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PAIN 155 (2014) 2274–2281
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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 a,⇑, Manoel Jacobsen Teixeira a,b, Lin Tchia Yeng a,c, Mirlene Gardin Cantara a,c,
Viviane Gentil Faria a,c, Victor Liggieri a,c, Adrianna Loduca a, Barbara Maria Müller a, Andrea C.M.S. Souza a,
Daniel Ciampi de Andrade a,d
a
Pain Center, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil
Neurosurgery Division, Department of Neurology, School of Medicine, University of São Paulo, São Paulo, Brazil
Physical Medicine, Department of Orthopedics, School of Medicine, University of São Paulo, São Paulo, Brazil
d
Instituto do Câncer do Estado de São Paulo Octávio Frias de Oliveira, University of São Paulo, São Paulo, Brazil
b
c
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history:
Received 18 March 2014
Received in revised form 12 August 2014
Accepted 13 August 2014
Keywords:
Complex regional pain syndrome
Sympathetic nerve block
Upper limbs
Thoracic column
a b s t r a c t
Pain relief in complex regional pain syndrome (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. The study objective was to evaluate the analgesic effect of TSB in CRPS. Patients with CRPS type
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), pain dimensions (McGill Pain Questionnaire [MPQ]), neuropathic characteristics (Neuropathic
Pain Symptom Inventory [NPSI]), mood, upper limb function (Disabilities of Arm, Shoulder and Hand), and
quality of life were assessed before, and at 1 month and 12 months after the procedure. Thirty-six patients
(19 female, 44.7 ± 11.1 years of age) underwent the procedure (17 in the TSB group). Average pain intensity
at 1 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 (Hospital Anxiety and Depression Scale) were significantly lower in the TSB group compared to the control group at 1 and at 12 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.
Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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
⇑ Corresponding author. Address: Divisão de Clínica Neurocirúrgica do Hospital
das Clínicas da FMUSP, Secretaria da Neurologia, Instituto Central, Av. Dr. Enéas de
Carvalho Aguiar, 255, 5° andar, sala 5084 – Cerqueira César, São Paulo, SP 05403900, Brazil. Tel./fax: +55 11 26 61 71 52.
E-mail address: [email protected] (R.O. Rocha).
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 [4,17,50].
Different techniques of sympathetic blocks are frequently
grouped together in efficacy analyses and CRPS reviews [49]. However, these procedures are not all similar, and their clinical efficacy
may depend on variables such as the target anatomical structures,
http://dx.doi.org/10.1016/j.pain.2014.08.015
0304-3959/Ó 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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R.O. Rocha et al. / PAIN 155 (2014) 2274–2281
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 [6,26,27,38].
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 second (and to a lesser extent
in the third) 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 2 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 [1,57].
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 12-month randomized, double-blinded,
active-control study to evaluate the efficacy of TSB for upper limb
CRPS type I.
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.
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
International Association for the Study of Pain 1994 diagnostic criteria for CRPS type I were used in 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 [24,51]. To be eligible, adult patients (18–70 years) needed to
have CRPS I for at least 6 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
(eg, 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
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rehabilitation and pharmacological treatment (Fig. 1) for 4 weeks
consisting of the following:
a. A physical therapy program guided by a physiatrist and
physical therapists. The standardized physical therapy program included a once-weekly session for 8 weeks (4 weeks
before and 4 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), nonantiinflammatory 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 4 times a day [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
(Fig. 1).
c. Psychological assessment: 2 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 (Fig. 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 (Fig. 1).
From the 8th to the 52nd week of the study (ie, from 4 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 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 and 1- 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 1 and 12 months after
the procedure (Fig. 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) [9,48] and
its symptom profile based on the Neuropathic Pain Symptoms Inventory (NPSI) [10,15] 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) (Fig. 1).
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R.O. Rocha et al. / PAIN 155 (2014) 2274–2281
Study design
intervention
C
B
A
pharmacological treatment
physical therapy
1 mo.
1 mo.
1 mo.
Fig. 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. 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; DASH, Disabilities of Arm,
Shoulder and Hand questionnaire; WHOQOL-bref, World Health Organization Quality of Life Questionnaire short form; HADS, Hospital Anxiety and Depression Scale; TSB,
thoracic sympathetic block.
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 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 (B. Braun, Melsungen, Germany) needle for spinal
anesthesia was positioned in the T2 plane under fluoroscopic guidance (Supplementary Fig. 1). The needle was inserted into the skin
and advanced to 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 (Supplementary Fig. 1). 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 (Supplementary Fig. 1B). Fluoroscopic
films documented the procedure. After blocking, the temperature
in the limb was measured using a touch thermometer (TS-201,
Techline, São Paulo, Brazil) over the volar aspect of the forearm
at operating room temperature 21 ± 2°C. A difference > 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 1 and 12 months after the blocking procedure. Secondary
outcomes measures were the other pain intensity and interference
scores from the BPI, NPSI, and MPQ at 1 and 12 months after the
blocking procedure. Quality of life (WHOQOL-bref) and mood
(HADS) were assessed before and 12 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 1 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 to undergo the procedure
again if it was offered to you? (yes/no).
2.8. Sample size and data analysis
This study was powered to detect a 2-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 4 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 (eg, 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% (2-sided), and a 20% of estimation error. Then, 50 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): a 6 5% risk of committing a type I error and a b 6 20% risk
of committing a type II error. Data were expressed as the
means ± SDs. The Kolmogorov-Smirnov test for normality was
performed on the quantitative variables. Nonparametric data were
compared with the Kruskal-Wallis, Mann-Whitney Test, and
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R.O. Rocha et al. / PAIN 155 (2014) 2274–2281
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 v2 test. When categories
had < 20 individuals, we adopted the Fisher’s exact test. We
assumed, throughout the study, a 6 5% risk of committing type I,
and 20% b risk of committing type II errors.
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, 14 patients were
excluded before undergoing the blocking procedure: 5 had been
screened for CRPS based on the previous diagnostic criteria, and
9 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, 36 patients underwent
the blocking procedure (TSB; n = 17, control n = 19). After the
12-month follow-up, 15 patients were available for evaluation in
the TSB group (2 lost) and 14 were available in the control group
(5 lost) (Fig. 2).
3.1. Patient characteristics
Nineteen women (52.8%) participated in the study (8 [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).
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
> 2°C increase on the treated hand right after the procedure. Local
Assessed for eligibility (n=63 )
Excluded (n=12)
not meeting inclusion criteria (n=9)
declined to participate (n=3 )
Consent to participate (n=51)
improved after standardized
treatment (n=9)
use of former criteria (n=5)
Randomized (n= 37)
Allocation
Allocated to TSB group (n=18)
Received allocated intervention (n= 17)
Did not receive allocated intervention (seizures)
(n= 1)
Assessment
Assessment
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 )
analyzed 12 mo. (n=15)
lost follow up (n=2 )
analyzed 12 mo. (n=14)
lost follow up (n=5 )
Fig. 2. Study flowchart. TSB, thoracic sympathetic block.
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R.O. Rocha et al. / PAIN 155 (2014) 2274–2281
Table 1
Baseline characteristics of study population.
Characteristics
Control (n = 19)
n (%)
TSB (n = 17)
n (%)
Total (n = 36)
n%
P-value
n
Female
Male
Age (range)
Duration of pain (mo.)
Right upper limb affected*
Left upper limb affected*
Presence of dystonia
Abnormal electromyography
Presence of myofascial pain syndrome
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
Systemic hypertension
Diabetes mellitus
Smokers
Alcoholics
Illicit drug users
Individual income (US$)
Sue issues
19 (52.8)
11 (57.9)
8 (47.1)
44.4 ± 8.9
21 ± 21.6
9 (47.4)
10 (52.6)
2 (10.5)
9 (56.3)
12 (63.2)
17 (47.2)
8 (42.1)
9 (52.9)
42.0 ± 13.5
22.7 ± 26.3
16 (94.1)
1 (5.9)
5 (29.4)
9 (52.9)
8 (47.1)
36 (100.0)
19 (100.0)
17 (100.0)
44.7 ± 11.1
21.8 ± 23.6
25 (69.4)
11 (30.6)
7 (19.4)
18 (50)
20 (55.6)
0.51
5 (26.3)
5 (26.3)
14 (73.7)
9 (47.4)
8
3
6
5
(47.1)
(17.6)
(35.3)
(29.4)
13 (36.1)
8 (22.2)
20 (55.6)
14 (38.9)
0.19
0.53
0.02*
0.27
9 (47.4)
16 (84.2)
7 (36.8)
9 (47.3)
2 (10.5)
2 (10.5)
12 (63.2)
4 (21.1)
6 (31.6)
3 (10.5)
1 (5.3)
382 US$
5 (27.8)
7 (41.2)
16 (94.1)
6 (35.3)
6 (35.3)
2 (11.8)
2 (11.8)
6(35.3)
1 (5.9)
5 (25.0)
3 (18.8)
2 (11.8)
315 US$
4 (25.0)
16 (44.4)
32 (88.9)
13 (36.1)
15 (41.7)
4 (11.1)
4 (11.1)
18 (50)
5 (13.9)
11 (30.6)
6 (16.7)
3 (8.3)
363US$
9 (25.0)
0.71
0.56
0.98
0.86
0.53
0.53
0.10
0.19
0.67
0.53
0.53
0.13
0.85
0.70
0.45
0.01
0.15
1
0.33
NSAID, nonsteroidal antiinflammatory drug.
Baseline data in values absolute frequencies (n), relative frequencies (%), mean, and SD.
*
P < 0.05. Mann-Whitney Test.
*
*
Control
TSB
**
NRS
temperature ranged from 27.1 ± 3.1°C before to 35.9 ± 0.8°C 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 8 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 P 50% attendance to the sessions. All
participants had 100% compliance to the physical therapy sessions
performed before the blocking procedure (total of 4 sessions).
3.3. Primary and secondary outcomes
The mean of the BPI average pain intensity item at 1 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) (Fig. 3). Some secondary
outcome measures improved after TSB. Compared to baseline values, the current pain intensity score (BPI) at 1 month decreased from
5.59 ± 2.9 to 3.53 ± 3.7 (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 1 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 1 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), 1 month after the
Fig. 3. Numeric-rating scale of average pain (Brief Pain Inventory) scores in patients
receiving thoracic sympathetic block (TSB) or control block (control). Bars represent
mean and lines represent SD. ⁄P < 0.05. NRS, numeric rating scale.
nerve block (Table 2). There were no significant differences
between the groups in the number of patients taking other rescue
drugs, including morphine, at 1 month or 12 months after the
blocking procedure (2 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 12 months after the procedure, except on 4 subitems (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,
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R.O. Rocha et al. / PAIN 155 (2014) 2274–2281
Table 2
Results after TSB and control block during the study.
Average NRS (BPI)
Maximal NRS (BPI)
Minimum NRS (BPI)
Current NRS (BPI)
Pain interference (BPI)
MPQ
NPSI
NPSI (average evoked pain score)
DN4
Tramadol
WHOQOL-bref
HADS-Anxiety
HADS-Depression
DASH
Group
Baseline
1 month
Control
TSB
Control
TSB
Control
TSB
Control
TSB
Control
TSB
Control
TSB
TSB
6.37 ± 1.9
5.35 ± 2.1
8.31 ± 1.8
7.52 ± 2.6
4.74 ± 2.5
4.35 ± 1.9
6.16 ± 3.0
5.59 ± 2.9
6.62 ± 2.6
6.68 ± 2.3
41.78 ± 13.4
48.33 ± 10.1
6.16 ± 2.1
5.51 ± 1.9
7.01 ± 1.6
5.59 ± 1.7
7.22 ± 2.8
8.00 ± 2.5
47.4% (9/19)
31.3% (5/16)
52.97 ± 1.7
53.67 ± 2.2
11.33 ± 5.6
13.11 ± 2.5
9.89 ± 5.75
10.78 ± 2.2
90.2 ± 19.8
87.4 ± 19.1
4.84 ± 2.7
3.59 ± 3.2
6.68 ± 3.1]
4.94 ± 4.0]
4.10 ± 2.8
2.94 ± 2.9
5.84 ± 2.9
3.53 ± 3.7*,]
5.46 ± 3.0
4.81 ± 2.9
42.33 ± 8.5
36.56 ± 16.2*
5.56 ± 2.4
4.17 ± 2.8
5.93 ± 1.7
3.43 ± 1.8*,]
8.44 ± 1.3
7.56 ± 2.9
52.6% (10/19)
18.8%(3/16)*,]
Control
TSB
Control
TSB
Control
TSB
Control
TSB
Control
TSB
Control
TSB
Control
TSB
78.2 ± 21]
75.5 ± 23.2]
P-value
0.037
0.019
0.045
0.035
0.024
0.035
0.038
0.039
12 month
P-value
5.86 ± 2.9
3.47 ± 3.5*
7.00 ± 3.2
4.60 ± 4.2]
4.00 ± 3.0
2.13 ± 3.1]
5.50 ± 3.6
3.40 ± 3.8]
5.24 ± 3.5
3.54 ± 3.6]
45.43 ± 23.6
27.20 ± 22.2*
5.16 ± 3.3
3.61 ± 2.8
6.04 ± 1.0
3.02 ± 1.9*,]
8.44 ± 1.3
7.56 ± 2.9
57.1% (8/14)
40% (6/15)
45.15 ± 1.3
53.15 ± 3.0
12.33 ± 2.9
10.11 ± 4.3
11.22 ± 2.9
9.89 ± 3.4*
0.046
0.022
0.003
0.035
0.005
0.042
0.020
0.024
0.035
0.003
0.004
TSB, thoracic sympathetic block; 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. Data are shown as means ± SE.
]
P < 0.05 [effect of time].
*
P < 0.05 [effect of group].
the depression scores were significantly lower in the TSB group
compared to the control group at 12 months (Table 2). Scores from
the DN4 and DASH did not differ between the groups.
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 outpatient clinic and were available
for supplementary assessment during follow-up. Because the trial
only included 3 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).
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 1 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 2 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 1 week after a single
TSB procedure in 85 CRPS patients [1,57]. These studies assessed
pain intensity based on the visual analogue scale and Likert scale,
with no specific measurements of neuropathic pain components,
mood, or quality of life [1,57]. 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 2 were double-blinded [3,43].
In 5 studies, the blinding procedure was unclear [7,37,45,52,56],
and one was not blinded at all [47]. The number of patients
included in these trials ranged from 4 to 82 [43,47]. The timing
of assessment also was quite variable, ranging from right after
the blocking procedure [43] to 3 months post treatment [47]. Some
studies (n = 6) used control blocks with active drugs such as
guanethidine [7], lidocaine with clonidine [37], phentolamine
[45,56], or continuous infraclavicular brachial plexus block [52].
In one study, physical therapy was added to the baseline treatment
[47]. Two placebo-controlled studies were negative [3,43]. The
2280
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R.O. Rocha et al. / PAIN 155 (2014) 2274–2281
remaining active-control studies reported negative (n = 5)
[7,37,45,52,56] 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 et al. [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 detected
only 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
[32,55]. 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 dorsal root ganglia, sympathetic ganglion, and the spinal
cord, and this has been suggested as a possible underlying mechanism of the development of CRPS [5,13,23,30,34,54]. 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 [11,19,28,53]. Triamcinolone long-acting repository formulations are absorbed slowly from the injection site and provide
anti-inflammatory effects for 1–4 weeks. The hypothalamicpituitary-adrenal axis may be inhibited for up to 6 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 activecontrol 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 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 1-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 computed tomography scans, adverse events occurred
in 7.1% of the procedures and included 3 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 (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 CRPS type I 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.
Conflict of interest statement
There are no conflicts of interest to report.
Acknowledgements
The Pain Center, Neurology Department, University of São
Paulo, Brazil funded this study.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.pain.2014.08.015.
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R.O. Rocha et al. / PAIN 155 (2014) 2274–2281
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