Tipos de estudios

Se incluyeron los ensayos controlados aleatorios (ECA) con evaluación doble ciego de los resultados de los participantes después de dos semanas de tratamiento o más (aunque el énfasis de la revisión estuvo en los estudios de ocho semanas o más). Se requirió la publicación completa en revistas, con la excepción de los resúmenes de los resultados de ensayos clínicos en línea por otra parte inéditos y los resúmenes con datos suficientes para el análisis. No se incluyeron resúmenes cortos (generalmente informes de reuniones). Se excluyeron los estudios no aleatorios, los estudios de dolor experimental, los informes de casos y las observaciones clínicas.

Tipos de participantes

Los estudios incluyeron participantes adultos de 18 años de edad y más. Los participantes presentaban una o más de una amplia variedad de afecciones crónicas de dolor neuropático que incluyen:

1. neuropatía asociada con el cáncer;

2. dolor neuropático central;

3. síndrome de dolor regional complejo (SDRC) Tipo II;

4. neuropatía por el virus de la inmunodeficiencia humana (VIH);

5. neuropatía diabética dolorosa (NDD);

6. dolor del miembro fantasma;

7. neuralgia posherpética (NPH);

8. dolor neuropático postoperatorio o traumático;

9. lesión de la médula espinal;

10. neuralgia del trigémino.

Cuando los estudios incluyeron participantes con más de un tipo de dolor neuropático, se planificó analizar los resultados según la afección primaria.

Tipos de intervenciones

Se incluyeron los estudios que utilizaron AINE a cualquier dosis, por vía oral, administrados para el alivio del dolor neuropático y en comparación con placebo o cualquier comparador activo (por ejemplo, otro AINE).

Tipos de medida de resultado

Se previó que los estudios utilizarían diversas medidas de resultado y la mayoría de los estudios utilizaría escalas estándar subjetivas (escala de calificación numérica [ECN]) o escala analógica visual [EAV]) para la intensidad del dolor o el alivio del dolor, o ambos. Hubo un interés particular en las definiciones de la Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) del efecto beneficioso moderado y significativo en los estudios de dolor crónico (Dworkin 2008). Éstos se definieron como al menos el 30% de alivio del dolor a partir del valor inicial (moderado), al menos el 50% de alivio del dolor a partir del valor inicial (significativo), mucho mejor o muchísimo mejor según la Patient Global Impression of Change (PGIC) (moderado) y muchísimo mejor según la PGIC (significativo). Estos resultados son diferentes de los utilizados en la mayoría de las revisiones anteriores (Seidel 2013), que se concentran en resultados dicotómicos en los que las respuestas de dolor no siguen una distribución normal (gaussiana). Las personas con dolor crónico desean niveles altos de analgesia, idealmente más del 50%, y con un dolor que no sea peor que leve (O'Brien 2010). En esta revisión el punto temporal preferido de las medidas de resultado fue a la semana 12, que se considera un punto de medición estándar y generalmente es solicitado por los organismos reguladores (Moore 2010a). Sin embargo, se previó que habría datos muy limitados y se han incluido estudios que informan resultados en otros puntos temporales, desde dos semanas en adelante.

Se planificó incluir una tabla "Resumen de los hallazgos" como señala la guía de los autores (Cochrane PaPaS Group 2012). No se ha incluido una tabla de "Resumen de los resultados" porque no hubo información útil para incluir.

Búsquedas electrónicas

We searched the following databases, without language restrictions.

• Cochrane Central Register of Controlled Trials (CENTRAL, via the Cochrane Register of Studies Online database (CRSO)) to 29 May 2015.

• MEDLINE (via Ovid) from 1946 to 29 May 2015.

• EMBASE (via Ovid) from 1974 to 29 May 2015.

The search strategies for CENTRAL, MEDLINE, and EMBASE are listed in Appendix 2, Appendix 3, and Appendix 4, respectively.

Búsqueda de otros recursos

We reviewed the bibliographies of identified RCTs and review articles, contacted authors and known experts in the field, and searched ClinicalTrials.gov (ClinicalTrials.gov) and World Health Organization International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/) to identify additional published or unpublished data.

Selección de los estudios

We determined eligibility by reading the abstract of each study identified by the search. We eliminated studies that clearly did not satisfy inclusion criteria, and we obtained full copies of the remaining studies. Two review authors read these studies independently and reached agreement by discussion. We did not anonymise the studies in any way before assessment.

Extracción y manejo de los datos

Two review authors independently extracted data using a standard form and checked for agreement before entry into the Cochrane Collaboration's statistical software, Review Manager 2014, or any other analytical tool. We included information about the pain condition and number of participants treated, drug and dosing regimen, study design (placebo or active control), study duration and follow‐up, analgesic outcome measures and results, withdrawals and adverse events (participants experiencing any adverse event, or a serious adverse event).

Evaluación del riesgo de sesgo de los estudios incluidos

We used the Oxford Quality Score as the basis for inclusion, limiting inclusion to studies that were randomised and double‐blind as a minimum (Jadad 1996).

Two authors independently assessed the risk of bias in each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion.

We assessed the following for each study.

1. Random sequence generation (checking for possible selection bias). We assessed the method used to generate the allocation sequence as: low risk of bias (any truly random process, eg random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). We excluded studies using a non‐random process (eg odd or even date of birth; hospital or clinic record number).

2. Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment. We assessed the methods as: low risk of bias (eg telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). We excluded studies that did not conceal allocation and were, therefore, at a high risk of bias (open list) (eg open list).

3. Blinding of outcome assessment (checking for possible detection bias). We assessed the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study stated that it was blinded and described the method used to achieve blinding, eg identical tablets; matched in appearance and smell); unclear risk of bias (study stated that it was blinded but did not provide an adequate description of how it was achieved). We excluded studies that were not double‐blind.

4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data). We assessed the methods used to deal with incomplete data as: low risk (less than 10% of participants did not complete the study and/or used 'baseline observation carried forward' analysis); unclear risk of bias (used 'last observation carried forward' analysis); high risk of bias (used 'completer' analysis).

5. Size of study (checking for possible biases confounded by small size). We assessed studies as being at low risk of bias (200 or more participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (fewer than 50 participants per treatment arm).

Medidas del efecto del tratamiento

We planned to calculate the NNT as the reciprocal of the absolute risk reduction (ARR) (McQuay 1998). For unwanted effects, the NNT would became the number needed to treat to harm (NNH) and be calculated in the same manner. We planned to use dichotomous data to calculate risk ratio (RR) with 95% confidence intervals (CIs) using a fixed‐effect model unless we found significant statistical heterogeneity (Assessment of heterogeneity). We would not use continuous data in analyses. In the event, we did not carry out any analysis.

Cuestiones relativas a la unidad de análisis

We accepted randomisation to individual participant only. The control treatment arm would be split between active treatment arms in a single study if the active treatment arms were not combined for analysis.

Manejo de los datos faltantes

We planned to use an intention‐to‐treat (ITT) analysis where the ITT population consisted of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one post‐baseline assessment. Missing participants would be assigned zero improvement where possible. In the event, we did not carry out any analysis.

Evaluación de la heterogeneidad

We planned to deal with clinical heterogeneity by combining studies that examined similar conditions. We planned to assess statistical heterogeneity visually (L'Abbé 1987), and using the I² statistic. When the I² value was greater than 50%, we intended to consider possible reasons for this. There were insufficient data to carry out any assessment of heterogeneity.

Evaluación de los sesgos de notificación

The aim of this review was to use dichotomous data of known utility (Moore 2010d). The review did not depend on what authors of the original studies chose to report or not, although clearly difficulties arose if studies failed to report dichotomous results.

We planned to assess publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean an NNT of 10 or higher) (Moore 2008). In the event there were insufficient data to assess publication bias.

Síntesis de los datos

We planned to analyse according to individual painful conditions, because placebo response rates with the same outcome can vary between conditions, as can the drug‐specific effects (Moore 2009a). We would use a fixed‐effect model for meta‐analysis, but planned to use a random‐effects model if there was significant clinical heterogeneity and it was considered appropriate to combine studies.

We examined data for each painful condition in three tiers, according to outcome and freedom from known sources of bias.

The first tier used data meeting current best standards, where studies reported the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method other than baseline observation carried forward (BOCF) for dropouts, reported an ITT analysis, lasted eight or more weeks, had a parallel‐group design, and had at least 200 participants (preferably at least 400) in the comparison (Moore 2010a; Moore 2012a). We planned to report these top‐tier results first.

The second tier used data from at least 200 participants, but where one or more of the above conditions was not met (for example, reporting at least 30% pain intensity reduction, using LOCF or a completer analysis, or lasting four to eight weeks).

The third tier of evidence used data from fewer than 200 participants, or where there were expected to be significant problems because, for example, of very short duration studies of less than four weeks, where there was major heterogeneity between studies, or where there were shortcomings in allocation concealment, attrition, or incomplete outcome data. For this third tier of evidence, no data synthesis is reasonable, and may be misleading, but an indication of beneficial effects might be possible.

In the event, no pooling of data was possible because there were not at least two studies involving at least 200 participants that reported dichotomous data in any one type of neuropathic pain.

Análisis de subgrupos e investigación de la heterogeneidad

We planned to conduct subgroup analyses to investigate heterogeneity according to:

1. different dosages of NSAIDs;

2. different time points of outcome measurement.

However, there were insufficient data.

Análisis de sensibilidad

We planned to conduct a sensitivity analysis by excluding studies with high risk of bias (having one or more domains on the 'Risk of bias' tool judged as 'high risk' as per the guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), with all remaining trials judged at low risk of bias). However, there were insufficient data.