or untreated
psychiatric illness.
2.3. Treatments
2.3.1. Systematic standardized treatment.
After study entry, all patients underwent a psychological assessment and were
started on comprehensive standardized rehabilitation and pharmacological treatment
(Figure 1) for four weeks consisting of the following:
a. A physical therapy program guided by a physiatrist and physical therapists. The
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standardized physical therapy program included a once weekly session for eight weeks
(four weeks before and four weeks after the intervention). A Disabilities of the Arm,
Shoulder and Hand (DASH) questionnaire was completed before and after (at 8 weeks)
the standardized physical therapy sessions [41].
b. Oral analgesic polytherapy was started: antidepressants (amitriptyline 25-75
mg/day or imipramine 25-75 mg/day), opioid analgesics (tramadol 100-400 mg/day;
codeine 60-240 mg/day), non-anti-inflammatory analgesics (metamizole sodium 2-6
g/day or acetaminophen 1.5-3 g/day) and gabapentin (900-1800 mg/day). Patients
remained on the same drug regimen throughout the duration of the study. Acute pain
medications were allowed: morphine (10 mg q.i.d), tramadol (50 mg q.i.d.) or codeine
(30 mg q.i.d.). Patients who failed to comply with baseline medications were withdrawn
from the study (Figure 1).
c. Psychological assessment: two interviews with a pain psychologist were
performed to detect and evaluate major mood disorders and to assess patients’ coping
strategies related to the presence of pain (Figure 1).
Patients who were pain-free after this standardized treatment phase of the study
were excluded from the protocol. Patients who remained symptomatic (NRS>4) were
randomized into either TSB or control treatment and underwent the intervention (Figure
1).
From the 8th to the 52th week of the study (i.e., from four weeks after the blocking
procedure until the 12 month follow-up visit), patients were seen in an outpatient setting.
During this period, patients who were originally seen in our outpatient clinic and
presented for follow-up consultations were asked to undergo a blinded supplementary
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clinical evaluation. For these patients, supplemental data from 2, 3, 6, and 9 months after
the blocking procedure were obtained in addition to the baseline, one- and 12-month
assessments performed in all patients (supplementary table 1).
2.4. Clinical assessment
Blinded researchers who had no role in the blocking procedure or patient screening
performed all clinical assessments. Assessments were performed at baseline, and at one
and 12 months after the procedure (Figure 1); they included the following:
a. Pain location, intensity and interference with daily activities were assessed using
the short form of the Brief Pain Inventory (BPI) [18].
b. The presence of a neuropathic component based on the Douleur Neuropathique 4
questionnaire (DN4) [10, 48] and its symptom profile based on the Neuropathic Pain
Symptoms Inventory (NPSI) [9, 15] were assessed as well as the different dimensions of
chronic pain using the McGill Pain Questionnaire (MPQ) [35, 42].
c. Mood was assessed using the Hospital Anxiety and Depression Scale (HADS)
[8] assessed at baseline and at the end of the study (12 months after the procedure).
d. Quality of life was assessed by the short form of the World Health Organization
Quality of Life questionnaire (WHOQOL-bref) [20] administered at baseline and at the
end of the study (12 months after the procedure) (Figure 1).
2.5. Blocking procedure
Patients were randomly assigned to receive either TSB or control block. The
randomization participants were asked to select a manila envelope from an urn containing
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60 envelopes. Under sterile conditions, the patient was placed in the ventral decubitus
position with their head covered with a blanket so that they were not able to observe the
procedure. Both groups received the block in the same dorsal region on the same side as
the affected limb. TSB was performed according to the technique described by Leriche
and Fontaine in 1925 [33]. Before needle puncture, 5 ml of 1% lidocaine was used for
skin and soft tissue anesthesia. A number 22-Quincke (BBraun, Melsungen, Germany)
needle for spinal anesthesia was positioned in the T2 plane under fluoroscopic guidance
(Figure 1 A supplementary data). The needle was inserted into the skin and advanced
until the posterior third of the second thoracic vertebra. Then, 1 ml of iopamidol-755
mg/ml (Patheon Italia S.p.A.- Ferentino - Italy) contrast was injected to ensure that the
needle was properly placed and was not in the intravascular, intrapleural or intramedullar
spaces (Figure 1 A supplementary). Then, 10 ml of anesthetic + corticosteroid solution (5
ml of 0.75% ropivacaine [AstraZeneca, London, UK] + 5 ml of 2% triamcinolone
[Apsen; São Paulo; Brazil]) was injected into the T2 sympathetic thoracic ganglion,
paralateral to the T2 vertebrae on the affected side. Fluoroscopy was always used to assist
in needle positioning and to document the final location of the needle. For patients in the
control group, the same type of needle (22 Quincke) was used to puncture the skin before
being positioned subcutaneously at the T2 level. In addition, the same 10 ml of anesthetic
+ corticosteroid solution (5 ml of 0.75% ropivacaine + 5 ml of 2% triamcinolone) was
injected at this site using radioscopy, but the solution was injected into the subcutaneous
space. Fluoroscopy was used to document the location of the injection (Figure 1 B
supplementary). Fluoroscopic films documented the procedure. After blocking, the
temperature in the limb were measured using a touch thermometer (TS-201, Techline,
9
São Paulo) over the volar aspect of the forearm at operating room temperature 21± 2°C.
A difference greater than 2°C indicated that the TSB was successful [27].
2.6. Outcome measurements
Primary outcomes were the average pain score item from the BPI at one and twelve
months after the blocking procedure. Secondary outcomes measures were the other pain
intensity and interference scores from the BPI, NPSI, and MPQ at one and twelve months
after the blocking procedure. Quality of life (WHOQOL bref) and mood (HADS) were
assessed before and twelve months after the block.
2.7. Side effects and blinding assessment
Patients were systematically assessed for adverse events related to the intervention
right after the procedure and one month afterwards. Major side effects were defined as
any event leading to hospitalization, death or increase in pain of >50% based on the NRS.
Common minor side effects previously observed after sympathetic blocks performed in
our institution and published in the literature were ranked and listed in a questionnaire
and systematically assessed in all patients [1, 40]. Blinding was assessed by asking
patients a set of direct questions at the end of the study after their last assessment. These
questions included the following: How much pain did you experience during the
procedure? (NRS 0-10); Would you be able to tell which treatment you received?
(yes/no); Which type of intervention do you think you received? (active/control); Would
you be willing undergo the procedure again if it was offered to you? (yes/no).
10
2.8. Sample size and data analysis
This study was powered to detect a two-point reduction in NRS in the TSB
compared to the control group. Based on the results of the sympathetic blocks performed
at our institution in the four years preceding the study, we observed a 53% improvement
(NRS) in patients treated with a thoracic sympathetic block vs. an 18% improvement in
patients who received other peripheral procedures (e.g., dry needling, nerve trunk block).
We estimated that based on NRS reduction observed after TSB, it would be necessary to
include 20 patients in each arm of the study, given a power of 0.95, a beta error < 20%
and alpha < 5% (two-sided) and a 20% of estimation error. Then, fifty patients were
expected to be included in the study based on a 20% dropout rate in the 12-month follow-
up. Statistical analysis included all patients according to the intention-to-treat principle.
Our main goal was to evaluate patients’ response to pain, for which we used the average
pain intensity (BPI): α ≤ 5% risk of committing a Type I error and a β ≤ 20% risk of
committing a Type II error. Data were expressed as the means ± standard deviations. The
Kolmogorov-Smirnov test for normality was performed on the quantitative variables.
Non-parametric data were compared with the Kruskall-Wallis, Mann-Whitney Test and
Wilcoxon Signed Rank Test when indicated. Categorical data are presented as absolute
frequencies (N) and relative frequencies (%). The associations between categorical
variables according to the outcomes were analyzed with the Chi-square test. When
categories had less than 20 individuals, we adopted the Fisher exact test. We assumed
throughout the study α ≤ 5% risk of committing type I, and 20%β risk of committing
type II errors.
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3. Results
Sixty-three patients were screened for eligibility. Fifty-one were included in the
study and underwent the systematic, standardized treatment phase. During this initial
phase, fourteen patients were excluded before undergoing the blocking procedure: five
had been screened for CRPS based on the previous diagnostic criteria, and nine became
pain-free after the standardized treatment phase. The remaining patients (n=37)
underwent the baseline evaluation and were randomized. After randomization but before
the procedure, one patient from the TSB group was excluded due to the occurrence of
unprovoked seizures. Thus, thirty-six patients underwent the blocking procedure (TSB
n=17, control n=19). After the 12-month follow-up, fifteen patients were available for
evaluation in the TSB group (two lost) and fourteen were available in the control group
(five lost) (Figure 2).
3.1. Patient characteristics
Nineteen women (52.8%) participated in the study (eight [42.1%] in the TSB group
and 11 [57.9%] in the control group). The mean age was 42.0±13.5 years in the TSB and
44.4±8.9 years in the control group. The mean disease duration was 22.7±26.3 months in
the TSB group and 21.0±21.6 in the control group (p>0.4) (Table 1). A history of
previous general surgical interventions was significantly more common in the control
group (n=14) than in the TSB group (n=6), p=0.021. The left upper limb was more
frequently affected in the control group (n=10) than in the TSB group (n=1; p=0.002).
Except for these differences, both treatment groups had similar baseline clinical, pain
related and demographic characteristics (p>0.1) (Table 1).
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3.2. Block procedure and safety
The blockage procedure was performed in 36 patients. There were no major
adverse events during the study in either group. Minor adverse events occurred in both
groups (supplementary table 2). The total number of minor adverse events was similar
between the groups (2.88±2.3 vs. 2.35±2.4 in the TSB and control groups, respectively
p=0.531). All patients in the TSB group had a greater than two degrees Celsius increase
on the treated hand right after the procedure. Local temperature ranged from 27.1±3.1oC
before to 35.9±0.8oC after the block. Seven (41,2%) patients in the TSB and none in the
control group exhibited Claude-Bernard Horner’s sign after the blocking procedure.
The attendance to all scheduled physical therapy sessions appointments (total of
eight sessions) was 100% for 12 (70,6%) patients in the TSB and 14 (73,7%) patients in
the control group. All of the remaining participants had at least >50% attendance to the
sessions. All participants had 100% compliance to the physical therapy sessions
performed before the blocking procedure (total of four sessions).
3.3. Primary and secondary outcomes
The mean of the BPI average pain intensity item at one month was not
significantly different in the TSB (3.59±3.2) compared to the control group (4.84±2.7;
p=0.249). At 12 months, however, this score was significantly lower in the TSB group
(3.47±3.5) compared to the control group (5.86±2.9; p=0.046) (Figure 3). Some
secondary outcome measures improved after TSB. Compared to baseline values, the
current pain intensity score (BPI) at one month decreased from 5.59±2.9 to 3.53±3.7
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(p=0.035) in the TSB group but did not significantly change in the control group
(6.16±3.0 to 5.84±2.9) (Table 2). The MPQ total score was significantly lower in the
TSB (36.56±16.2) compared to the control group (42.33±8.5; p=0.024) at one month. At the
12-month assessment, the TSB group continued to report significantly lower scores on
the MPQ (27.20±22.2) compared to the control group (45.43±23.6; p=0.042), (Table 2). The
subscores of evoked pain in the NPSI (question 8, 9 and 10) in the TSB group (5.59±1.7)
were significantly lower at one month (3.43±1.8; p=0.035) and 12 months (3.02±1.9;
p=0.02) compared to the control group (Table 2).
More patients in the control group took tramadol as a rescue medication than in the
TSB group (p=0.039), one month after the nerve block (Table 2). There were no
significant differences between the groups in the number of patients taking other rescue
drugs, including morphine, at one month or 12 months after the blocking procedure (two
patients in the control group and one in the TSB group).
The quality of life scores (WHOQOL-bref) were similar between groups at baseline
and did not differ twelve months after the procedure, except on four sub items (of 24)
related to self-satisfaction, sexual life, acceptance of body appearance and perceived need
to take medications, all of which were significantly improved by TSB. The baseline
anxiety and depression (HADS) scores were similar between the groups at baseline.
Although the anxiety scores did not differ between the groups at the 12-month
assessment, the depression scores were significantly lower in the TSB group compared to
the control group at 12 months (Table 2). Scores from the DN-4 and DASH did not differ
between the groups.
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3.4. Interim analyses
Twenty-six patients (72.2%) were available for interim pain analysis at 2, 3, 6, and
9 months. These patients were already followed by our institution’s out-patient clinic and
were available for supplementary assessment during follow-up. Because the trial only
included three assessments as obligatory (baseline, 1 month and 12 months) and covered
travel expenses, these interim assessments were performed exclusively in patients
attending our center on an outpatient basis. Data from these assessments suggest a better
outcome in the TSB group than in the control group and are shown in the supplementary
materials (supplementary Table 1). A supplementary analysis was performed comparing
the scores and clinical characteristics from patients who were available for interim
assessment compared to those who were not. The analyses showed that both groups of
patients had similar pain and demographic characteristics.
3.5. Blinding
A trained researcher assessed blinding with no other role in the research at the end
of the study. The intensity of pain during the procedure did not differ between the groups;
in addition, the number of patients who reported that they could guess which treatment
group they were in and the type of treatment they received also did not differ between the
groups (p>0.1). Similarly, the number of patients who would be willing to undergo a new
procedure did not differ between the groups (p>0.1).
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4. Discussion
Compared to the control group, patients undergoing TSB reported significantly
lower scores on the MPQ, decreased evoked pain scores, lower current pain intensity
(BPI), and lesser analgesic use of rescue tramadol at one month after the procedure. At
the 12-month assessment, most of these improvements persisted and were accompanied
by further improvements in the average pain scores, depressive symptoms and some
aspects of quality of life.
This is the first randomized, double-blinded, controlled study of TSB in CRPS and
is one of the largest using sympathetic blockade in general. To date, only two
uncontrolled studies have assessed the effects of TSB in this patient group. They found
an average of 50% pain intensity reduction lasting for at least one week after a single
TSB procedure in 85 CRPS patients [1, 53]. These studies assessed pain intensity based
on the VAS and Likert scales, with no specific measurements of neuropathic pain
components, mood or quality of life [1, 53]. Eight prospective randomized studies
assessed the analgesic effects of anesthetic block of the SGB for upper limb CRPS. These
studies have marked methodological heterogeneity. For instance, only one clearly
described the randomization process [52] and only two were double-blinded [3, 43]. In
five studies, the blinding procedure was unclear [7, 37, 45, 52, 57], and one was not
blinded at all [47]. The number of patients included in these trials ranged from four to 82
[43, 47]. The timing of assessment also was quite variable, ranging from right after the
blocking procedure [43] to three months post-treatment [47]. Some studies (n=6) used
control blocks with active drugs such as guanethidine [7], lidocaine with clonidine [37],
phentolamine [45, 57], or continuous infraclavicular brachial plexus block [52]. In one
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study, physical therapy was added to the baseline treatment [47]. Two placebo-controlled
studies were negative [3, 43]. The remaining active-control studies reported negative
(n=5) [7, 37, 45, 52, 57] or minimal responses (n=1) after SGB [47].
Some have suggested that the stellate ganglion may not be the most suitable target
for upper limb sympathetic block in CRPS patients [6, 14, 17, 27]. This suggestion is
mainly due to the fact that SGB may miss the sympathetic nerve fibers traveling to the
upper limb in a significant proportion of individuals [31]. Thus, by blocking T2 and T3
ganglia rather than the stellate ganglion, all of the sympathetic fibers are affected by the
block. In fact, Hogan [27] showed that in 100 consecutive technically well-performed
SGB procedures monitored by pupillary and hand temperature changes, the clinical signs
of upper limb sympathetic blockade were only detected after 27 of the procedures [27].
Kuntz [31] has demonstrated that in 20% of individuals the ganglionic sympathetic fibers
projected to the upper limb directly, thus bypassing the stellate ganglion after synapsing
in the upper thoracic ganglia [17, 44, 46]. This is important given the major difference
between TSB and SGB. In TSB, the blocking agent is injected at the location of the cell
bodies of the third-order sympathetic neurons. It has been demonstrated that neuronal
cell bodies have more receptors to steroids and are more amenable to chemical
modulation than peripheral axons [32, 56]. Hence, one important methodological aspect
of the current study is that we directly injected corticosteroids into the thoracic
sympathetic ganglion. Autoimmune attack against peripheral nerves might trigger
leukocyte extravasation, autoantibody exudation, neuroinflammation and neuroimmune
activation in associated DRGs, sympathetic ganglion and the spinal cord, and this has
been suggested as a possible underlying mechanism of the development of CRPS [5, 13,
17
23, 30, 34, 55]. There are data supporting pain improvement in CRPS patients after the
use of systemic steroids [11, 19, 28]. Because steroids injected into sympathetic ganglia
and the subcutaneous space will also act systemically, one cannot rule out that part of the
analgesic effect observed was due to the use of this medication (and local anesthetic) in
both groups [11, 19, 28, 54]. Triamcinolone long-acting repository formulations are
absorbed slowly from the injection site and provide anti-inflammatory effects for 1-4
weeks. The hypothalamic-pituitary-adrenal axis may be inhibited for up to six weeks
after intramuscular or spinal injection
[4, 21]. However, it is highly unlikely that the
effect of a single acute infusion of steroids lasted for all of the 12-month follow-up
period. We hypothesize that the early (1-2 month) effect of the blocking procedure
positively influenced other aspects of pain and its treatment, such as the efficacy of
physical therapy [2], reduced use of medication and positive effects on mood that as a
whole provided long-term positive effects. In fact, our results suggest that the positive
effect of the treatment built up during the early study phase and persisted for 12 months.
This is also an important issue when considering the active-control group used in
the present study. If, on one hand, this “fully treated” control group increases the number
of patients necessary to prove an active intervention as actually effective, on the other
hand, it expands the external validity of these findings because the protocol approaches
what actually happens in clinical practice.
Long follow-ups are frequently associated with an increase in dropouts and
blinding issues [29]. We had a lower than 20% dropout rate, which was similar to other
long-term studies [16]. We also performed a systematic blinded interim assessment in the
patients in our outpatient clinic at 2, 3, 6, and 9 months (supplementary table 1). Despite
18
the low number of patients available for this assessment, these patients did not
significantly differ in terms of clinical pain and sociodemographic characteristics from
those who did not present to our center during this period. These assessments suggest that
while the one-month evaluation had some positive results favoring TSB over the control
group, these changes are clearer in the second month after treatment. Blinding is equally
a central subject in long duration clinical trials. In addition to diligently preventing
patients from observing the site of injections during the procedure by placing them in a
ventral decubitus position and performing all assessments and evaluations in a double-
blinded fashion, we assessed the quality of blinding by using a standardized
questionnaire. Patients from both groups answered the questions similarly. In addition to
all these measures, one cannot be completely sure that the presence of Claude-Bernard-
Horner’s sign or blurred vision after the procedure would not bias blinding. However,
because all the other minor side effects were similar between the groups and because
patients were sympathetic block naïve, we believe that these aspects did not play a major
role in biasing the results. Another important issue is the safety of the procedure. Based
on the present results, there were no major adverse events related to the blocking
procedure and most minor side effects were similarly distributed between both groups.
Therefore, we believe that TSB is a safe procedure. Larger controlled trials are needed to
confirm this initial impression. In a larger open study including results from 322 TSB
procedures guided by computerized tomography scans [1], adverse events occurred in
7.1% of the procedures and included three cases of pneumothorax and one spinal cord
puncture [1]. In a study on 557 neurolytic TSB with phenol or alcohol and fluoroscopy
guidance [40], complications occurred in 7.5% of the procedures and included neuritis
19
(n=23), Horner’s syndrome (n=14) and pneumothorax (n=3) [40].
A clear limitation of the study is its relatively small sample size. We calculated the
number of patients based on our clinical experience with TSB, but this estimation method
is clearly associated with limitations. In addition, the dropout rates expected in a long-
term trial led to a relatively small overall percentage of patients who completed the study
(81.6%). While this is one of the largest published trials based in this area that used a
controlled, double-blinded methodology, we believe that a study with a larger number of
patients would more strongly support the external validity of our finding. At the end of
the study, recruitment was much lower than expected and we could not include the
expected 20 patients per arm described in the original plan. In addition, randomization
would be more accurate if performed in blocks, which was not the case and could be the
reason why some variables were not evenly distributed in both groups such as
handedness and the number of previous surgical interventions.
In conclusion, our data showed that a single TSB is a safe procedure and has both
short (1 month) and long (12 month) term positive impact on upper limb type-I CRPS as
an add-on treatment to a standardized rehabilitation and pharmacological treatment
program. While the impact of the procedure on quality of life is slightly significant, pain
reduction, decrease in evoked pain and amelioration of depressive symptoms were
significantly superior to the control treatment.
20
Acknowledgments
Funding
The Pain Center, Neurology Department, University of São Paulo, Brazil funded this
study.
Conflict of Interest
None
21
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31
Figure legends
Figure 1 - Study design
A: pain evaluation (BPI, MPQ, NPSI, DN4), physical evaluation (DASH), psychological
evaluation (WHOQOL-bref and HADS). B: pain evaluation (BPI, MPQ, NPSI, DN4),
physical evaluation (DASH). C: pain evaluation (BPI, MPQ, NPSI, DN4), psychological
evaluation (WHOQOL-bref and HADS). Intervention: TSB or control block. Physical
therapy: standardized eight physiotherapy sessions. Pharmacological treatment:
standardized pharmacotherapy.
Figure 2 - Study flowchart
Figure 3 - Numeric-rating scale of average pain (BPI) scores in patients receiving
thoracic sympathetic block (TSB) or control block (control). Bars represent mean and
lines represent standard deviation. * P< 0.05.
Supplementary figure 1 A: Fluoroscopy after TSB at the level T2, iodine contrast
infusion. B: Fluoroscopy after control block, needle in subcutaneous position.
32
Pain relief in CRPS remains a major challenge in part due to the lack of evidence-
based treatment trials specific for this condition. We performed a long-term
randomized, double-blinded active-control study to evaluate the efficacy of
thoracic sympathetic block (TSB) for upper limb type-I CRPS. OBJECTIVES:
Evaluate the analgesic effect of TSB in CRPS. METHODS: Patients with CRPS-I
were treated with standardized pharmacological and physical therapy and were
randomized to either TSB or control procedure as an add-on treatment. Clinical
data, pain intensity and interference (Brief Pain Inventory-BPI), pain dimensions
(McGill Pain Questionnaire-MPQ), neuropathic characteristics (Neuropathic Pain
Symptom Inventory-NPSI), mood, upper limb function (Disabilities of Arm,
Shoulder and Hand-DASH) and quality of life were assessed before, at one and at
twelve months after the procedure. RESULTS: Thirty-six patients (19 female,
44.7±11.1y.o.) underwent the procedure (17 in TSB group). Average pain
intensity at one month was not significantly different after TSB (3.5±3.2)
compared to control procedure (4.8±2.7;p=0.249). At 12 months, however, the
average pain item was significantly lower in the TSB group (3.47± 3.5) compared
to the control group (5.86± 2.9;p=0.046). Scores from the MPQ, evoked-pain
symptoms subscores (NPSI), and depression scores (HADS) were significantly
lower in the TSB group compared to the control group at one and at twelve
months. Other measurements were not influenced by the treatment. Quality of life
was only slightly improved by TSB. No major adverse events occurred. Larger,
multicentric trials should be performed to confirm these original findings.
33
Summary
17 chronic upper limb CRPS patients treated with TSB were better than 19
controls about pain, life quality and mood 1, 2 and 12 months.
34
CONSORT 2010 checklist of information to include
when reporting a randomised trial*
35
Section/Topic Item No Checklist item
Reported on page No
Title and abstract 1a Identification as a randomised trial in the title 1
1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) abstract
Introduction Background and objectives
2a Scientific background and explanation of rationale 2 2b Specific objectives or hypotheses 3
Methods Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 3-4
3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons 3
Participants 4a Eligibility criteria for participants 3 4b Settings and locations where the data were collected 3
Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were actually administered
4-8
Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed
8
6b Any changes to trial outcomes after the trial commenced, with reasons Sample size 7a How sample size was determined 8
7b When applicable, explanation of any interim analyses and stopping guidelines Randomisation: Sequence
generation 8a Method used to generate the random allocation sequence 6-7 8b Type of randomisation; details of any restriction (such as blocking and block size) 6-7
Allocation concealment mechanism
9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned
6-7
Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions
6-7
Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing outcomes) and how
7
36
11b If relevant, description of the similarity of interventions 7 Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 8
12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 8
Results Participant flow (a diagram is strongly recommended)
13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome
9
13b For each group, losses and exclusions after randomisation, together with reasons 9, 3-4 Recruitment 14a Dates defining the periods of recruitment and follow-up 9
14b Why the trial ended or was stopped 9 Baseline data 15 A table showing baseline demographic and clinical characteristics for each group 4-5 Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was
by original assigned groups 9-12
Outcomes and estimation
17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval)
9-12
17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended 9-12 Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing
pre-specified from exploratory 9-12
Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) 12
Discussion Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 14,16 Generalisability 21 Generalisability (external validity, applicability) of the trial findings 12-17 Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 12-17
Other information
Registration 23 Registration number and name of trial registry NCT01612364
Protocol 24 Where the full trial protocol can be accessed, if available Funding 25 Sources of funding and other support (such as supply of drugs), role of funders
37
*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and
Elaboration for important clarifications on all the items. If relevant, we also recommend reading
CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-
pharmacological treatments, herbal interventions, and pragmatic trials. Additional extensions are
forthcoming: for those and for up to date references relevant to this checklist, see www.consort-
statement.org.
physical therapy
pharmacological treatment
A
intervention
1 mo. 1 mo.
Study design
B
1 mo.
C
Figure 1
Assessed for eligibility (n=63 )
Excluded (n=12)
not meeting inclusion criteria (n=9)
declined to participate (n=3 )
Randomized (n= 37)
Allocated to TSB group (n=18)
Received allocated intervention (n= 17)
Did not receive allocated intervention (seizures)
(n= 1)
allocated to control group (n=19)
received allocated intervention (n=19)
did not receive allocated intervention (n= 0)
lost to follow-up (n=0 )
discontinued study (n= 0)
lost to follow-up (n=0 )
discontinued study(n=0)
analyzed 1 mo (n=17)
excluded from analysis (n=0 )
analyzed 1 mo (n=19)
excluded from analysis (n=0 )
Allocation
Assessment
Consent to participate (n=51)
improved after standardized
treatment (n=9)
use of former criteria (n=5)
analyzed 12 mo. (n=15)
lost follow up (n=2 )
analyzed 12 mo. (n=14)
lost follow up (n=5 ) Assessment
Figure 2
Contro
l TSB
* *
NR
S
*
*
Figure 3
Table 1 Baseline characteristics of study population
Characteristics
Control
(n=19) TSB (n=17) Total (n=36)
p
N (%) N (%) N %
N 19 (52.8) 17 (47.2) 36 (100.0)
0.51 Female 11 (57.9) 8(42.1) 19 (100.0)
Male 8 (47.1) 9(52.9) 17 (100.0)
Age (range) 44.48.9 42.013.5 44.711.1 0.70
Duration of pain (mo.) 2121.6 22.726.3 21.823.6 0.45
Right upper limb affected* 9 (47.4) 16 (94.1) 25 (69.4) 0.01
Left upper limb affected* 10 (52.6) 1 (5.9) 11 (30.6)
Presence of dystonia 2 (10.5) 5 (29.4) 7 (19.4) 0.15
Abnormal electromyography 9 (56.3) 9 (52.9) 18 (50) 1
Presence of myofascial pain syndrome 12 (63.2) 8 (47.1) 20 (55.6) 0.33
Triggering factors
Bone fracture
Contusion
Surgery
Work related musculoskeletal disorder
Medications in baseline
Use of angiotensin converting
enzyme (ACE) inhibitor
Use of tricyclic antidepressants
Use metamizole
Use tramadol
Use of acetaminophen
Use of NSAID
5 (26.3)
5 (26.3)
14 (73.7)
9 (47.4)
9 (47.4)
16 (84.2)
7 (36.8)
9 (47.3)
2 (10.5)
2 (10.5)
8 (47.1)
3 (17.6)
6 (35.3)
5 (29.4)
7 (41.2)
16 (94.1)
6 (35.3)
6 (35.3)
2 (11.8)
2 (11.8)
13 (36.1)
8 (22.2)
20 (55.6)
14 (38.9)
16 (44.4)
32 (88.9)
13 (36.1)
15 (41.7)
4 (11.1)
4 (11.1)
0.19
0.53
0.02*
0.27
0.71
0.56
0.98
0.86
0.53
0.53
Table 1
Systemic hypertension
Diabetes Mellitus
Smokers
Alcoholics
Illicit drug users
12(63.2)
4 (21.1)
6 (31.6)
3 (10.5)
1 (5.3)
6(35.3)
1 (5.9)
5 (25.0)
3 (18.8)
2 (11.8)
18(50)
5 (13.9)
11 (30.6)
6 (16.7)
3 (8.3)
0.10
0.19
0.67
0.53
0.53
Individual income (US$)
Sue issues
382 US$
5 (27.8)
315 US$
4 (25.0)
363US$
9 (25.0)
0.13
0.85 * P<0.05. Mann-Whitney Test Baseline data in values absolute frequencies (N), relative frequencies (%), mean and standard deviation.
Table 2
Results after TSB and control block during the study.
Group Baseline 1 month p 12 month p
Average NRS (BPI) Control
TSB 6.371.9
5.352.1
4.842.7
3.593.2
5.862.9
3.473.5*
0.046
Maximal NRS (BPI) Control
TSB 8.311.8
7.522.6
6.683.1♯
4.944.0♯
0.037
0.019 7.003.2
4.604.2♯
0.022
Minimum NRS (BPI) Control
TSB 4.742.5
4.351.9
4.102.8
2.942.9
4.003.0
2.133.1♯
0.003
Current NRS (BPI) Control
TSB 6.163.0
5.592.9
5.842.9
3.533.7*♯
0.045
0.035 5.503.6
3.403.8♯
0.035
Pain Interference (BPI) Control
TSB 6.622.6
6.682.3
5.463.0
4.812.9
5.243.5
3.543.6♯
0.005
MPQ Control
TSB 41.7813.4
48.3310.1
42.338.5
36.5616.2*
0.024 45.4323.6
27.2022.2*
0.042
NPSI TSB 6.162.1
5.511.9
5.562.4
4.172.8
5.163.3
3.612.8
NPSI (average evoked pain score) Control
TSB 7.011.6
5.591.7
5.931.7
3.431.8*♯
0.035
0.038 6.041.0
3.021.9*♯
0.020
0.024
DN4 Control
TSB 7.222.8
8.002.5
8.441.3
7.562.9
8.441.3
7.562.9
tramadol Control
TSB
47.4% (9/19)
31.3% (5/16)
52.6% (10/19)
18.8%(3/16)*♯
0.039
57.1% (8/14)
40% (6/15)
WHOQOL-bref Control
TSB 52.971.7
53.672.2
45.151.3
53.153.0
HADS-Anxiety Control
TSB 11.335.6
13.112.5
12.332.9
10.114.3
HADS-Depression Control
TSB 9.895.75
10.782.2
11.222.9
9.893.4*
0.035
DASH Control 90.219.8 78.221♯ 0.003
Table 2
TSB 87.419.1 75.523.2♯ 0.004
Data are shown as means ± SE. ♯p<0.05 [effect of time] *p < 0.05 [effect of group]. NRS: numeric rating scale (0-10).
BPI (Brief Pain Inventory); MPQ (McGill Pain Questionnaire), NPSI (Neuropathic Pain Symptom Inventory), evoked pain subscore (NPSI questions
8, 9 and 10), DN4 (Douleur Neuropathique-4), WHOQOL-bref (World Health Organization Quality of Life Questionnaire short form), HADS
(Hospital Anxiety and Depression Scale) DASH (Disabilities of Arm, Shoulder and Hand questionnaire).