Bloqueo simpático con anestésicos locales para el síndrome de dolor regional complejo
Resumen
Antecedentes
Esta revisión es una actualización de una revisión publicada anteriormente en la Base de Datos Cochrane de Revisiones Sistemáticas (Cochrane Database of Systematic Reviews), 2005, número 4 (y actualizada por última vez en la Base de Datos Cochrane de Revisiones Sistemáticas, 2013 número 8), sobre el bloqueo anestésico local (BSAL) de la cadena simpática para tratar a personas con síndrome de dolor regional complejo (SDRC).
Objetivos
Evaluar la eficacia del BSAL para el tratamiento del dolor en el SDRC y evaluar la incidencia de efectos adversos del procedimiento.
Métodos de búsqueda
Para esta actualización se hicieron búsquedas en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials, CENTRAL) (2015, número 9), MEDLINE (Ovid), EMBASE (Ovid), LILACS (Birme), resúmenes de conferencias de los World Congresses of the International Association for the Study of Pain y en varios registros de ensayos clínicos hasta septiembre de 2015. También se examinó la bibliografía de los artículos identificados en busca de estudios adicionales.
Criterios de selección
Se consideraron los ensayos controlados aleatorizados (ECA) que evaluaron el efecto del bloqueo simpático con anestésicos locales en niños o adultos con SDRC en comparación con placebo, ningún tratamiento o tratamientos alternativos.
Obtención y análisis de los datos
Se utilizaron los procedimientos metodológicos estándar previstos por Cochrane. Los desenlaces de interés fueron la reducción de la intensidad del dolor, la proporción de personas que lograron un alivio moderado o considerable del dolor, la duración del alivio del dolor y la presencia de efectos adversos en cada grupo de tratamiento. La evidencia se evaluó mediante GRADE (Grading of Recommendations Assessment, Development and Evaluation) y se creó una tabla "Resumen de los hallazgos".
Resultados principales
En esta actualización se incluyeron cuatro estudios adicionales (n = 154). En esta actualización se excluyeron los estudios que no hicieron un seguimiento de los pacientes durante más de 48 horas. Como resultado, se excluyeron cuatro estudios de la revisión anterior en esta actualización. En general se incluyeron 12 estudios (n = 461) y todos se consideraron con riesgo de sesgo alto o poco claro. La calidad de la evidencia fue baja a muy baja, disminuida debido a las limitaciones, la inconsistencia, la imprecisión, las medidas indirectas o una combinación de estas.
Dos estudios pequeños compararon BSAL con placebo/simulación (n = 32). No demostraron un efecto beneficioso significativo a corto plazo del BSAL en cuanto a la intensidad del dolor (evidencia de calidad moderada).
Un estudio pequeño (n = 36) con alto riesgo de sesgo comparó el bloqueo simpático torácico con corticosteroide y anestésico local versus la inyección de los mismos agentes en el espacio subcutáneo, e informó de diferencias estadísticamente significativas y clínicamente importantes en la intensidad del dolor al año de seguimiento, pero no en el seguimiento a corto plazo (evidencia de calidad muy baja).
De los dos estudios que investigaron el BSAL agregado al tratamiento de rehabilitación, el único estudio que informó sobre los desenlaces de dolor no demostró efectos beneficiosos adicionales del BSAL (evidencia de calidad muy baja).
Ocho estudios aleatorizados pequeños compararon el bloqueo simpático con varias otras intervenciones activas. La mayoría de los estudios no encontraron diferencias en los desenlaces de dolor entre el bloqueo simpático versus otros tratamientos activos (evidencia de calidad baja a muy baja).
Un estudio pequeño comparó el BSAL guiado por ecografía con el BSAL no guiado y no encontró diferencias clínicamente importantes en los desenlaces de dolor (evidencia de calidad muy baja).
Seis estudios informaron sobre eventos adversos, todos ellos con efectos leves informados.
Conclusiones de los autores
Los resultados de esta actualización son similares a los de las versiones anteriores de esta revisión sistemática y las principales conclusiones no han cambiado. Todavía existe escasez de evidencia publicada y falta de evidencia de calidad alta para apoyar o refutar el uso del bloqueo simpático con anestésicos locales para el SDRC. A partir de la evidencia existente no es posible establecer conclusiones firmes con respecto a la eficacia ni la seguridad de esta intervención, pero los datos limitados disponibles no indican que el BSAL sea eficaz para reducir el dolor en el SDRC.
PICO
Resumen en términos sencillos
Bloqueo simpático con anestésicos locales para el síndrome de dolor regional complejo
Antecedentes
El bloqueo simpático con anestésicos locales (BSAL) es un tratamiento frecuente para el síndrome de dolor regional complejo (SDRC). Implica el bloqueo de la actividad de los nervios simpáticos a lo largo de la columna vertebral. El sistema nervioso simpático controla principalmente las acciones inconscientes como el ritmo cardíaco, el flujo sanguíneo y la transpiración. La inyección de un fármaco anestésico local alrededor de los nervios bloquea temporalmente la función de los mismos. Esta revisión actualizada procuró resumir la evidencia disponible con respecto a si el BSAL es efectivo para reducir el dolor en el SDRC, cuánto tiempo puede durar cualquier alivio del dolor y si el BSAL es seguro.
Resultados clave y calidad de la evidencia
En septiembre de 2015, se encontró un número limitado de ensayos pequeños, todos con deficiencias en el diseño. No se encontró evidencia de que el BSAL fuera mejor que placebo para reducir el dolor o que proporcionara un alivio adicional del dolor cuando se añadía a la rehabilitación. Aunque varios estudios pequeños compararon el BSAL con otros tratamientos, la mayoría no encontró que el BSAL fuera mejor. En un estudio pequeño se comprobó que inyectar los nervios simpáticos torácicos (parte superior de la espalda) con anestesia local y esteroides fue mejor que inyectar los mismos fármacos justo debajo de la piel en el seguimiento de un año, pero el estudio puede haber sido propenso a sesgo. Sólo seis estudios informaron sobre el tipo y la cantidad de efectos secundarios. Estos estudios informaron sólo de efectos secundarios leves, pero como algunos estudios no proporcionaron esta información no es posible establecer conclusiones firmes sobre la seguridad del BSAL. En general, la evidencia fue de calidad baja o muy baja.
En general, la evidencia es limitada, contradictoria y de calidad baja. Aunque no es posible establecer conclusiones firmes, la evidencia existente no es alentadoras.
Authors' conclusions
Summary of findings
| Patient or population: adults with CRPS Setting: secondary care Intervention/comparison: LASB vs various comparisons Outcome: pain intensity 0‐10 (VAS or NRS) | ||||
| Comparison | Studies | No of participants | Result (effect estimates reported where available from study report) | Quality of the evidence |
|---|---|---|---|---|
| LASB vs placebo | 23 (2) | No significant between‐group difference | ⊕⊕⊕⊝ Moderatea | |
| Thoracic LASB + steroid vs subcutaneous local anaesthetic+ steroid | 36 (1) | Favours LASB Mean difference (0‐10 scale) One month −1.25 (95% CI −3.2 to 0.7) One year −2.39 (95% CI −4.72 to −0.06) | ⊕⊝⊝⊝ Very lowb | |
| LASB vs ultrasound block | 18 (1) | No significant between‐group difference | ⊕⊕⊝⊝ Lowc | |
| LASB vs IVRB guanethidine | 19 (1) | No significant between‐group difference | ⊕⊝⊝⊝ Very lowb | |
| LASB lumbar plexus vs pulsed radiofrequency lumbar plexus | 40 (1) | No significant between‐group difference | ⊕⊝⊝⊝ Very lowb | |
| LASB (lidocaine + clonidine) vs IVRB (lidocaine + clonidine) | 43 (1) | No significant between‐group difference | ⊕⊝⊝⊝ Very lowb | |
| LASB + PT+ pharmacological vs PT + pharmacological | 82 (1) | Favours SGB group | ⊕⊝⊝⊝ Very lowb | |
| LASB + PT vs PT | 60 (1) | No significant between‐group difference | ⊕⊝⊝⊝ Very lowb | |
| Continuous LASB vs continuous brachial plexus block | 33 (1) | Favours brachial plexus block | ⊕⊕⊝⊝ Lowc | |
| Image‐guided LASB vs nonimage‐guided LASB | 42 (1) | Mean difference 2 weeks postinjection −0.58 (95% CI −1.51 to 0.35) 4 weeks postinjection −0.74 (95% CI −1.36 to −0.12) | ⊝⊝⊝⊝ Very lowd | |
| Outcome: hand pain 0‐3 scale | ||||
| LASB vs oral corticosteroids | 38 (1) | 15 day follow‐up, no significant between‐group difference at 30 day follow‐up 0.4 (95% CI −0.69 to −0.11), favours LASB with steroid | ⊝⊝⊝⊝ Very lowd | |
| Outcome: duration of pain relief | ||||
| LASB bupivacaine + BTA vs LASB bupivacaine | 9 (1) | Increased duration of relief with BTA Median time to analgesic failure (days): LASB bupivacaine + BTA 71 (95% CI 12 to 253) LASB bupivacaine 10 (95%CI 0 to 12) | ⊕⊕⊝⊝ Lowc | |
| a Downgraded once for imprecision. | ||||
Background
This review is an update of a previously published review in the Cochrane Database of Systematic Reviews, 2005, Issue 4 (and last updated in the Cochrane Database of Systematic Reviews, 2013 Issue 8), on local anaesthetic sympathetic blockade for complex regional pain syndrome.
Description of the condition
Complex regional pain syndrome (CRPS) is an umbrella term for a variety of clinical presentations characterised by chronic persistent pain that is disproportionate to any preceding injury (if any) and that is not restricted anatomically to the distribution of a specific peripheral nerve (Bruehl 2010). The International Association for the Study of Pain (IASP) introduced the diagnostic label of CRPS in the 1990s (Merskey 1994), and since then, others have updated it in an attempt to improve its specificity (Harden 2006; Harden 2010). We present these modified diagnostic criteria (the 'Budapest criteria') in Table 1. The term CRPS encompasses a variety of earlier diagnostic terms, including reflex sympathetic dystrophy (RSD), reflex neurovascular dystrophy, Sudeck's atrophy, causalgia, and algodystrophy/algoneurodystrophy (Stanton‐Hicks 1995). CRPS can be classified into two subtypes: CRPS‐I, in which there is no identified peripheral nerve injury, and CRPS‐II, where symptoms are associated with a definable nerve lesion (Harden 2006). This distinction is not always easily made (Harden 2006). Both subtypes of CRPS are characterised by severe pain that is disproportionate to the inciting event, most commonly affecting the hand or foot but sometimes spreading to other body regions (Stanton‐Hicks 2002; Van Rijn 2011). Additionally CRPS presents with some or all of the following symptoms in the affected body parts: sensory disturbances; temperature changes; abnormal patterns of perspiration; swelling/oedema; reduced joint range of motion; movement abnormalities such as weakness, tremor, or dystonia; trophic changes such as skin atrophy, altered hair and nail growth, or localised osteoporotic changes (Bruehl 2010; De Mos 2009; Shipton 2009); and alterations in body perception (Lewis 2007; Lotze 2007; Moseley 2006). CRPS occurs most commonly following wrist fracture and subsequent immobilisation. However, cases can potentially occur after relatively minor trauma and may even occur spontaneously, albeit rarely (De Mos 2007; De Mos 2008; Sandroni 2003). The underlying pathophysiological mechanisms of CRPS are incompletely understood, although there is growing consensus that it is primarily a disorder of the nervous system. Research has identified abnormalities in the tissues of the affected area and the peripheral and central nervous systems (Jänig 2003; Marinus 2011). These include signs of increased neurogenic inflammation (Birklein 2001; Schinkel 2006; Schmelz 2001), an altered local immune response (Birklein 2014; Tan 2005), altered activity in the sympathetic nervous system (SNS) (Drummond 2004; Niehof 2006), increased sensitivity to normal SNS activity (Albrecht 2006; Ali 2000; Drummond 2001), and local tissue hypoxia (Birklein 2000; Koban 2003). Studies have also demonstrated changes in the brain in CRPS (Swart 2009), including alterations of the cortical (higher brain) representation of the affected body part (Maihöfner 2004; Pleger 2006), localised reductions in grey matter density and connectivity (Geha 2008), and altered inhibitory control (Schwenkreis 2003).
| To make the clinical diagnosis, the following criteria must be met:
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| 1. Continuing pain, which is disproportionate to any inciting event
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| 2. Must report at least one symptom in three of the four following categories.
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| 3. Must display at least one sign at time of evaluation in two or more of the following categories:
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| 4. There is no other diagnosis that better explains the signs and symptoms
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For research purposes, diagnostic decision rule should be at least one symptom in all four symptom categories and at least one sign (observed at evaluation) in two or more sign categories. A sign is counted only if it is observed at time of diagnosis.
Description of the intervention
Sympathetic blockade includes procedures that aim to temporarily impede the local function of the sympathetic nervous system. Usually an anaesthesiologist performs the procedure, injecting local anaesthetic directly into sympathetic neural structures that serve the affected limb(s) such as the stellate ganglion or the lumbar sympathetic chain (Nelson 2006). Radiologic guidance such as fluoroscopy or computerised tomography (CT) scan often ensures the accuracy of needle tip placement, and successful blockade is often monitored by direct (e.g., galvanic skin response) or indirect (increase in blood flow to the extremity or increase in temperature) assessment (Breivik 2009). This approach is distinct from the injection of neurolytic agents in an effort to destroy sympathetic nerves. LASBs are also commonly called stellate ganglion blockades (SGB) or, when performed in the lower body, lumbar sympathetic blockades (LSB).
How the intervention might work
People with persistent pain following nerve injury have long been observed to have abnormalities of autonomic nervous system function in the affected limb (temperature, blood flow, sweating) and abnormal skin texture or hair and nail growth attributed, at least in part, to local autonomic dysfunction (Bruehl 2010; De Mos 2009). Early uncontrolled observations of persistent improvement in signs and symptoms following local anaesthetic sympathetic blockade in people with what is now termed CRPS suggested that excessive sympathetic activity provoked or perpetuated this type of persistent pain (Campbell 1996). However, recent evidence regarding adrenaline content in venous effluents from affected limbs has not supported this hypothesis and suggests instead that any benefit of sympathetic blockade in CRPS may reflect transient reversal of a heightened local sensitivity to adrenaline (Binder 2009). These clinical impressions of persistent benefit from transient local anaesthetic sympathetic blockade in CRPS, reinforced by similar longstanding impressions of prolonged benefit after temporary local anaesthetics blockade in peripheral neuralgias, led to the incorporation of sympathetic block into current consensus treatment algorithms for CRPS (Carr 2011), although doubt remains over the contribution of the sympathetic nervous system to pain and the concept of sympathetically maintained pain in CRPS (Harden 2013).
Why it is important to do this review
Despite preclinical evidence that suggests the sympathetic nervous system is involved in the pathophysiology of CRPS, there is debate surrounding the contribution of the sympathetic nervous system to the clinical syndrome (Ochoa 1995; Schott 1995; Verdugo 1994a; Verdugo 1994b). The value of blocking the sympathetic nervous system is also disputed (Fine 1994; Hogan 1997; Jadad 1995; Verdugo 1994a). It is therefore important to evaluate the efficacy of sympathetic blockade with local anaesthetic in the treatment of CRPS. A meta‐analysis of the effect of sympathetic blockade with local anaesthetics in people with CRPS reported that up to 44% of those subjected to sympathetic blockade would be expected to have no pain relief. Due to the lack of randomised controlled trials, investigators obtained this estimate from pooling the results of observational studies (Cepeda 2002). Moreover, the review only evaluated English‐language studies, and it could have overlooked relevant RCTs. Hence, to overcome this limitation, we decided to perform a systematic review of the literature with no language restriction to determine both the efficacy and safety of sympathetic blockade with local anaesthetics to alleviate pain in people with CRPS.
Objectives
To assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure.
Methods
Criteria for considering studies for this review
Types of studies
We considered randomised controlled trials (RCTs). As blinding of sympathetic block is not always possible, we included trials that were either double‐blind, single‐blind, or open. We included studies that compared LASB with placebo interventions, no treatment, or alternative interventions. We also included studies that investigated the effect of adding LASB to other interventions.
Types of participants
We included studies that evaluated the effect of sympathetic blockade with local anaesthetics to treat CRPS in children or adults. We included studies even if the authors did not describe the constellation of symptoms necessary to diagnose CRPS and stated only that "patients with RSD/CRPS were included". We took this approach to avoid excluding any of the relatively few RCTs of this intervention. We placed no restrictions regarding the number of participants recruited to trials.
We excluded trials that evaluated sympathetic blockade for other pain syndromes such as radiculopathy, herpes zoster, postherpetic neuralgia, fibromyalgia, or phantom pain.
Types of interventions
We included studies that evaluated selective sympathetic blockade with local anaesthetics. We excluded studies that only evaluated somatic nerve blocks or studies that evaluated the effect of local anaesthetics or sympatholytic drugs administered orally, intravenously, or epidurally. We excluded studies that reported the results of combined sympatholytic therapies, such as surgical sympathectomy or guanethidine intravenous regional block plus local anaesthetic blockade of the sympathetic chain. We also excluded studies of ganglionide local opioid analgesia (GLOA), a technique in which clinicians locally inject opioids such as buprenorphine into the stellate ganglion, because this procedure does not block sympathetic activity.
Types of outcome measures
The outcomes of interest were pain intensity levels, duration of pain relief. and adverse events. For this update, we excluded studies that had only immediate follow‐up data (≤ 48 h), because this information provides little clinically relevant information about the effectiveness of this treatment. We applied this new criterion to studies that had been included in previous updates of this review.
Search methods for identification of studies
For this update, we used identical search strategies to that of our 2013 review update. For the search strategies, see Appendix 1 for the Cochrane Central Register of Controlled Trials (CENTRAL), Appendix 2 for MEDLINE, Appendix 3 for EMBASE, and Appendix 4 for LILACS.
We performed the search for the original review from November 2003 to January 2004 updated it on 17 November 2011 and 22 November 2012 (2013 update). The present update encompasses searches run from 22 November 2012 to 16 September 2015.
We evaluated non‐English language papers for inclusion.
For the 2016 update, we did not search the Cochrane Pain, Palliative and Supportive Care Group Specialised Register, as it is no longer updated.
Electronic searches
We searched the following databases for the update of this review.
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CENTRAL (The Cochrane Library 2015, Issue 9).
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MEDLINE (Ovid) (1966 to September 2015).
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EMBASE (Ovid) (1974 to September 2015).
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LILACS (Birme) (1982 to September 2015).
Searching other resources
Reference lists
We searched the bibliographies of retrieved articles for additional studies.
Unpublished studies
In order to minimise the impact of publication bias, we reviewed conference abstracts of the World Congresses of the International Association for the Study of Pain from 1995 up to 2014. For this update, we expanded the search of the original review by also searching relevant clinical trial registers (from inception) for upcoming trials. We searched the following clinical trial registers: the controlled trials register (15 October 2015; www.controlled-trials.com/), the United States National Institute of Health service ClinicalTrials.gov (15 October 2015; www.clinicaltrials.gov/); the Australian New Zealand Clinical trials register (15 October 2015; www.anzctr.org.au/), and the European Clinical Trials Register (7 December 2012; www.clinicaltrialsregister.eu/).
Personal contact
We attempted to communicate with authors if we needed additional information that was not provided in the trial report. In addition, we provided the reference list of included studies to experts in the field to determine if any additional references were appropriate for the review.
Data collection and analysis
Selection of studies
Two review authors independently read each of the titles and abstracts of the reports identified by the search and discarded narrative reviews, case series, and case reports. If there was no abstract, we retrieved the full‐text report. If there was disagreement, the authors met to reach consensus, consulting an independent third review author if necessary. We retrieved in full all abstracts and reports that made reference to a trial of sympathetic blockade with local anaesthetics. Two review authors then independently assessed the full‐text articles. We did not anonymise the reports for the assessment.
Data extraction and management
Two review authors independently extracted the data. If there was disagreement, they met to reach consensus, consulting an independent third review author if necessary. We extracted the following data from each study.
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Study details: study design (parallel or cross‐over), method of randomisation, presence or absence of blinding.
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Demographic characteristics: age, sex, number of participants recruited, number of study withdrawals or drop‐outs, if any.
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Participant clinical characteristics: duration of pain before sympathetic block, site of pain (arm, leg, mixed, or other such as facial).
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Type of noxious initiating event (if known): surgery, fracture, crush injury, projectile, or stab injury.
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Type of tissue injured: nerve, soft tissue, bone.
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Presence of medico‐legal factors that may influence the experience of pain and the outcomes of therapeutic interventions.
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Concomitant treatments that may affect outcome: antidepressants, physical therapy, etc.
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Treatment characteristics: site of sympathetic block (cervical or lumbar), type of local anaesthetic used (including concentration and volume), evaluation of the technical adequacy of the block, duration of follow‐up, duration of the pain relief, number of blocks performed, method of pain assessment, and presence of complications or adverse effects.
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Information on postprocedure analgesic requirements.
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Information on conflicts of interest and statements of study support.
If authors reported pain intensity using a visual analogue scale or numeric rating scale, we extracted the mean and standard deviation of pain intensity in each study arm. If authors reported pain relief, we extracted the proportion of participants in each category of pain relief.
Assessment of risk of bias in included studies
We used a modified version of the Cochrane 'Risk of bias' tool with additional domains added in response to the recommendations of Moore 2010. On this basis we added two domains, 'size' and 'duration', using the thresholds for judgement suggested by Moore 2010. We have not added the 'outcome' domain as this is covered already by our choice of primary outcome measures. Thus in addition to the standard items in the 'Risk of bias' tool:
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selection bias (random sequence generation, allocation concealment);
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performance bias (blinding of participants and personnel);
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detection bias (blinding of outcome assessment);
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attrition bias (incomplete outcome data; consideration of analysis methods, e.g., imputation method);
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reporting bias (selective reporting); and
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other sources of bias;
We also assessed the following domains as recommended by Moore 2010.
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Size (rating studies with fewer than 50 participants per arm as being at high risk of bias, those with between 50 and 199 participants per arm as being at unclear risk of bias, and 200 or more participants per arm as being at low risk of bias).
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Duration (rating studies with follow‐up of two weeks as being at high risk of bias, two to seven weeks as being at unclear risk of bias and eight weeks or longer as being at low risk of bias).
Two review authors completed the 'Risk of bias' assessment for each included study independently. If there was disagreement, the authors met to reach consensus, consulting an independent third review author if necessary.
Measures of treatment effect
We compared the post‐treatment pain intensity scores between the trial arms. Where possible, we calculated the proportion of participants with a specific degree of pain relief and converted it into dichotomous information to yield the number of participants who obtained a moderately important benefit (30% pain relief) or a substantially important benefit (50% or more pain relief) as defined by the IMMPACT recommendations (Dworkin 2008). We planned to calculate the risk ratio (RR) as the measure of treatment effect and used this to calculate the number needed to treat for an additional beneficial outcome (NNTB) for 30% and 50% pain relief. We also collected data on the duration of pain relief postintervention where available.
For this update, we used the OMERACT 12 group's recommendations for minimally important difference for pain outcomes reported on a continuous scale (Busse 2015). They recommend 10 mm on a 0‐100 mm visual analogue scale (VAS) as the threshold for minimal importance for average between‐group change. They highlight that should be interpreted with caution as estimates that fall closely below this point may still reflect a treatment that benefits a considerable number of patients. We used this threshold but interpreted it cautiously.
Unit of analysis issues
No unit of analysis issues arose since we were unable to conduct a meta‐analysis due to insufficient data.
Dealing with missing data
Where insufficient data were presented to enter a study into the meta‐analysis, we contacted study authors to request access to the missing data.
Assessment of heterogeneity
We planned to assess heterogeneity and its impact using the Chi2 test and the I2 test (Higgins 2003; Higgins 2011). Where significant heterogeneity (P < 0.1) was present, we planned to conduct subgroup analyses. Preplanned comparisons included CRPS‐I versus CRPS‐II, children versus adults, and continuous versus single block. However, no meta‐analysis was possible.
Assessment of reporting biases
We considered the possible influence of publication/small study biases on review findings. For studies that utilised dichotomised outcomes, where possible, we planned to test for the possible influence of publication bias on each outcome by estimating the number of participants in studies with zero effect required to change the NNTB to an unacceptably high level (defined as an NNTB of 10) as outlined by Moore 2008.
Data synthesis
We pooled results where adequate data supported this, using Review Manager 5 software (RevMan 2012). Separate preplanned meta‐analyses included sympathetic blockade versus sham/placebo procedure and sympathetic blockade versus no treatment or usual care. We used a random‐effects model to combine the studies. We considered separate meta‐analyses for short‐term (up to two weeks postintervention), mid‐term (more than two to less than seven weeks postintervention) and long‐term (seven weeks or longer postintervention) outcomes where we identified adequate data.
Assessment of quality of available evidence
For this update we used the GRADE approach to assess the quality of evidence (Guyatt 2011a; Guyatt 2011b). Two reviewers independently applied the GRADE criteria to each key comparison. If there was disagreement, the authors met to reach consensus, consulting an independent third review if necessary. We present a summary of our judgements for each comparison in Appendix 5.
To ensure consistency of GRADE judgements, we applied the following criteria to each domain equally for all key comparisons of the primary outcome.
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Limitations of studies: downgrade once if more than 25% of participants were from studies classified as being at a high risk of bias across any domain, excluding the 'study size' domain as this is accounted for in the assessment of imprecision.
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Inconsistency: downgrade once if heterogeneity is statistically significant and the I2 value is more than 40%. When a meta‐analysis was not performed we downgraded once if trials did not show effects in the same direction.
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Indirectness: downgrade once if more than 50% of the participants were outside the target group.
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Imprecision: downgrade once if fewer than 400 participants for continuous data and fewer than 300 events for dichotomous data.
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Publication bias: downgrade once where there is direct evidence of publication bias or if estimates of effect based on small scale, industry‐sponsored studies raising a high index of suspicion of publication bias.
Two review authors (NEO, BMW) judged whether these factors were present. We considered single studies to be inconsistent and imprecise, unless more than 400 participants were randomised for continuous outcomes or more than 300 for dichotomous outcomes. We applied the following definitions of the quality of the evidence (Balshem 2011).
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High quality: We are very confident that the true effect lies close to that of the estimate of the effect.
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Moderate quality: We are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
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Low quality: Our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
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Very low quality: We have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
'Summary of findings' table
We included a 'Summary of findings' table to present the main findings in a transparent and simple tabular format. In particular, we included key information concerning the quality of evidence, the magnitude of effect of the interventions examined, and the sum of available data on the outcome pain intensity, hand pain, and duration of pain relief.
Subgroup analysis and investigation of heterogeneity
We assessed heterogeneity and its impact using the Chi2 test and the I2 test (Higgins 2003; Higgins 2011). Where significant heterogeneity (P < 0.1) was present we planned to conduct subgroup analyses. Preplanned comparisons included CRPS‐I versus CRPS‐II, children versus adults, and repeated versus single blocks.
Where possible we used the proportion of people with adverse side effects in each treatment group to calculate the number needed to treat for an additional harmful outcome (NNTH).
Sensitivity analysis
When sufficient data were available, we conducted sensitivity analyses on the effect of including/excluding studies classified as being at unclear or high risk of bias.
Results
Description of studies
Results of the search
The previous update of this review included twelve studies (Aydemir 2006; Bonelli 1983; Carroll 2009; Meier 2009; Nascimento 2010; Price 1998, Raja 1991; Rodriguez 2005; Toshniwal 2012; Verdugo 1995, Wehnert 2002; Zeng 2003; combined N = 386). For this update, we included an additional four studies (Freitas 2013; Lim 2007; Rocha 2014; Yoo 2012; combined N = 154]). As our modified criteria excluded studies with follow‐up of 48 hours or less, we excluded four studies from this update that had been included in previous versions of this review (Meier 2009; Raja 1991; Verdugo 1995; Wehnert 2002; combined N = 79). Overall, we included 12 studies with 461 participants in this update.
One new study is awaiting classification, as it was published as a protocol for a trial and in abstract format only, and it is unclear whether the trial was completed (Kostadinova 2012).
Figure 1 presents a flow chart of the search screening process for the present update. We identified 461 studies through the database search strategy and none from searching other sources. After removing duplicates and screening titles and abstracts, we retrieved the full text for five studies. Of these, we included four new studies in the review.
#Study flow diagram for updated searches
For this update we attempted to contact the authors of two studies: to retrieve essential data for Freitas 2013 and to check the status of the trial and request a report if available for Kostadinova 2012.
Included studies
We present full details of the studies in the Characteristics of included studies tables.
Study participants
All included studies evaluated only adult participants (Aydemir 2006; Bonelli 1983; Carroll 2009; Freitas 2013; Lim 2007; Nascimento 2010; Price 1998; Rocha 2014; Rodriguez 2005; Toshniwal 2012; Yoo 2012; Zeng 2003).
Nine studies included only people with upper limb CRPS treated with stellate ganglion blockade (Aydemir 2006; Bonelli 1983; Lim 2007; Nascimento 2010; Rocha 2014; Rodriguez 2005; Toshniwal 2012; Yoo 2012; Zeng 2003), and two studies included only people with lower limb CRPS treated with lumbar sympathetic blockade (Carroll 2009; Freitas 2013). The remaining study included a mix of upper and lower limb CRPS (Price 1998).
Study designs
Two studies used a cross‐over design (Carroll 2009; Price 1998), and 10 employed a parallel design (Aydemir 2006; Bonelli 1983; Freitas 2013; Lim 2007; Nascimento 2010; Rocha 2014; Rodriguez 2005; Toshniwal 2012; Yoo 2012; Zeng 2003). All included studies were small, with total numbers of participants ranging from 7 to 82.
LASB versus placebo
Two studies compared LASB versus placebo (Aydemir 2006; Price 1998).
Price 1998 (N = 7) compared stellate ganglion block (n = 4, 15 ml lidocaine 1%) versus lumbar sympathetic block (n = 3, 10 ml bupivacaine 0.125%) with normal saline injection in people with CRPS of the upper or lower extremities based on the IASP diagnostic criteria and investigated the proportion of participants who experienced 50% pain relief. Price 1998 also measured the duration of pain relief and the mean between‐group difference in pain relief on a visual analogue scale (VAS). Aydemir 2006 (N = 25) compared stellate ganglion lidocaine block (10 ml lidocaine 1%) plus sham stellate ganglion ultrasound block (n = 9) to a double‐sham condition (sham stellate ganglion lidocaine (10 ml saline) and ultrasound blocks). Both groups received rehabilitation treatment. Investigators measured spontaneous pain post‐treatment and at one‐month follow‐up.
LASB versus other interventions
In contrast to the original version of this review, we included studies, totaling nine, that compared LASB to other interventions (Aydemir 2006; Bonelli 1983; Carroll 2009; Freitas 2013; Lim 2007; Nascimento 2010; Rocha 2014; Toshniwal 2012; Yoo 2012).
Aydemir 2006 compared stellate ganglion lidocaine block (10 ml of 1%) plus sham stellate ganglion ultrasound block (n = 9) to stellate ganglion ultrasound 'block' (consisting of ultrasound delivered non‐invasively over the stellate ganglion) plus sham stellate ganglion lidocaine block (10 ml of saline; n = 9). Both groups received rehabilitation treatment. Investigators measured the primary outcome of spontaneous pain post‐treatment and at one‐month follow‐up.
Bonelli 1983 (N = 19) compared stellate ganglion block with bupivacaine (15 ml of 0.5%; n = 10) versus intravenous regional blockade (IVRB) with guanethidine (20 mg; n = 9) in patients with reflex sympathetic dystrophy. The primary outcome was the intensity of pain (measured using a 100 mm linear scale) measured post‐treatment at 15 minutes, 60 minutes, 24 hours and 48 hours as well as at one and three months.
Carroll 2009 (N = 9, of whom seven completed the study) compared sympathetic block with botulinum toxin A (75 units) plus bupivacaine (10 ml of 0.5%) versus bupivacaine alone (10 ml of 0.5%) in people with CRPS of the lower extremity. The primary outcome was the duration that pain (measured using a VAS) remained below baseline levels.
Freitas 2013 (N = 40) compared sympathetic block of the lumbar plexus with lidocaine and clonidine versus pulsed radiofrequency treatment of the same structure. Investigators measured pain intensity for up to six months follow‐up.
Lim 2007 (N = 36) compared a course of five stellate ganglion blocks with lidocaine versus a two‐week course of corticosteroids (prednisolone) in patients with CRPS following stroke. They used a self developed four‐point scale (0 to 3) of hand pain with passive movement and followed patients up to 30 days from the start of treatment.
Nascimento 2010 (N = 43) compared sympathetic block with lidocaine (70 mg 1% lidocaine) versus sympathetic block with lidocaine (70 mg 1% lidocaine) plus clonidine (30 μg) versus IVRB with lidocaine plus clonidine (7.0 ml solution, 1% lidocaine, 1 μg/kg clonidine). Investigators measured intensity of pain (VAS) and duration of pain relief post‐treatment and at one‐week follow‐up.
Rocha 2014 (N = 36) compared image‐guided thoracic sympathetic block with ropivacaine and triamcinolone versus injection of the same agents into the subcutaneous space. Authors described this comparison condition as an "active control" as it might be predicted to induce physiological effects. This allowed blinding of participants. Investigators followed up participants using the Brief Pain Inventory as an outcome measure at one month and one year. This study did not report a responder analysis.
Toshniwal 2012 compared continuous stellate ganglion block (SGB; n = 18; 280 ml, 0.125% bupivacaine at 2 ml/h for seven days) versus continuous infraclavicular brachial plexus block (n = 12; 400 ml, 0.125% bupivacaine at 5 ml/h for seven days) in people with CRPS‐I of the upper extremity. Both groups received concurrent physiotherapy sessions. The primary outcome was the subscale scores on the neuropathic pain scale measured over a four‐week period post‐treatment.
Yoo 2012 (N = 42) compared stellate ganglion block with image guidance to the same block versus no image guidance in participants with CRPS following stroke. Of note, the group with image guidance received a higher dose of lidocaine (10 ml) than the non‐guided group (5 ml). Investigators measured pain intensity with a VAS at two‐ and four‐week follow‐up.
LASB in addition to other therapies
Two studies evaluated the efficacy of LASB as an addition to other therapeutic management (Rodriguez 2005; Zeng 2003). Rodriguez 2005 evaluated physical therapy and pharmacological treatment with or without SGB (N = 41 per group, 10 cc, equal parts 2% lidocaine and 0.5% bupivacaine) in people with upper limb CRPS with a confirmed sympathetic component to their pain (50% pain reduction with screening, prerandomisation SGB). Investigators measured pain intensity, therapeutic efficacy (proportion with at least 50% pain reduction), and relapse rate at two months post‐treatment. Zeng 2003 compared SGB (dose not reported) plus rehabilitation versus rehabilitation alone in a group (N = 60) with shoulder‐hand syndrome following stroke. Pain (verbal rating scale) was measured at 10 and 20 days post‐treatment.
Excluded studies
In total, we excluded 26 studies. For this update, we excluded one study at the full‐text stage as it was not an RCT (Kastler 2013). In the last review we excluded two studies (Rodriguez 2006; Rodriguez 2008), as it was not clear whether they represented original trials in distinct cohorts or an expansion of the included trial by Rodriguez 2005, comprising many of the same participants' data. For this update we have reclassified these two studies to Studies awaiting classification and have again attempted to contact the study authors for clarification. See the table Characteristics of excluded studies for details of all studies excluded from all versions of this review.
We also identified one further study awaiting classification (Kostadinova 2012).
Risk of bias in included studies
We present the summary results of the 'Risk of bias' assessment in Figure 2 and Figure 3. We considered no studies to be at low risk of bias across all domains.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Allocation
Only two studies clearly described an adequate randomisation process (Freitas 2013; Toshniwal 2012); we considered the other ten studies to be at unclear risk of bias for this domain. We judged four studies as being at a low risk of bias for allocation concealment (Aydemir 2006; Rocha 2014; Rodriguez 2005; Toshniwal 2012), and we assessed six studies as being at unclear risk of bias (Bonelli 1983; Freitas 2013; Lim 2007; Nascimento 2010; Yoo 2012; Zeng 2003). The remaining studies used a cross‐over study design (risk of bias for allocation concealment not applicable).
Blinding
We considered three studies to have blinded participants and personnel adequately (Aydemir 2006; Carroll 2009; Price 1998) (low risk of performance bias). We considered six studies to be at unclear risk of bias across this domain (Bonelli 1983; Freitas 2013; Nascimento 2010; Rocha 2014; Toshniwal 2012; Yoo 2012) as though the interventions were distinguishable, both were active invasive interventions. Three studies were at high risk of bias (Lim 2007; Rodriguez 2005; Zeng 2003;) as clinicians delivering the interventions were not blinded or the intervention conditions were clearly distinguishable. The outcome of interest for this review was self‐reported pain. In this situation, the patient acts as the assessor; therefore risk of detection bias is primarily dependent on participant blinding. For blinding of outcome assessment, we judged five studies to be at low risk of detection bias as they clearly reported blinding of the participants (Aydemir 2006; Carroll 2009; Freitas 2013; Price 1998; Rocha 2014), four studies at unclear risk of bias as it was unclear whether patients were adequately blinded (Bonelli 1983; Nascimento 2010; Toshniwal 2012; Yoo 2012), and three studies were judged to have high risk of detection bias because patients were not adequately blinded (Lim 2007; Rodriguez 2005; Zeng 2003).
Incomplete outcome data
We considered seven studies to be at unclear risk of bias due to incomplete outcome data (Aydemir 2006; Carroll 2009; Freitas 2013; Lim 2007; Rocha 2014; Rodriguez 2005; Yoo 2012) as a result of the levels of drop‐out reported or incomplete reporting of attrition.
Selective reporting
We judged three studies to be at high risk of bias for this domain due to incomplete reporting of pain scores (Freitas 2013; Price 1998; Rodriguez 2005). Carroll 2009 carried an unclear risk of bias for incomplete reporting of pain score at a secondary end point.
Adequate sample size?
We judged all studies to be at high risk of bias with regard to sample size as all had less than 50 participants per arm.
Adequate duration of follow‐up?
We considered all but four studies to be at high or unclear risk of bias based on inadequate duration of follow‐up (Bonelli 1983; Freitas 2013; Rocha 2014; Rodriguez 2005).
Other potential sources of bias
We judged two studies to be at high risk of bias for other reasons (Bonelli 1983; Rocha 2014). In Bonelli 1983, the LASB group had a significantly shorter duration of symptoms at baseline than the IVRB guanethidine group, and participants were significantly older. Rocha 2014 had average pain scores at baseline that differed by greater than one point between groups, but authors did not present tests for comparability at baseline. Three studies were at unclear risk of bias (Freitas 2013; Yoo 2012). Freitas 2013 and Rodriguez 2005 provided no baseline data, and neither Freitas 2013 nor Yoo 2012 gave details regarding concomitant treatments. We judged the two cross‐over studies to be at low risk of bias for carry‐over effects (Carroll 2009; Price 1998).
There were insufficient data to support a formal statistical analysis of reporting/small study biases for any comparison.
Sources of funding and conflicts of interest
While not formally included within the 'Risk of bias' assessment, we extracted information regarding study funding and potential conflicts of interest. Seven study reports offered no details regarding these issues (Aydemir 2006; Bonelli 1983; Freitas 2013; Nascimento 2010; Price 1998; Yoo 2012; Zeng 2003).
Carroll 2009 declared that the authors had filed a patent for the inclusion of botulinum toxin A in sympathetic blocks. Rodriguez 2005 declared financial support from governmental and non‐profit organisations. No study declared funding from industry sources. Toshniwal 2012 and Rocha 2014 declared no conflict of interest.
Effects of interventions
See: Summary of findings 1 LASB for pain intensity and duration of pain relief in adults with CRPS
For a summary of all core findings, see summary of findings Table 1.
LASB versus placebo
For the comparison of LASB versus placebo, we rated all evidence as being of moderate quality.
Pain intensity
In Price 1998, there was no difference between lidocaine and normal saline; the same number of participants (6/7) achieved at least 50% pain relief at two weeks. In Aydemir 2006, spontaneous pain scores were no different from baseline to post‐treatment in either the group receiving lidocaine plus sham ultrasound SGB (Z = −0.18, P = 0.86) or in the group receiving sham lidocaine plus sham ultrasound (Z = −0.76, P = 0.45). Authors did not report between‐group comparisons.
Duration of pain relief
Price 1998 evaluated the duration of pain relief, finding that when local anaesthetic was administered, the mean duration of relief was longer (three days versus 19.9 hours in the saline group). However, short‐term relief was similar in both groups. In Aydemir 2006, spontaneous pain scores were no different from baseline to one‐month follow‐up in either the group receiving lidocaine (plus sham ultrasound SGB; Z = −1.05, P = 0.29) or in the group receiving sham lidocaine and sham ultrasound (Z = −0.68, P = 0.50). Authors reported no between‐group comparisons. None of the included studies reported postintervention analgesic requirements.
Adverse Events
Price 1998 and Aydemir 2006 did not report adverse events.
LASB versus other interventions
Pain relief
Most comparative studies reported no significant difference in pain between groups (Bonelli 1983; Freitas 2013; Nascimento 2010; low to very low quality evidence). Aydemir 2006 did not explicitly report between‐group differences, although they did not find any within‐group differences in spontaneous pain scores between baseline and post‐treatment nor at one‐month follow‐up in either the group receiving lidocaine SGB plus sham ultrasound SGB (Z‐scores listed above) or in the group receiving ultrasound SGB plus sham lidocaine (Z = −0.59, P = 0.55; Z = −0.63, P = 0.53, respectively; low quality evidence). Due to the variation in the interventions, there were not adequate data to allow pooling of the results.
Lim 2007 reported no significant difference in hand pain intensity (scale from 0 to 3) between LASB plus corticosteroid versus oral corticosteroids at 15‐day follow‐up (mean difference 0.00, 95% confidence interval (CI) −0.35 to 0.35; very low quality evidence) and a statistically significant difference in favour of LASB with steroid at 30 days (mean difference 0.40, 95% CI −0.69 to −0.11; very low quality evidence).
Rocha 2014 reported that thoracic LASB with ropivacaine and steroid did not result in a statistically significant difference in average pain scores compared to injection of the same agents into the subcutaneous space (described as an "active placebo" at one month (0 to 10 scale mean difference −1.25, 95% CI −3.20 to 0.70; very low quality evidence), but there was a statistically significant difference at one‐year follow‐up in favour of thoracic LASB (mean difference −2.39, 95% CI −4.72 to −0.06; very low quality evidence). While not significant at one‐month follow‐up, the point estimate at both time points exceeds our threshold for clinical importance. However, it is worth noting that at one‐year follow‐up, attrition in the active group was 16% and in the control group 26%, introducing a possible risk of bias.
Toshniwal 2012 reported significantly lower short‐term pain scores (on a 0 to 10 scale) in favour of the group receiving the continuous infraclavicular brachial plexus block versus the group receiving the continuous stellate ganglion block. Specifically, at 30 minutes, 2 hours and 12 hours, those receiving the continuous brachial plexus block had significantly lower intensity of pain (0.7, 0.5, and 0.7, respectively) and unpleasantness of pain (0.7, 0.7, and 0.8, respectively) compared with those receiving a continuous stellate ganglion block (intensity: 3.3, 2.7, and 1.9; unpleasantness: 3.0, 2.7, and 1.9). Dull pain intensity scores were significantly reduced for the brachial plexus block group versus the stellate ganglion block group at 2 hours (0.1 versus 2.4), 12 hours (0.6 versus 1.9), and 24 hours (1.3 versus 2.6) with deep pain also significantly reduced at these time points (2 hours −0.1 versus 2.3; 12 hours −0.7 versus 1.6; 24 hours −1.4 versus 2.4), as well as at 30 minutes postcannulation (0.1 versus 2.3). There were no statistically significant differences between groups for short‐term scores on any of the other Neuropathic Pain Scale components. Furthermore, there was no evidence of increased effectiveness for long‐term pain relief in one group over the other and no between‐group differences at any other time points. There was no statistical comparison of quality of pain differences between groups. We rated this evidence as being of low quality.
Yoo 2012 found no statistically significant or clinically important difference between image‐guided and non‐guided stellate ganglion block at two weeks postinjection (0 to 10 pain VAS mean difference −0.58, 95% CI −1.51 to 0.35; very low quality evidence); there was a statistically significant but clinically unimportant difference at four weeks postinjection (mean difference −0.74, 95% CI −1.36 to −0.12; very low quality evidence) in participants with CRPS following stroke.
Duration of pain relief
Carroll 2009 reported a significantly longer duration of analgesia in the botulinum toxin A group (median time to analgesic failure 71 days (95% CI 12 to 253; low quality evidence) compared with bupivacaine alone (< 10 days, 95% CI 0 to 12; P < 0.02; low quality evidence). However, while the authors reported that pain intensity declined significantly in the botulinum toxin A group, they did not provide numeric pain scores for either treatment group.
Adverse events
Only six studies provided specific data regarding adverse events, and the level of detail of this reporting was mixed.
Carroll 2009 reported moderate adverse events in one participant (14.2%) following the botulinum toxin type A LASB. This participant had significant nausea and emesis that began five5 hours after the injection and lasted two days, resolving spontaneously.
Freitas 2013 reported that paraesthesia during needle positioning in "1 out of 10" in the LASB group and "2 out of 10" in the pulsed radiofrequency group. This is likely to be an error as it suggests that there were 20 participants in total while the trial reports 40 participants. The study reports that all participants in both groups reported soreness at the injection site lasting five to seven days.
Nascimento 2010 also found mild adverse events for all three groups. The SGB group receiving lidocaine and clonidine (gGroup 2) reported the highest frequency of adverse events: 93.3% reported drowsiness (14/15), 13.3% dizziness (2/15), 13.3% hoarseness (2/15), 6.7% reported pain at the injection site (1/15), and 26.7% reported a feeling of dry mouth (4/15). The SGB group receiving only lidocaine (gGroup 1) reported the lowest frequency of adverse events, with nausea occurring in 6.5% (1/14), dizziness in 14.3% (2/14), hoarseness in 6.5% (1/14), and pain at the injection site in 6.5% (1/14). Lastly, the group receiving the IVintravenous (IV) regional block with lidocaine and clonidine (gGroup 3) reported drowsiness (46.1%; 6/13) and dizziness (7.7%; 1/13).
Rocha 2014 reported a similar overall rate of minor adverse events following thoracic blockade or subcutaneous injection with local anaesthetic and steroid and no major adverse events. Minor eventsThese included dizziness, blurred vision, puncture pain, increased pain, headache, nausea, vomiting, dysphagia, hoarseness, haematoma, dyspnoea, shivering, cold feeling, face swelling, and mouth numbness. Of note, 65% of participants in both groups reported "puncture pain";, 24% in the thoracic block group reported dyspnoea compared with 6% in the subcutaneous group. 35%Thirty‐five per cent in the thoracic block group reported dizziness compared to 12% in the subcutaneous group. Twenty‐four per cent in the thoracic block group reported dizziness compared to no participants in the subcutaneous group.
Toshniwal 2012 found adverse events in both groups. In the continuous stellate ganglion block group, Horner's syndrome was most common (94.7%) while initial motor weakness was the most common adverse event in the continuous infraclavicular brachial plexus group (100%). Positive catheter tip culture occurred in 61.1% (11/18) of the stellate ganglion block group and in 8.3% (1/12) in the brachial plexus group; investigators observed no signs of infection at the catheter site were observed in either group. Catheter migration was found in 5.2% (1/19) of the stellate ganglion block group (versus 7.1% (1/14) of the brachial plexus group). Lastly, hoarseness of voice (for initial 12 hours) was found in 16.7% (3/18) of participants in the stellate ganglion block group reported hoarseness of voice (for initial 12 hours).
Yoo 2012 reported no adverse events in the group who received ultrasound guided blocks and two haematomas at the injection site for those who received unguided blocks.
LASB in addition to other interventions
Pain relief
Zeng 2003 and Rodriguez 2005 investigated the effectiveness of adding LASB to rehabilitation versus rehabilitation or medication alone. Zeng 2003 found no benefit of adding LASB at 10 days (0‐10 Verbal Rating scale mean difference 0.2, 95% CI −1.3 to 1.7; very low quality evidence) or 20 days (mean difference 0.1, 95% CI −0.97 to 1.17; very low quality evidence). Rodriguez 2005 reported treatment efficacy (proportion with at least 50% pain reduction) at the two‐month follow‐up to be 46% in favour of the SGB group, an absolute risk reduction of 17% in favour of the SGB group with a number needed to treat for an additional beneficial outcome (NNTB) of 6. The NNTB suggests that six people with CRPS would need to be treated with SGB (in addition to physical and pharmacological therapy) to prevent one relapse. There was a higher relapse rate in the control group (37%) versus the SGB group (20%) (hazard ratio (HR) 2.7, 95% CI 1.1 to 6.7; very low quality evidence). The Kaplan‐Meier estimates of the cumulative probability of not having a relapse at two months was 80% in the SGB group and 63% in the control group. However, this study did not report data for pain intensity or the proportion who achieved meaningful pain relief.
Duration of pain relief
No studies specifically presented data on the duration of pain relief for this comparison.
Adverse events
Zeng 2003 and Rodriguez 2005 did not report adverse events.
Discussion
Summary of main results
The objective of this review was to assess the efficacy of LASB for the treatment of pain in CRPS and to evaluate the incidence of adverse effects of the procedure.
Previous versions of this review revealed the scarcity of published evidence to support the use of LASB for CRPS and raised questions about its efficacy.
LASB versus placebo or no treatment
This update reveals little progress in developing high quality evidence to support the use of LASB for CRPS since the last update in 2013. There are only two placebo‐controlled randomised studies that met our modified inclusion criteria for this update (Aydemir 2006; Price 1998), both of which have very small sample sizes. We can draw no firm conclusions from this evidence. It is notable that the results to date are not suggestive of a significant effect of LASB over placebo even in the very short term (30 minutes to two hours), the time frame that theory would suggest local anaesthetic is likely to have its maximum benefit. We could not estimate the duration of pain relief, if any.
LASB versus other interventions
In a change from the original version of this review, we took the decision to include trials that compared LASB with alternative interventions or that evaluated the effect of adding LASB to other treatments. We identified a number of such studies investigating a range of comparisons, and the majority of these demonstrated no significant difference between the intervention and control groups. It is notable that in one small study (Bonelli 1983), LASB did not demonstrate superior effectiveness when compared to intravenous regional blockade (IVRB) with guanethidine, an intervention for which there is consistent evidence of no effect (Jadad 1995; McQuay 1997; O'Connell 2013).
One small study (N = 36) at high risk of bias suggests a potentially clinically important effect for thoracic sympathetic blockade with bupivacaine and triamcinolone on average daily pain at one month and one year when compared to injection of the same agents into the subcutaneous space, though this difference was not statistically significant at one‐ month follow‐up (Rocha 2014). The subcutaneous injection in this study was used as an active control condition, and might be expected to have systemic effects.
Carroll 2009 provided limited evidence that, compared with LASB alone, sympathetic blockade with botulinum toxin A added to local anaesthetic may prolong analgesia. Another single study, Rodriguez 2005, provided limited evidence to suggest that when added to usual physical therapy and pharmacological treatment, LASB may reduce the risk of relapse, but we found this study to be at high risk of bias across multiple domains; it did not report data for pain relief, and the lack of a sham condition raises the possibility that the observed improvement may have resulted from non‐specific effects. In contrast, Zeng 2003 found no benefit of adding cervical sympathetic blockade to usual comprehensive rehabilitative treatment for pain outcomes.
There is limited evidence that, compared with continuous infraclavicular brachial plexus blocks, continuous stellate ganglion LASB results in less relief in short‐term pain intensity, pain unpleasantness, deep pain and dull pain (Toshniwal 2012). The same study also provides limited evidence of no difference in longer‐term pain relief (up to four weeks) between groups (Toshniwal 2012).
Given the limited evidence available and the various sources of potential bias and uncertainty, we conclude that there is little credible evidence to support the use of LASB for CRPS and that the majority of the limited evidence available suggests that LASB may be ineffective.
Adverse events
The reporting of adverse events in the identified studies was inconsistent and limited. Given this lack of reporting and the small size of all of the included studies, we cannot confidently draw conclusions regarding the safety of LASB. While those adverse events that have been reported appear to be minor, it is not currently possible to rule out the potential for rare but serious adverse events. To obtain a better estimate of the incidence and nature of adverse events, it might be necessary to review evidence from non‐randomised observational study designs, but that was beyond the scope of this review.
Overall completeness and applicability of evidence
By undertaking a systematic search of unpublished and grey literature and consulting experts in the field, we have limited the risk of excluding important and relevant evidence. We judged all of the included studies as being at unclear risk of bias in at least one domain, reflecting a common lack of clarity in many study reports. We deemed three as being at high risk of bias specifically for the selective reporting of outcomes. This represents a significant challenge to a confident interpretation of an already limited evidence base.
We attempted to contact the authors of seven studies, with mixed success. Two responded and provided available data (Nascimento 2010; Toshniwal 2012). However, as we were unable to source two studies (Kostadinova 2012; Salinas Cerda 1997), did not receive a response from one to provide full data (Freitas 2013), and were unable to include two studies due to lack of clarity over whether the participant population overlapped with another included study (Rodriguez 2006; Rodriguez 2008), it is possible that we are missing relevant data.
Quality of the evidence
We did not judge any of the included studies to be at low risk of bias across all domains. Indeed, all but two studies carried an unclear risk of bias for random sequence generation and all but four for allocation concealment. These factors have been demonstrated to exaggerate the effects of studies, particularly those with subjective outcomes, such as pain (Schulz 1995; Wood 2008). We assessed all studies to be at high risk of bias for inadequate sample size and only four studies to be at low risk of bias for adequate duration of follow‐up. Small studies may well be underpowered to detect a clinical effect, but conversely there is empirical evidence that small published clinical trials in pain have a tendency to exaggerate treatment effects (Moore 2010; Nüesch 2010). These numerous sources of potential bias might alone explain any observed positive effects in the included studies. Thus, all of the evidence identified should be interpreted with caution.
Applying the GRADE approach, ratings across all comparisons were either low or very low quality except for the comparison of LASB versus placebo, which was of moderate quality. This rating is the result of the criteria we decided upon a priori when updating the searches. However, this moderate rating still merits some caution, since it is based on so few data. It is our view that for future updates, the rating of imprecision might be downgraded twice in the event that a comparison consists of fewer than 100 participants. Since each comparison consists of only one or two very small studies, and since all studies are at unclear or high risk of bias across various domains, it would be reasonable to characterise the entire body of included evidence as of low or very low quality.
Potential biases in the review process
While we have attempted to identify all eligible trials using a comprehensive search strategy, we may have still missed some key literature. Only three included studies used a positive response to a prior LASB to attempt to establish sympathetically maintained pain as part of their inclusion criteria (Carroll 2009; Price 1998; Rodriguez 2005). This speaks to a wider issue concerning the use of LASB in CRPS. It is possible that LASB might only be effective in a subgroup of people with CRPS with sympathetic dysfunction, or perhaps in people with other characteristics. However, to date evidence of predictors of a positive response to LASB are elusive (Sethna 2012).
The decision to exclude studies with only very short term follow‐up (≤ 48 hours) has led to the exclusion of studies that had been included in previous updates of this review. We took this decision on the basis that such studies are of more value in terms of investigating the diagnostic potential of LASB, which was not the purpose of our review. These studies do not provide clinically useful information in terms of treatment effectiveness over a reasonable period of time. This review focused on pain as a primary outcome and did not consider outcomes such as function or other clinical signs. However, LASB is commonly conducted with the primary goal of pain relief.
Agreements and disagreements with other studies or reviews
Our results do not change the overall conclusions of earlier versions of this review. Similarly a number of earlier systematic reviews have included evaluations of the evidence for LASB, and all have similarly agreed that the evidence is limited and that there is no clear evidence for the efficacy of LASB (Forouzanfar 2002; Perez 2010; Tran 2010). Van Eijs 2011 recommended that LASB be considered for the treatment of CRPS if conservative multidisciplinary management has failed. However, they rated the evidence for the effectiveness of CRPS as level 2B+, characterised as "multiple RCTs, with methodologic weaknesses, yield contradictory results better or worse than the control treatment. Benefits closely balanced with risk and burdens, or uncertainty in the estimates of benefits, risk and burdens." This classification of the evidence seems consistent with our own conclusions, though we feel this level of evidence precludes clinical recommendations.
#Study flow diagram for updated searches
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
| Patient or population: adults with CRPS Setting: secondary care Intervention/comparison: LASB vs various comparisons Outcome: pain intensity 0‐10 (VAS or NRS) | ||||
| Comparison | Studies | No of participants | Result (effect estimates reported where available from study report) | Quality of the evidence |
|---|---|---|---|---|
| LASB vs placebo | 23 (2) | No significant between‐group difference | ⊕⊕⊕⊝ Moderatea | |
| Thoracic LASB + steroid vs subcutaneous local anaesthetic+ steroid | 36 (1) | Favours LASB Mean difference (0‐10 scale) One month −1.25 (95% CI −3.2 to 0.7) One year −2.39 (95% CI −4.72 to −0.06) | ⊕⊝⊝⊝ Very lowb | |
| LASB vs ultrasound block | 18 (1) | No significant between‐group difference | ⊕⊕⊝⊝ Lowc | |
| LASB vs IVRB guanethidine | 19 (1) | No significant between‐group difference | ⊕⊝⊝⊝ Very lowb | |
| LASB lumbar plexus vs pulsed radiofrequency lumbar plexus | 40 (1) | No significant between‐group difference | ⊕⊝⊝⊝ Very lowb | |
| LASB (lidocaine + clonidine) vs IVRB (lidocaine + clonidine) | 43 (1) | No significant between‐group difference | ⊕⊝⊝⊝ Very lowb | |
| LASB + PT+ pharmacological vs PT + pharmacological | 82 (1) | Favours SGB group | ⊕⊝⊝⊝ Very lowb | |
| LASB + PT vs PT | 60 (1) | No significant between‐group difference | ⊕⊝⊝⊝ Very lowb | |
| Continuous LASB vs continuous brachial plexus block | 33 (1) | Favours brachial plexus block | ⊕⊕⊝⊝ Lowc | |
| Image‐guided LASB vs nonimage‐guided LASB | 42 (1) | Mean difference 2 weeks postinjection −0.58 (95% CI −1.51 to 0.35) 4 weeks postinjection −0.74 (95% CI −1.36 to −0.12) | ⊝⊝⊝⊝ Very lowd | |
| Outcome: hand pain 0‐3 scale | ||||
| LASB vs oral corticosteroids | 38 (1) | 15 day follow‐up, no significant between‐group difference at 30 day follow‐up 0.4 (95% CI −0.69 to −0.11), favours LASB with steroid | ⊝⊝⊝⊝ Very lowd | |
| Outcome: duration of pain relief | ||||
| LASB bupivacaine + BTA vs LASB bupivacaine | 9 (1) | Increased duration of relief with BTA Median time to analgesic failure (days): LASB bupivacaine + BTA 71 (95% CI 12 to 253) LASB bupivacaine 10 (95%CI 0 to 12) | ⊕⊕⊝⊝ Lowc | |
| a Downgraded once for imprecision. | ||||
| To make the clinical diagnosis, the following criteria must be met:
|
| 1. Continuing pain, which is disproportionate to any inciting event
|
| 2. Must report at least one symptom in three of the four following categories.
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| 3. Must display at least one sign at time of evaluation in two or more of the following categories:
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| 4. There is no other diagnosis that better explains the signs and symptoms
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| For research purposes, diagnostic decision rule should be at least one symptom in all four symptom categories and at least one sign (observed at evaluation) in two or more sign categories. A sign is counted only if it is observed at time of diagnosis. |
