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Diclofenac para el dolor agudo en niños
Joseph F Standing, Imogen Savage, Deborah Pritchard, Marina Waddington
Esta revisión debería citarse como: Joseph F Standing, Imogen Savage, Deborah Pritchard, Marina Waddington. Diclofenac para el dolor agudo en niños (Revision Cochrane traducida). En: Biblioteca Cochrane Plus 2009 Número 4. Oxford: Update Software Ltd. Disponible en: http://www.update-software.com. (Traducida de The Cochrane Library, 2009 Issue 4 Art no. CD005538. Chichester, UK: John Wiley & Sons, Ltd.).

Resumen

Antecedentes

El diclofenac se utiliza frecuentemente para el dolor agudo en niños, pero no está autorizado para esta indicación en todos los grupos etarios.

Objetivos

1) Evaluar la eficacia del diclofenac para el dolor agudo en niños.
2) Evaluar la seguridad del diclofenac para consumo a corto plazo en niños.
3) Identificar las carencias en las pruebas para orientar las futuras investigaciones.

Estrategia de búsqueda

Se realizaron búsquedas en 17 bases de datos de informes de ensayos clínicos en febrero de 2005 (con una búsqueda de actualizaciones como parte de esta primera revisión en mayo de 2008). Se realizó una búsqueda manual de Anestesia Pediátrica y se obtuvieron resúmenes de informes de reacciones adversas del UK Yellow Card Scheme y del Centro de Monitorización de la Organización Mundial de la Salud (OMS). También se hicieron búsquedas en las listas de referencias de los estudios incluidos.

Criterios de selección

Cualquier informe publicado, en cualquier idioma, sobre la administración de diclofenac en pacientes de 18 años de edad o menos para el dolor agudo con detalles sobre la monitorización de la eficacia o la seguridad.

Obtención y análisis de los datos

Dos autores de la revisión evaluaron de forma independiente la calidad de los estudios y extrajeron los datos. Cuando fue necesario, se contactó con los autores. Para el análisis se utilizó la versión 5 del programa Review Manager.

Resultados principales

1) Eficacia: ensayos controlados aleatorios (ECA) que compararon diclofenac con placebo/cualquier tratamiento que utilizaran puntuaciones de dolor (evaluadas o informadas), o que requirieran analgesia de rescate.

2) Seguridad: cualquier tipo de estudio que investigara los eventos adversos (independientemente de la causa). Por evento adverso se entiende cualquier evento adverso o perjudicial informado a un paciente tratado con diclofenac para el dolor agudo.

El análisis final incluyó siete publicaciones sobre la eficacia del diclofenac y 79 sobre la seguridad (74 estudios más cinco informes de casos). Comparado con el placebo/ningún tratamiento, el diclofenac redujo significativamente la necesidad de analgesia de rescate postoperatoria (riesgo relativo [RR] 0,6; número necesario a tratar para beneficiar (NNT) 3,6; intervalo de confianza [IC] del 95%: 2,5 a 6,3).

Comparado con cualquier otro fármaco no AINE, los pacientes tratados con diclofenac presentaron menos náuseas o vómitos, o ambos (RR 0,6; NNT 7,7 [5,3 a 14,3]). Al parecer no hubo un aumento de hemorragias que requirieron intervención quirúrgica en los pacientes con diclofenac durante el período perioperatorio. Menos de 0,24% de los niños tratados por dolor agudo presentaron reacciones adversas graves al diclofenac. Los tipos de reacciones adversas graves eran similares a las informadas en adultos.

Conclusiones de los autores

El diclofenac es un analgésico efectivo para el dolor agudo perioperatorio en niños. Las reacciones adversas graves en niños son similares a las de los adultos, aunque son poco frecuentes. Se necesita una mayor investigación sobre la dosis y la seguridad en niños asmáticos.

Resumen en términos sencillos

Diclofenac para el alivio del dolor en niños

El diclofenac se utiliza frecuentemente para el alivio del dolor a corto plazo en niños, especialmente cerca del momento de la cirugía. Existen pruebas convincentes de que el diclofenac es efectivo para el alivio del dolor en adultos; los efectos secundarios como el trastorno gástrico son bien conocidos. Sin embargo, debido a diferencias del desarrollo los niños pueden reaccionar de un modo diferente a los adultos. Es importante evaluar si el diclofenac también es efectivo en niños, y comprender el tipo y la frecuencia de las reacciones adversas causadas por el diclofenac en los niños. Esta revisión halló que, al igual que en los adultos, el diclofenac es efectivo para el alivio del dolor después de una cirugía. Cuando se administra en el momento de la cirugía, el diclofenac reduce a la mitad el número de niños que requieren un alivio del dolor adicional. Al parecer el diclofenac es dos veces más efectivo que el paracetamol (acetaminofeno) para el dolor quirúrgico, y esto también es válido para los adultos. El diclofenac aparentemente causa reacciones adversas graves similares (como hemorragias gástricas y reacciones de tipo alérgico), pero estas son raras y se presentan en menos de 3 de cada 1000 niños que toman el fármaco. Además, se pretendía investigar si el diclofenac aumentaba las sibilancias en niños asmáticos, pero no fue posible debido a la falta de información al respecto. Las principales conclusiones de la presente revisión son que el diclofenac es efectivo para aliviar el dolor agudo postquirúrgico en niños y presenta un bajo riesgo de reacciones adversas graves. Deben evitarse las inyecciones intramusculares de diclofenac, debido al riesgo de problemas en el sitio de inyección. Las preguntas que quedan por responder son: ¿Cuál es la dosis óptima que se debe administrar? y ¿debe evitarse el diclofenac en niños con asma?

Antecedentes

El antiinflamatorio no esteroideo (AINE) diclofenac, es un derivado del ácido fenilacético usado para tratar el dolor y la inflamación, generalmente en forma de sal sódica. Se absorbe con facilidad por las vías oral, rectal e intramuscular; éstas constituyen las vías principales de administración sistémica (Sweetman 2002). Las acciones analgésica y antiinflamatoria de los AINE se deben principalmente a la inhibición de la ciclooxigenasa, aunque también podría contribuir la disminución de la producción de leucotrieno y de ácido araquidónico. Los AINE también ejercen una acción antinociceptiva central, de cuyo mecanismo poco se conoce (Cashman 1995).

Dos isoformas de la ciclooxigenasa (COX-1 y COX-2) han sido ampliamente estudiadas y el diclofenac inhibe ambas (Van 2000). La COX-2 se expresa en niveles bajos en diversos tipos de células. Su producción es inducida en los sitios de lesión tisular y cataliza la formación de prostaglandina a partir de ácido araquidónico y causa dolor a través de la generación de potenciales de acción en las neuronas nociceptivas (Cashman 1995). Probablemente la inhibición de la COX-2 es responsable de las propiedades analgésicas y antiinflamatorias del diclofenac. La COX-1 está presente en la mayoría de los tejidos y cataliza la formación de prostaglandinas con funciones homeostáticas como el mantenimiento de la mucosa gástrica, el flujo sanguíneo renal y la activación plaquetaria. Algunos de los efectos adversos del diclofenac podrían estar mediados por la inhibición de la COX-1 (Cashman 1995).

Los principales efectos adversos del diclofenac son los trastornos digestivos altos incluidas las hemorragias y las úlceras. En adultos, el riesgo de este tipo de hemorragias con AINE parece aumentar con la dosis y la edad (Garcia 2004) y la causa sería la exposición crónica a los AINE y no el consumo agudo a corto plazo. Prolongación del tiempo de sangría, vómitos, desmejoramiento de la función renal y broncoespasmo (Sweetman 2002) son otras de las reacciones adversas informadas del diclofenac que pueden resultar de especial importancia para su uso en el dolor agudo como en el período postoperatorio. Las revisiones sistemáticas anteriores determinaron la eficacia del diclofenac en adultos con dolor postoperatorio (Barden 2004; Collins 2004) además se recomendó usar AINE en adultos con dolor agudo provocado por un cólico renal (Holdgate 2004).

A pesar de no estar autorizado para el dolor agudo en niños, el diclofenac suele emplearse para esta indicación (Conroy 2001; Turner 1998). Cuando se utiliza un fármaco sin respetar las licencias del producto existe un mayor riesgo de reacciones adversas (Choonara 2002), por ello es fundamental la seguridad del consumo de diclofenac en niños. El mayor reconocimiento del dolor padecido por los niños trajo aparejado un mejor tratamiento y una mayor utilización de intervenciones farmacológicas en este grupo etario (Howard 2003; Lloyd-Thomas 1999). Los AINE, incluido el diclofenac, representan opciones simples, económicas y relativamente seguras y suelen recomendarse para el alivio del dolor agudo en niños (AAP 2001; Lloyd-Thomas 1999; Zacharias 1998). Estas recomendaciones deben sustentarse con pruebas sólidas sobre la seguridad y la eficacia.

El diclofenac sufre un extenso metabolismo de primer paso (Todd 1988), principalmente a través de la hidroxilación en la posición 4 por el citocromo P450 (CYP) 2C9 aunque también ocurre hidroxilación en la posición 5 en CYP3A4, CYP2C19, CYP2C8 y CYP2C18 (Kirchheiner 2003). El diclofenac posee una alta fijación a las proteínas plasmáticas, principalmente la albúmina, y se excreta tanto con la bilis como con la orina en conjugados de glucurónido y sulfato (Todd 1988). Los niños en las diferentes etapas del desarrollo poseen diferentes capacidades de metabolizar, conjugar y eliminar fármacos (Kearns 2003; Morselli 1980) esto significa que no se puede extrapolar los datos de los adultos para determinar si el diclofenac es seguro y efectivo en niños.

Las revisiones pediátricas anteriores solían centrarse en el consumo perioperatorio de AINE en general (Krishna 2003; Romsing 1997). Como el diclofenac se usa ampliamente en niños con dolor agudo (Conroy 2001; Turner 1998), es necesario realizar una revisión sistemática sobre su seguridad y eficacia en este grupo de pacientes.

Objetivos

  1. Evaluar la eficacia del diclofenac para el dolor agudo en niños.

  2. Evaluar la seguridad del diclofenac para el consumo a corto plazo (tres meses o menos) en niños.

  3. Identificar las carencias de las pruebas sobre el consumo de diclofenac en niños para orientar las futuras investigaciones.

Métodos

Criterios para la valoración de los estudios para esta revisión

Tipos de estudios

  1. Eficacia Para investigar la eficacia del diclofenac en el dolor agudo en niños, se buscaron ensayos controlados aleatorios (ECA) que comparaban diclofenac con placebo u otro tratamiento. Las medidas de eficacia empleadas fueron la puntuación del dolor por el paciente o por un evaluador, o el uso de analgesia de rescate.

  2. Seguridad: Para investigar las reacciones adversas causadas por el diclofenac en los niños tratados por dolor agudo, se buscó cualquier tipo de estudio que investigara los eventos adversos (independientemente de la causa). Por evento adverso se entiende cualquier evento adverso o perjudicial informado a un paciente tratado con diclofenac para el dolor agudo.

Los ECA cuyas tasas de eventos adversos se basan en pacientes que recibieron y que no recibieron diclofenac permiten comparar las tasas de eventos. Sin embargo, es posible que los ECA no hayan documentado sistemáticamente los eventos adversos (Ioannidis 2002), por lo tanto se tuvo en cuenta un rango más amplio de diseños de estudio en un análisis telemétrico (Aronson 2005). Se incluyeron todos los estudios en los cuales se conocía el número de niños expuestos al diclofenac como tratamiento del dolor agudo. Entre éstos se incluían ECA cegados y abiertos, estudios de cohortes retrospectivos y prospectivos, además de ECA sobre otras intervenciones que emplearon diclofenac como tratamiento complementario para el dolor agudo.

Se informaron todos los efectos adversos mortales, potencialmente mortales y graves, ya sea que prolongaran la hospitalización, causaran incapacidad permanente o significativa o que requirieran una intervención farmacológica o quirúrgica, independientemente de que hayan sido o no atribuidos al diclofenac. La importancia de informar dichos eventos, a fines de reconocer el modelo, queda evidenciada por el desastre del practolol (Abraham 2006), donde se cometió el grave error de no informar una reacción adversa porque se pensaba que el practolol no era el agente causal.

Tipos de participantes

Niños (participantes de 18 años de edad o menos).

Tipos de intervenciones

Diclofenac sistémico para el dolor agudo por las siguientes vías de administración: oral, rectal, intramuscular, intravenosa. El dolor agudo se definió como cualquier situación que requirió diclofenac durante un período breve p.ej.: dolor perioperatorio; migraña; cólico renal; fractura/lesión de partes blandas.

Tipos de medida de resultado

Eficacia:

  • intensidad del dolor informada por el paciente,

  • escalas de alivio del dolor,

  • calificación del dolor por terceros,

  • necesidad de analgesia con opioides,

  • tiempo transcurrido hasta la administración de analgesia de rescate,

  • efectos ahorradores de opioides.

Seguridad:

Todas las reacciones adversas en pacientes que recibieron un ciclo corto (tres meses o menos) de diclofenac, definido ya sea como; a) un aumento estadísticamente significativo de los eventos versus placebo, o b) una asociación causal entre un evento adverso y el diclofenac en el informe. En el caso de los ensayos controlados con placebo, se registraron y se informaron los eventos adversos en el grupo de placebo.

Métodos de búsqueda para la identificación de los estudios

Búsquedas electrónicas

Se buscaron las siguientes fuentes de datos en febrero de 2005 (con una búsqueda de actualizaciones en mayo de 2008).

  1. EMBASE

  2. MEDLINE

  3. CINAHL

  4. CENTRAL

  5. The Cochrane Library

  6. Pascal (French)

  7. Lilacs (sudamericana)

  8. Sigle (literatura gris)

  9. Dissertation abstracts

  10. ISI (conference abstracts)

  11. National Research Register

  12. Current Controlled Trials

  13. Clinicaltrials.gov

  14. IPA (International Pharmaceutical Abstracts)

  15. Pharmline

  16. BIOSIS

  17. Las compañías farmacéuticas del Reino Unido que comercializan el diclofenac en comprimidos de 25 mg o supositorios de 12,5 mg/25 mg solicitaron datos no publicados en niños

  18. Búsqueda manual de Paediatric Anaesthesia (Anestesia Pediátrica) (1970 a 2004)

El principio general de las búsquedas en todas las bases de datos fue el siguiente:

[Diclofenac text word (not exploded as may get other NSAIDs) OR Diclofenac and related subject headings OR Brand names] AND [Terms for pain (exploded) OR Pain and management OR Cause/type of pain text words OR Cause/type of pain subject headings OR Treatments for pain text word and subject heading] AND Children

Los estudios escogidos para la sección de eficacia también se consideraron para el estudio de seguridad. Los términos de búsqueda se modificaron según las limitaciones de cada base de datos (consultar el Apéndice 1 para la estrategia de búsqueda en EMBASE). Cuando resultó apropiado, se pasaron los títulos junto con los resúmenes al programa Reference Manager, además se buscaron y eliminaron los resultados duplicados. Se empleó una planilla de cálculo de Microsoft Excel para administrar los resultados de la búsqueda inicial, los resultados y los análisis de datos se administraron con Review Manager versión 4.2.10, y la versión final se exportó a Review Manager versión 5.

Obtención y análisis de los datos

La estrategia de búsqueda identificó estudios en los cuales se utilizó diclofenac en niños como analgésico a corto plazo. Se emplearon dos tipos de criterios de inclusión para los estudios identificados: uno para la eficacia y uno para la seguridad. JFS y DP identificaron los estudios de eficacia y extrajeron los datos de forma independiente. IS y JFS identificaron los estudios de seguridad y extrajeron los datos de forma independiente.

Eficacia:

ECA que utilizaron diclofenac como analgésico a corto plazo. Se requirió cierto grado de alivio del dolor (p.ej. puntuación de dolor, necesidad de analgesia de rescate, interrogatorio de los pacientes). Cuando fue posible, se combinaron los estudios con las mismas medidas de eficacia. Se realizó y se registró la evaluación de la calidad del proceso de asignación al azar, la ocultación de la asignación y el seguimiento.

En la práctica, el diclofenac suele combinarse con otros analgésicos como opioides, paracetamol (acetaminofeno) y anestésicos locales. En el mejor de los casos, se buscaron estudios que compararan diclofenac con placebo (para demostrar la eficacia como analgésico) y diclofenac con otro AINE/inhibidores de la COX 2 (para informar los opciones en la práctica). Sin embargo, como hubo un número pequeño de estudios de calidad metodológica adecuada realizados exclusivamente en niños, se incluyeron también los estudios de diseño adecuado que compararan diclofenac con otro tratamiento. Los estudios se agruparon en las siguientes categorías: Diclofenac versus ningún tratamiento/placebo; otros AINE/inhibidores de la COX-2; opioides; paracetamol (acetaminofeno); otros tratamientos (p.ej. anestésicos locales, terapias complementarias).

Seguridad:

Se realizaron tres tipos de análisis para calcular la frecuencia y las clases de reacciones medicamentosas adversas a corto plazo al diclofenac en niños de menos de 18 años de edad:

  1. Una comparación cuantitativa de las reacciones adversas en pacientes que recibieron y que no recibieron diclofenac de los ECA.

  2. Un análisis de los eventos adversos informados en todos los estudios en los cuales se conocía el número total de niños expuestos al diclofenac. Este análisis incluyó ECA cegados y abiertos, comparaciones abiertas no aleatorias y auditorías prospectivas y retrospectivas.

  3. Un análisis cualitativo de los informes de casos de las reacciones adversas al diclofenac informados en la bibliografía y a los organismos de regulación. Se realizó una consulta a la Medicines and Healthcare Regulatory Authority (MHRA) sobre las reacciones adversas al diclofenac en niños menores de 18 años con los datos de la Yellow Card Scheme. También se consultó al centro Uppsala de Monitorización de la Organización Mundial de la Salud (OMS). Estos datos se combinaron con los informes de casos de la revisión bibliográfica.

Los estudios incluidos en las categorías citadas 1 y 2 se clasificaron como de calidad alta, moderada o baja según los criterios expuestos en la Tabla adicional 1. Ver Tabla 1

Resultados

Descripción de los estudios

Ver: Características de los estudios incluidos; Características de los estudios excluidos.

La búsqueda produjo 1094 estudios (no se incluye la búsqueda manual de Anestesia Pediátrica). La selección inicial de los resúmenes de estos estudios fue realizada por IS y JFS. Cuando no quedaba claro a partir del resumen si un estudio debía incluirse, o si no se disponía de un resumen, se obtuvo el artículo completo.

Se seleccionaron 142 artículos para evaluarlos en profundidad. de éstos, 63 fueron excluidos (Características de los estudios excluidos) y 79 (74 ensayos más cinco informes de casos) cumplieron los criterios de inclusión (Características de los estudios incluidos). Estos 79 artículos aportaron datos sobre 3616 participantes expuestos al diclofenac.

Eficacia:

Siete estudios (Baer 1992; Bone 1988; Littlejohn 1996; Nishina 2000; Samarkandi 2005; Tay 2002; Watters 1988) eran ECA que comparaban diclofenac perioperatorio (168 niños) ya sea con placebo/ningún tratamiento (178) o con otro analgésico (58 niños). Lamentablemente cada estudio usó diferentes escalas o métodos para cuantificar el dolor, por lo tanto no se pudo combinar los resultados. Sin embargo, estos estudios efectivamente informaron el número de participantes que requirieron analgesia de rescate en cada grupo, lo que permitió realizar una comparación combinada (Análisis 1.1; Análisis 2.1; Figura 1; Figura 2).

Seguridad:

  1. Dieciocho ECA (incluidos los ECA del análisis de eficacia) informaron la monitorización de los eventos adversos (Análisis 3.1; Análisis 3.2; Análisis 4.1; Análisis 4.2; Figura 3; Figura 4; Figura 5).

  2. Setenta y cuatro estudios (los 18 ECA mencionados más otros 56) contenían información sobre el número total de niños expuestos al diclofenac (3611), además de pruebas de la monitorización de los efectos adversos.

  3. Se identificaron cinco informes de casos adicionales: (Lai 2005; Nikolic 2001; Seaton 2000; Sen 2001; Robinson 1994). Además de estos informes de casos, se incluyeron datos de 77 reacciones adversas al diclofenac de la Medicines and Healthcare products Regulatory Agency (MHRA) del Committee of Safety of Medicine Yellow Card Scheme. No se incluyeron los datos del centro Uppsala de Monitorización de la OMS en el análisis final, por los siguientes motivos.

Tras una evaluación más profunda, se excluyeron 63 estudios. El motivo principal de exclusión fue que todos los participantes eran mayores de 18 años de edad, o bien, cuando hubo niños y adultos, no fue posible extraer los datos de los niños. Un número pequeño de artículos analizó el diclofenac de uso externo.

Riesgo de sesgo en los estudios incluidos

Los detalles de la evaluación de la calidad de cada uno de los 74 estudios incluidos en esta revisión pueden encontrarse en la tabla “Características de los estudios incluidos".

Solamente 18 estudios tuvieron una calidad adecuada para el análisis comparativo de seguridad (los 18) o de eficacia (7 de 18). Excepto dos, todos los estudios trataron la administración de diclofenac durante el período perioperatorio; los estudios restantes (Gananca 1991; Miniti 1993) incluyeron a participantes con amigdalitis tratados exclusivamente con antibióticos y analgésicos. Se estableció contacto con los autores de todos los estudios que hubieran excluido participantes del análisis. En caso de no recibir respuesta, o si la información no fue suficiente, se procedió a excluir el estudio sin realizar un análisis por intención de tratar.

Eficacia:

La principal medida de eficacia que permitió combinar los resultados de los estudios fue el uso de analgesia de rescate proporcionada por una persona cegada a la asignación al tratamiento. En un ECA, solamente siete estudios cumplieron estos criterios. Cinco estudios (Bone 1988, amigdalectomía; Littlejohn 1996, extracción dental; Nishina 2000, cirugía ocular; Samarkandi 2005, herniotomía; Watters 1988, amigdalectomía) eran estudios de control con placebo/ningún tratamiento en los cuales los fármacos del estudio se administraban en el quirófano tras la inducción. De este modo se impide el sesgo del paciente, aunque es posible que halla otros tipos de sesgos ya que los autores aportaron escasos datos acerca de quién conservaba los códigos de la asignación al tratamiento, o acerca de cómo se mantuvo el cegamiento del tratamiento luego de abandonar el quirófano.

Los dos estudios que compararon diclofenac versus paracetamol (Baer 1992, amigdaloadenoidectomía; Tay 2002, timpanotomía) fueron de inferior calidad, ya que no era seguro que los fármacos se dieran en el quirófano y hubo una mayor incertidumbre acerca del cegamiento del tratamiento.

Se impusieron criterios levemente diferentes para la inclusión de estudios en los análisis comparativos de eficacia y de seguridad. Como se empleó la analgesia de rescate para marcar la eficacia, sólo se incluyeron los estudios donde la persona que administró la analgesia de rescate estaba cegada al tratamiento. Para las comparaciones de efectos adversos (náuseas o vómitos, y hemorragia que requirió intervención quirúrgica), se incluyeron los estudios desenmascarados.

Seguridad:

  1. El análisis comparativo de seguridad incluyó cuatro estudios desenmascarados (Gananca 1991; McGowan 1998; Miniti 1993; Tawalbeh 2001). Dos estudios afirmaban que hubo cegamiento, pero no aportaron mayores datos sobre el método empleado (Baer 1992; Tay 2002), por lo tanto se los incluyó en ambos análisis comparativos de eficacia y de seguridad, aunque con un riesgo de sesgo del investigador.

  2. La mayoría de los 74 estudios que aportaron los datos del denominador para las reacciones adversas se calificaron como moderados según los criterios de calidad de la seguridad (consultar tablaAdicional 1), la mayoría no cumplió con los criterios por no seguir a los participantes después del alta.

  3. El análisis final de informes de casos de reacciones graves no incluyó los datos de la OMS. En primer lugar, no hubo indicios de que el diclofenac fuera prescrito para el dolor agudo o para los trastornos crónicos, y la presente revisión se centra exclusivamente en el diclofenac para el dolor agudo. En segundo lugar, no se pudo asegurar, a partir de los datos de la Yellow Card, cuáles de los informes de la lista de la OMS estaban duplicados.

Efectos de las intervenciones

Eficacia:

Como se indicó anteriormente, la única medida de dolor que pudo usarse para comparar los estudios era la decisión, de un evaluador cegado, de administrar analgesia de rescate. Comparación 01/01 (Análisis 1.1; Figura 1) incluye 239 participantes de cinco estudios (Bone 1988; Watters 1988; Littlejohn 1996; Nishina 2000; Samarkandi 2005) que comparan un tratamiento analgésico perioperatorio con o sin diclofenac, y hallaron que el diclofenac disminuye significativamente el número de niños que requirieron analgesia de rescate (RR 0,6; IC del 95%: 0,5 a 0,7). La proporción de participantes que requirieron analgesia de rescate después de recibir diclofenac fue de 39,5% (47/119); rango entre 5% (extracciones dentales) y 70% (herniotomía). La proporción de participantes que requirieron analgesia de rescate con placebo/ningún tratamiento fue de 67% (80/120); rango 25% (extracción) y 100% (amigdalectomía). Estas cifras acusan un NNT para prevenir la necesidad de analgesia de rescate de 3,6 (IC del 95%: 2,5 a 6,3).

Los dos estudios (Baer 1992; Tay 2002) que compararon 107 niños asignados al azar al diclofenac o al paracetamol (Análisis 2.1; Figura 2) hallaron una reducción similar, aunque no significativa, en la necesidad de analgesia de rescate.

Seguridad:

Sólo un estudio (Romsing 2000) proporcionó una comparación directa entre el diclofenac y otro tratamiento (fármaco no AINE) con estandarización del resto de los fármacos administrados. Sin embargo, se realizaron análisis de tipo intención de tratar de la prevalencia de los eventos adversos de náuseas o vómitos, y hemorragia que requirió intervención quirúrgica (Análisis 3.1; Análisis 3.2; Análisis 4.1; Análisis 4.2). Una combinación de 13 estudios (Bhattacharya 2005; Baer 1992; Bone 1988; Littlejohn 1996; McGowan 1998; Nishina 2000; Oztekin 2002; Romsing 2000; Samarkandi 2005; Tawalbeh 2001; Tay 2002; Thiagarajan 1993; Watters 1988) que incluyó a 775 niños asignados al azar al diclofenac u otro tratamiento con fármacos no AINE (placebo, paracetamol u opioides) (Análisis 3.1; Figura 3) halló que el diclofenac redujo significativamente la incidencia de náuseas o vómitos. La proporción de participantes que manifestaron náuseas y vómitos después del diclofenac perioperatorio fue del 18% (69/389); rango entre 0% (amigdaloadenoidectomía; extracción dental; circuncisión; timpanotomía; herniotomía) a 56% (amigdalectomía). La proporción de participantes con náuseas y vómitos después de cualquier otro tratamiento con fármacos no AINE fue del 31% (119/386); rango entre 0% (timpanotomía; amigdaloadenoidectomía) y 80% (amigdalectomía). Estas cifras acusan un NNT para prevenir de 7,7 (5,3 a 14,3).

Siete estudios evaluaron la hemorragia que requirió intervención quirúrgica (Baer 1992; Berry 1992a; Gadiyar 1995; Littlejohn 1996; McGowan 1998; Tawalbeh 2001; Thiagarajan 1993) e incluyeron a 463 niños asignados al azar al diclofenac o cualquier otro tratamiento con fármacos no AINE (Análisis 3.2; Figura 4); no se hallaron diferencias significativas en ninguno de los brazos de tratamiento. Cuatro estudios compararon la incidencia de las náuseas o vómitos en 289 participantes asignados al azar para recibir diclofenac u otro AINE (Gananca 1991; Mendham 1996; Miniti 1993; Nishina 2000). Estos estudios no hallaron diferencias significativas en la incidencia de náuseas o vómitos con diclofenac y con otros AINE (Análisis 4.1; Figura 5).

En el análisis de los eventos adversos graves, 3611 niños recibieron al menos una dosis de diclofenac para el dolor agudo, y 74 estudios monitorizaron los eventos adversos (todos los estudios se enumeran en la tabla adicional 1 "Características de los estudios incluidos"). Hubo 26 eventos adversos graves (ver Tabla 2 adicional ). Todas las complicaciones, excepto tres, fueron complicaciones postoperatorias y los autores no especificaron si el responsable era el diclofenac. Tres casos de dos estudios (ver Tabla adicional 2) analizaron el uso del diclofenac para el tratamiento no quirúrgico del dolor en la amigdalitis. Ambos autores. (Duarte 1997; Kierszenbaum 1991) consideraron que estos eventos fueron causados por el diclofenac y se suspendió el fármaco. Por lo tanto, la incidencia de reacciones adversas graves al diclofenac (intervalo de confianza del 95%) es de 0,08% (0,02 a 0,24%).

Se identificaron cinco informes de casos de eventos adversos graves: Lai 2005 (necrosis tisular después de una inyección intramuscular), Nikolic 2001 (nefritis tubulointersticial), Seaton 2000 (vasculitis gastrointestinal), Sen 2001 (mortalidad por reacciones de tipo alérgico) y Robinson 1994 (tres casos de hemorragia postamigdalectomía atribuida al diclofenac en una revisión retrospectiva). Ver Tabla 2

La Tabla adicional 3 presenta un resumen de informes de casos publicados combinado con los datos de la Yellow Card. De estos 77 casos, 29 estaban relacionados con niños tratados con diclofenac por trastornos crónicos, la indicación fue poco clara en 12 casos, y en 36 casos los participantes recibían tratamiento para el dolor agudo. Ocho de las reacciones fueron clasificadas por el investigador como no graves, 49 no se clasificaron y 20 se informaron como graves. De éstas, seis eran reacciones graves en el sitio de la inyección intramuscular. Ver Tabla 3

Hubo dos muertes, una a causa de una reacción aguda de tipo alérgico que desencadenó una respuesta inflamatoria y broncoespasmo, y una hemorragia gástrica que derivó en una peritonitis; ambas se produjeron en participantes tratados con diclofenac para el dolor agudo. No se disponía de denominador para estos datos, en consecuencia no se pudo determinar la incidencia de estas reacciones adversas.

Los estudios analizados informaron un rango cinco veces superior para las dosis únicas de diclofenac para el dolor agudo en niños: desde 0,5 mg/kg (Tay 2002) hasta 2,5 mg/kg (McGowan 1998). Todos los estudios farmacocinéticos eran descriptivos (Korpela 1990; Murphy 2000; van der Marel 2004), y ninguno procuró recomendar una dosis.

Ningún estudio informó el uso de diclofenac para el dolor agudo en niños asmáticos; los niños asmáticos o bien se excluyeron, o no se informó al respecto. Se le preguntó a cada uno de los autores consultados por otros motivos si algunos de los participantes eran asmáticos, pero ninguno pudo aportar números concretos al respecto.

Discusión

Esta revisión se centró en evaluar el posicionamiento del diclofenac en el tratamiento del dolor agudo en niños utilizando variables principales de evaluación relevantes para las situaciones clínicas. Si bien se trató de incluir todo tipo de dolor agudo, la gran mayoría de los estudios se realizó durante el período perioperatorio. Esto posiblemente refleje el hecho de que ciertas afecciones como el cólico renal son relativamente poco frecuentes y resultaría difícil estudiar la aparición súbita de estas afecciones dentro de un ensayo clínico. Por el contrario, el dolor postoperatorio es frecuente en la mayoría de los niños sometidos a una cirugía, y las intervenciones quirúrgicas suelen programarse y se realizan en un ambiente controlado propicio para los estudios clínicos.

Para la evaluación de la eficacia, no se pudieron combinar estudios que usaran puntuaciones de dolor debido a la gran diversidad de métodos empleados. La administración de analgesia suplementaria o de rescate por un investigador cegado a la asignación de tratamientos efectivamente proporcionó una medida estable del dolor que pudo compararse entre los estudios de dolor postoperatorio. La comparación de tratamientos analgésicos que sólo difirieron en la administración de diclofenac (Análisis 1.1; Figura 1) reveló que el diclofenac redujo a la mitad el número de participantes que requirieron analgesia de rescate.

Se halló que en adultos el diclofenac (50 mg) es aproximadamente dos veces más efectivo que el paracetamol (1 g) para el dolor postoperatorio (McQuay 1998). Se demostró que cuando se compara el diclofenac (0,5 mg/kg o dosis fija de 12,5 mg) con el paracetamol (15 mg/kg o dosis fija de 125 mg) (Análisis 2.1; Figura 2) la mitad de los niños tratados con diclofenac requirieron analgesia de rescate. Sin embargo, los números de este análisis fueron pequeños y la comparación no fue estadísticamente significativa.

No se pudo determinar a partir de los informes publicados si los participantes con eventos adversos (como náuseas o vómitos) también habían recibido analgesia de rescate. Esto significa que posiblemente ambos grupos no hayan recibido exactamente los mismos tratamientos. En la comparación de participantes asignados al azar para recibir diclofenac con otro fármaco no AINE (placebo, paracetamol u opioides) se halló una menor incidencia informada de náuseas o vómitos (Análisis 3.1; Figura 3) y no hubo diferencias en la tasa de hemorragia que requirió intervención quirúrgica (Análisis 3.2; Figura 4).

Existen diversas posibles explicaciones sobre el motivo por el cual los participantes asignados al azar al diclofenac manifestaron menos náuseas o vómitos. Debido a que el diclofenac proporcionó una mejor analgesia (Análisis 1.1; Figura 1), esto significó que más participantes del grupo de control recibieron analgesia de rescate, lo que de por sí podría resultar emetógeno. Aunque la analgesia de rescate no cause náuseas o vómitos, se ha sugerido que una adecuada analgesia puede reducir la incidencia de náuseas durante el período perioperatorio (Michaloliakou 1996), esto significa que las diferencias de eficacia podrían incidir en las diferencias en los eventos adversos.

Como en el caso de una revisión anterior sobre AINE en niños (Cardwell 2005) se investigó la hemorragia que requirió intervención quirúrgica y no se hallaron diferencias en las tasas entre los participantes asignados al azar al diclofenac y a otros fármacos no AINE. Entre los estudios que contribuyeron con la Comparación 03/02 (Análisis 3.1), tres estudios (Berry 1992a; Tawalbeh 2001; Thiagarajan 1993) se incluyeron niños sometidos a cirugía de alto riesgo en términos de hemorragia postoperatoria (amigdalectomía). Si bien esto puede sugerir que las dosis terapéuticas de diclofenac no inhiben la agregación plaquetaria dependiente de la COX-1 en un grado clínicamente significativo, es posible que factores como la inquietud debida una analgesia insuficiente durante el período postoperatorio colabore con la hemorragia. Los efectos analgésicos del diclofenac podrían entonces resultar en una menor inquietud y de este modo compensaría un posible aumento del riesgo de hemorragia.

Los datos sobre la seguridad se obtuvieron de 74 estudios que publicaron el número total de niños expuestos al diclofenac como tratamiento del dolor agudo, además hubo pruebas de que se investigaron los eventos adversos. La mayoría de estos estudios (56) no eran ensayos controlados; el objetivo fue realizar un análisis telemétrico como el descrito por Aronson 2005, en el cual se consideró que cada uno de los estudios estaba presente para aportar datos a la visión global de la seguridad del diclofenac en niños tratados por dolor agudo. El aporte de cada estudio correspondió a la evaluación personal de los revisores acerca de las causas probables de las reacciones adversas informadas por ellos mismos.

La inclusión de estudios en los cuales se monitorizaron los eventos adversos y donde se conocía el número de participantes con diclofenac para el dolor agudo permitió estimar la incidencia de reacciones medicamentosas graves causadas por el diclofenac. Hubo 26 eventos adversos graves sobre un total de 3611 niños (ver Tabla adicional 2 para consultar las referencias). Como se mencionó anteriormente, la persona que decidió si los eventos adversos fueron causados por el diclofenac fue el propio revisor. La mayoría de los eventos adversos eran las habituales complicaciones postoperatorias y los autores opinaron que ninguno de los eventos se debió al diclofenac. Se consideró que otros tres eventos adicionales fueron causados por el diclofenac (ver Tabla adicional 2). Por lo tanto, la incidencia (IC del 95%) de reacciones adversas graves causadas por el diclofenac como tratamiento del dolor agudo fue de 0,08% (0,02 a 0,24%).

El análisis cualitativo de los informes de casos halló que los niños parecen sufrir tipos similares de reacciones adversas graves al diclofenac que los adultos. Una revisión retrospectiva responsabilizó al diclofenac por la hemorragia posterior a la amigdalectomía en tres casos (Robinson 1994). Probablemente la causa de la hemorragia postoperatoria sea multifactorial, y podría incluir la depleción de factores de la coagulación, la inquietud durante el período postoperatorio y los trastornos hematológicos como la inhibición de la agregación plaquetaria. Para determinar si el diclofenac es un factor causal en la hemorragia postoperatoria, se analizaron estudios comparativos (Análisis 3.2; Figura 4), y no se halló un aumento del riesgo de hemorragia en los 463 niños tratados con diclofenac u otro fármaco no AINE. Una revisión sistemática de estudios comparativos sobre los AINE y la hemorragia con necesidad de intervención quirúrgica que incluyó a 955 niños sometidos a amigdalectomía (Cardwell 2005) tampoco halló un aumento en la hemorragia con los AINE. Los seis informes de casos de reacciones adversas graves en el sitio de inyección intramuscular revelaron que esta vía de administración no es apropiada para los niños.

Conclusiones de los autores

Implicaciones para la práctica

El diclofenac es un analgésico efectivo para el dolor agudo en niños, y su uso como parte del tratamiento analgésico durante el período perioperatorio reduciría la incidencia de náuseas o vómitos, o ambos. Al parecer, el diclofenac no aumenta la incidencia de hemorragia perioperatoria que requiere intervención quirúrgica, aunque se necesitan más pacientes para confirmar esta conjetura. Por lo tanto, la incidencia (IC del 95%) de reacciones adversas graves causadas por el diclofenac, administrado luego de la cirugía, fue de 0,08% (0,02 a 0,24%).


Implicaciones para la investigación

Resta evaluar cuál es la dosis óptima de diclofenac para el dolor agudo en niños, la presente revisión halló un rango con valores cinco veces superiores en las dosis únicas (0,5 a 2,5 mg/kg). No se sabe cuál es la prevalencia del broncoespasmo en los niños asmáticos tratados con diclofenac. Resultaría útil que los futuros estudios sobre los AINE en niños informaran el número de pacientes asmáticos incluidos; también sería útil contar con un estudio que investigue la frecuencia del broncoespasmo en niños asmáticos para que el profesional a cargo pueda decidir si debe negar o no un tratamiento analgésico efectivo a los niños asmáticos.


Agradecimientos

Se desea dar las gracias a las siguientes personas por su ayuda con la traducción: Maria Carvalho (Gananca 1991; Marczyk 1992); Noriko Conday (Azuma 1982; Kurimoto 1993; Nakayama 1982); Kirsti Karu, Snezana Pejic and Veljko Zizic (Leontev 2004; Leontev 2005; Nikolic 2001; Rozhkova 1983); Antije Neubert (Fischer 1992; Thomaser 2004); Ji-won Choi (Yoo 1999).

Datos y análisis

Comparación 1. Diclofenac versus ningún tratamiento/placebo

Título del subgrupo o resultado

Nº de estudios

Nº de participantes

Método estadístico

Tamaño del efecto

1 Número de pacientes que requirieron analgesia de rescate

5

239

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.59 [0.47, 0.74]



Comparación 2. Diclofenac vs paracetamol

Título del subgrupo o resultado

Nº de estudios

Nº de participantes

Método estadístico

Tamaño del efecto

1 Número de pacientes que requirieron analgesia de rescate

2

107

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.64 [0.40, 1.01]



Comparación 3. Diclofenac vs cualquier otro tratamiento

Título del subgrupo o resultado

Nº de estudios

Nº de participantes

Método estadístico

Tamaño del efecto

1 Náuseas y/o vómito

13

775

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

0.58 [0.47, 0.73]

2 Hemorragia que requirió intervención quirúrgica

7

463

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.25 [0.31, 4.97]



Comparación 4.Diclofenac versus otros AINE

Título del subgrupo o resultado

Nº de estudios

Nº de participantes

Método estadístico

Tamaño del efecto

1 Náuseas y/o vómito

4

289

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.24 [0.80, 1.92]

2 Hemorragia que requirió intervención quirúrgica

1

121

Cociente de riesgos (M-H, efectos fijos, IC del 95%)

1.63 [0.28, 9.41]



Apéndices

Appendix 1. EMBASE search strategy

1. diclofenac$ (textword)
2. diclofenac (subject heading) or diclofenac-potassium (subject heading) or diclofenac-diethylamine (subject heading) or diclofenac colestyramine (subject heading)
3. voltarol$ (textword) or Voltaren$ (textword) or diclomax (textword) or motifene (textword)
4. 1 or 2 or 3
5. (explode) pain subject heading
6. (explode) neuralgia (subject heading)
7. (explode) nociception (subject heading)
8. (pain or neuralgia or nociception or nociperception) and (manag$ or control$ or relief or relieve$) (textwords)
9. injur$ (textword) or fracture (textword) or headache (textword) or migraine (textword) or cephalalgia (textword) or hemicrania (textword) or neuralgi$ (textword) or hyperalgesi$ (textword) or earache (textword) or toothache (textword) or colic (textword)
10. postoperative-pain (subject heading) or kidney-colic (subject heading) or migraine (subject heading) or soft-tissue-injury (subject heading)
11. analgesi$ (textword) or antinocicept$ (textword)
12. (explode) analgesia (subject heading)
13. (explode) antinociception (subject heading)
14. postoperative-analgesia (subject heading)
15. 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14
16. child (textword) or adolescent (textword) or infant (textword) or paediatric (textword)
17. child (subject heading) or infant (subject heading) or baby (subject heading) or preschool-child (subject heading) or school-child (subject heading) or adolescent (subject heading)
18. 16 0r 17
19. 4 and 15 and 18

$ = truncation adj = adjacent to

Antecedentes

Primera publicación del protocolo: Número 4, 2005
Primera publicación de la revisión: Número 4, 2009

Contribuciones de los autores

MW realizó la búsqueda en la literatura. IS y JS buscaron las referencias, extrajeron y analizaron los datos y redactaron la revisión. Todos los autores diseñaron conjuntamente el protocolo y aportaron opiniones. IS será responsable de realizar la actualización de esta revisión.

Declaraciones de interés

No se buscó un financiamiento específico para esta revisión. JFS recibió una beca de investigación para médicos de Rosemont Pharmaceuticals para realizar estudios clínicos de seguridad y farmacocinéticos de diclofenac en niños. Rosemont Pharmaceuticals no promovió esta revisión sistemática ni formó parte de la conducción, la redacción, la edición ni la aprobación de su publicación.

Fuentes de financiación

Recursos internos

  • No specific funding was sought for this review, Not specified.

Recursos externos

  • No sources of support supplied

Información de contacto

Authors: Joseph F Standing2, Imogen Savage1, Deborah Pritchard3, Marina Waddington4


1School of Pharmacy, University of London, Department of Practice and Policy, 29-39 Brunswick Square, London, UK

2Uppsala Universitet, Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy, Uppsala Universistet BMC Box 591, Uppsala, Sweden

3Market Towers, MHRA Post Licensing Division Rm 13-207, 1 Nine Elms Lane, London, UK

4Royal Free Hospital, Medical Library, Rowland Hill Street, London, UK

Contact: Imogen Savage1 imogen.savage@pharmacy.ac.uk. Editorial group: Cochrane Pain, Palliative and Supportive Care Group (HM-SYMPT)

Referencias

( * indica la publicación principal del estudio)

Referencias de los estudios incluidos en esta revisión

Akinci 2005 {published data only}

Akinci SB, Kanbak M, Guler A, Aypar U. Remifentanil versus fentanyl for short-term analgesia-based sedation in mechanically ventilated postoperative children. Paediatric Anaesthesia 2005; 15(10): 870-8.

Andrzejowski 2002 {published and unpublished data}

Andrzejowski J, Lamb L. The effect of swabs soaked in bupivacaine and epinephrine for pain relief following simple dental extractions in children. Anaesthesia 2002; 57(3): 281-3.

Azuma 1982 {published data only}

Azuma F. The clinical efficacy and plasma concentration of a 25 mg suppository of diclofenac sodium in children with post-tonsillectomy pain and inflammation. Practica Otologica 1982; 75(6): 1445-53.

Baer 1992 {published data only}

Baer GA, Rorarius MGF, Kolehmainen S, Selin S. The effect of paracetamol or diclofenac administered before operation on postoperative pain and behaviour after adenoidectomy in small children. Anaesthesia 1992; 47(12): 1078-80.

Bebawy 2005 {published data only}

Bebawy NW, El Quesny KM, Greiss HF, Said AM. The effect of balanced analgesia on the incidence and severity of emergence agitation in children after sevoflurane versus halothan anaesthesia. Egyption Journal of Anaesthesia 2005; 21: 177-80.

Berry 1992a {published data only}

Berry CB, Irwin MG, Best CJ, Morton NS. Intravenous diclofenac for analgesia after adenotonsillectomy in children. The Journal of the Pain Society 1992; 10: 29-32.

Bhattacharya 2005 {published data only}

Bhattacharya D, Mondol MC, Dasgupta S, Chakraborty R. A comparison of rectal diclofenac with intravenous pethidine for pain relief following tonsillectomy and adenoidectomy in children. Journal of Anaesthesia and Clinical Pharmacology 2005; 21(2): 143-6.

Bone 1988 {published data only}

Bone ME, Fell D. A comparison of rectal diclofenac with intramuscular papaveretum or placebo for pain relief following tonsillectomy. Anaesthesia 1988; 43(4): 277-80.

Borkar 2005 {published data only}

Borkar J, Dave N. Analgesic efficacy of caudal block versus diclofenac suppository and local anesthetic infiltration following pediatric laparoscopy. Journal of Laparoendoscopic & Advanced Surgical Techniques 2005; 15(4): 415-8.

Duarte 1997 {published data only}

Duarte JLB. Comparative assessment on the efficacy and tolerability of nimesulide, diclofenac and dipyrone applied to inflammatory processes of the superior respiratory tract in the paediatric population [Avaliacai comparativa da eficacia e tolerabilidade do nifesuline, diclofenaco e dipirona sodica aplicados aos processos inflamatorios do trato respiratorio superior em populacao pediatrica]. Pediatria Moderna 1997; 33(4): 208-12.

Elhakim 2003 {published data only}

Elhakim M, Khalafallah Z, El F, Farouk S, Khattab A. Ketamine reduces swallowing-evoked pain after paediatric tonsillectomy. Acta Anaesthesiologica Scandinavica 2003; 47(5): 604-9.

Engelhardt 2001 {published data only}

Engelhardt T, Crawford M. Sublingual morphine may be a suitable alternative for pain control in children in the postoperative period. Paediatric Anaesthesia 2001; 11(1): 81-3.

Engelhardt 2003 {published data only}

Engelhardt T, Steel E, Johnston G, Veitch DY. Tramadol for pain relief in children undergoing tonsillectomy: A comparison with morphine. Paediatric Anaesthesia 2003; 13(3): 249-52.

Ericsson 2006 {published data only}

Ericsson E, Wadsby M, Hultcrantz E. Pre-surgical child behaviour ratings and pain management after two different techniques of tonsil surgery. International Journal of Pediatric Otorhinolaryngology 2006; 70: 1749-58.

Filatov 2000 {published data only}

Filatov SM, Baer GA, Rorarius MG, Oikkonen M. Efficacy and safety of premedication with oral ketamine for day-case adenoidectomy compared with rectal diazepam/diclofenac and EMLA. Acta Anaesthesiologica Scandinavica 2000; 44(1): 118-24.

Findlow 1997 {published data only}

Findlow D, Aldridge LM, Doyle E. Comparison of caudal block using bupivacaine and ketamine with ilioinguinal nerve block for orchidopexy in children. Anaesthesia 1997; 52(11): 1110-3.

Fischer 1992 {published data only}

Fischer J, Stachel P, Schulze G. Antiphlogistic postoperative therapy: Less side-effects with serratiopeptidase. Therapiewoche 1992; 42: 2980-5.

Fosel 2005 {published data only}

Fosel T, Fotsch S, Ebeling O. Postoperative pain therapy after tonsillectomy in children [Postoperative schmerztherapie nach tonsillektomie im kindesalter]. HNO 2005; 53: 722-7.

Funk 2008 {published data only}

Funk W, Hollnberger H, Geroldinger J. Physostigmine and anaesthesia emergence delirium in preschool children: a randomised blinded trial. European Journal of Anaesthesiology 2008; 25: 37-42.

Gadiyar 1995 {published data only}

Gadiyar V, Gallagher TM, Crean PM, Taylor RH. The effect of a combination of rectal diclofenac and caudal bupivacaine on postoperative analgesia in children. Anaesthesia 1995; 50(9): 820-2.

Gananca 1991 {published data only}

Gananca MM, Munhoz MSL, Caovilla HH, Munhoz ML, Gananca FF. Comparative study of nimesulide oral suspension versus diclofenac resinate in children suffering from pharyngo-tonsillitis. Revista Brasileira de Medicina 1991; 48: 120-2.

Hanafy 2004 {published data only}

Hanafy MA, El Z, Swellam AM. The effect of dexmedetomidine on the emergence agitation associated with desflurane anaesthesia in children. Egyptian Journal of Anaesthesia 2004; 20(2): 135-40.

Holder 1997 {published data only}

Holder KJ, Peutrell JM, Weir PM. Regional anaesthesia for circumcision. Subcutaneous ring block of the penis and subpubic penile block compared. European Journal of Anaesthesiology 1997; 14(5): 495-8.

Homer 2002 {published data only}

Homer JJ, Frewer JD, Swallow J, Semple P. An audit of post-operative analgesia in children following tonsillectomy. Journal of Laryngology and Otology 2002; 116(5): 367-70.

Hultcrantz 2004 {published data only}

Hultcrantz E, Ericsson E. Pediatric Tonsillotomy with the Radiofrequency Technique: Less Morbidity and Pain. Laryngoscope 2004; 114(5): 871-7.

Kierszenbaum 1991 {published data only}

Kierszenbaum JS, Vitral BG, Kierszenbaum AML, de Sousa PR. Evaluation of nimesulide oral suspension versus diclofenac resinate in upper respiratory tract infections in paediatrics [Avaliacao do nimesulide suspensao oral versus diclofenaco resinato em infeccoes das vias aereas superiores na pediatria]. Pediatria Moderna 1991; 27(7): 560-2.

Kokinsky 1999 {published and unpublished data}

Kokinsky E, Thornberg E, Ostlund AL, Larsson LE. Postoperative comfort in paediatric outpatient surgery. Paediatric Anaesthesia 1999; 9(3): 243-51.

Korpela 1990 {published and unpublished data}

Korpela R, Olkkola KT. Pharmacokinetics of intravenous diclofenac sodium in children. European Journal of Clinical Pharmacology 1990; 38: 293-5.

Kurokawa 2002 {published data only}

Kurokawa Y, Kanayama HO, Anwar A, Fukumori T, Yamamoto Y, Takahashi M, et al. Laparoscopic nephroureterectomy for dysplastic kidney in children: An initial experience. International Journal of Urology 2002; 9(11): 613-7.

Lai 2005 {published data only}

Lai M, Huang YC, Yao PC. Tissue necrosis after intramuscular administration of diclofenac: report of one case. Acta Paediatrica Taiwan 2005; 46: 24-6.

Lambert 2000 {published and unpublished data}

Lambert AW, Mayor A. Analgesic requirements for appendicectomy: The differences between adults and children. Annals of the Royal College of Surgeons of England 2000; 82(2): 111-2.

Leontev 2004 {published data only}

Leontev DV, Babaev BD, Shishkov MV, Povarnin OI, Ostreikov IF. Postoperative analgesia with nonsteroid anti-inflammatory drugs in children. Anesteziologiia i Reanimatologiia 2004; 1: 54-7.

Leontev 2005 {published data only}

Leontev DV, Babayev BD, Shishkov MV, Ostreikov IF. Haemodynamic changes in the use of nonsteroidal anti-inflammatory drugs and paracetamol in postoperative analgesia in children [In Russian characters]. Anesteziologiia I Reanimatologiia 2005; 1: 22-5.

Littlejohn 1996 {published data only}

Littlejohn IH, Tarling MM, Flynn PJ, Ordman AJ, Aiken A. Post-operative pain relief in children following extraction of carious deciduous teeth under general anaesthesia: A comparison of nalbuphine and diclofenac. European Journal of Anaesthesiology 1996; 13(4): 359-63.

Mak 2001 {published data only}

Mak MYL, Philip AE, Cho SC, Chan JTM. Postoperative analgesia in children day surgery circumcision: Comparison of three methods. Annals of the College of Surgeons of Hong Kong 2001; 5(4): 146-50.

Martindale 2004 {published data only}

Martindale SJ, Dix P, Stoddart PA. Double-blind randomized controlled trial of caudal versus intravenous S(+)-ketamine for supplementation of caudal analgesia in children. British Journal of Anaesthesia 2004; 92(3): 344-7.

McGowan 1998 {published and unpublished data}

McGowan PR, May H, Molnar Z, Cunliffe M. A comparison of three methods of analgesia in children having day case circumcision. Paediatric Anaesthesia 1998; 8(5): 403-7.

Mendham 1996 {published and unpublished data}

Mendham JE, Mather SJ. Comparison of diclofenac and tenoxicam for postoperative analgesia with and without fentanyl in children undergoing adenotonsillectomy or tonsillectomy. Paediatric Anaesthesia 1996; 6(6): 467-73.

Menezes 2002 {published data only}

Menezes MS, Gozzani JL. Postoperative analgesia in pediatric patients: comparative study among local anesthetics, opioids and non-steroidal anti-inflammatory drugs. Revista Brasileira de Anestesiologia. Revista Brasileira de Anestesiologia 2002; 52: 175-84.

Mikawa 1995 {published data only}

Mikawa K, Nishina K, Maekawa N, Asano M, Obara H. Oral clonidine premedication reduces vomiting in children after strabismus surgery. Canadian Journal of Anaesthesia 1995; 42(11): 977-81.

Miniti 1993 {published data only}

Miniti A, Bento RF, Senes LU. Comparative study with nimesulide drops versus diclofenac resinate in the treatment of pharyngo-tonsillitis in childhood [Estudo comparativo de nimesulide gotas versus diclofenaco resinato no tratamento de faringo-amigdalites na infancia]. Arquivos Brasileiros de Medicina 1993; 76; 76(4): 263-7.

Moores 1990 {published data only}

Moores MA, Wandless JG, Fell D. Paediatric postoperative analgesia. A comparison of rectal diclofenac with caudal bupivacaine after inguinal herniotomy. Anaesthesia 1990; 45(2): 156-8.

Morton 1999 {published data only}

Morton NS, Brien K. Analgesic efficacy of paracetamol and diclofenac in children receiving PCA morphine. British Journal of Anaesthesia 1999; 82(5): 715-7.

Mukherjee 2001 {published and unpublished data}

Mukherjee K, Esuvaranathan V, Streets C, Johnson A, Carr AS. Adenotonsillectomy in children: A comparison of morphine and fentanyl for peri-operative analgesia. Anaesthesia 2001; 56(12): 1193-7.

Murphy 2000 {published data only}

Murphy DB, Kavanagh P, O'Connor P, Sherrin P, McNamara S, O'Hare B. Pharmacokinetic profile of rectally administered diclofenac sodium in children undergoing adenotonsillectomy. Paediatric Anaesthesia. 2000; Vol. 10: 694-5.

Nakayama 1982 {published data only}

Nakayama K. Analgesic effect of voltaren suppository following tonsillectomy in children. Practica Otologica 1982; 75(6): 1455-60.

Nikolic 2001 {published data only}

Nikolic V, Bogdanovic R, Ognjanovic M, Stajic N. Acute tubulointerstitial nephritis in children. Srpski Arhiv za Celokupno Lekarstvo 2001; 129: 23-7.

Nishina 2000 {published data only}

Nishina K, Mikawa K, Shiga M, Takao Y, Maekawa N, Obara H. Diclofenac and flurbiprofen with or without clonidine for postoperative analgesia in children undergoing elective ophthalmological surgery. Paediatric Anaesthesia 2000; 10(6): 645-51.

Nordman 2006 {published data only}

Nordmann GR, Read JA, Sale SM, Stoddart PA, Wplf AR. Emergence and recovery in children after desflurane and isoflurane anaesthesia: effect of anaesthetic duration. British Journal of Anaesthesia 2006; 96(6): 779-85.

Nze 2006 {published data only (unpublished sought but not used)}

Nze PUN, Onyekwulu F. Intraoperative diclofenac for post-adenoidectomy analgesia in small children. Nigerian Journal of Clinical Practice 2006; 9(2): 102-4.

O'Donnell 2007 {published data only}

O'Donnell A, Henderson M, Fearne J, O'Donnell D. Management of postoperative pain in children following extractions of primary teeth under general analgesia: a comparison of paracetamol, Voltarol and no analgesia. International Journal of Paediatric Dentistry 2007; 17: 110-5.

Oztekin 2002 {published data only}

Oztekin S, Hepaguslar H, Kar AA, Ozzeybek D, Artikaslan O, Elar Z. Preemptive diclofenac reduces morphine use after remifentanil-based anaesthesia for tonsillectomy. Paediatric Anaesthesia 2002; 12: 694-99.

Riad 2007 {published data only (unpublished sought but not used)}

Riad W, Moussa A. Pre-operative analgesia with rectal diclofenac and/or paracetamol in children undergoing inguinal hernia repair. Anaesthesia 2007; 62: 1241-5.

Robinson 1994 {published data only}

Robinson PM, Ahmed I. Diclofenac and post-tonsillectomy haemorrhage. Clinical Otolaryngology and Allied Sciences 1994; 19(4): 344-5.

Romsing 2000 {published data only}

Romsing J, Ostergaard D, Drozdziewicz D, Schultz P, Ravn G. Diclofenac or acetaminophen for analgesia in paediatric tonsillectomy outpatients. Acta Anaesthesiologica Scandinavica 2000; 44(3): 291-5.

Ryhanen 1994 {published and unpublished data}

Ryhanen P, Adamski J, Puhakka K, Leppaluoto J, Vuolteenaho O, Ryhanen J. Postoperative pain relief in children. A comparison between caudal bupivacaine and intramuscular diclofenac sodium. Anaesthesia 1994; 49(1): 57-61.

Sahajananda 2003 {published data only}

Sahajananda H, Sanjay OP, Thomas J, Daniel B. General anaesthesia for lobectomy in an 8-year-old child with Kartagener's syndrome. Paediatric Anaesthesia 2003; 13(8): 714-7.

Samarkandi 2005 {published data only}

Samarkandi AH. Combined use of caudal bupivacaine and rectal diclofenac is not superior to the use of each analgesic regimen alone. Egyptian Journal of Anaesthesia 2005; 21(1): 63-6.

Schiffmann 2005 {published data only}

Schiffmann L, Kahrau S, Berger G, Buhr HJ. Colon perforation in an adolescent after short-term diclofenac intake. ANZ Journal of Surgery 2005; 75: 726-7.

Seaton 2000 {published and unpublished data}

Seaton RA, Nathwani D, Dick J, Smith D. Acute meningococcaemia complicated by late onset gastrointestinal vasculitis. Journal of Infection 2000; 41(2): 190-1.

Selin 2004 {published data only}

Selin BA, Ershov VL. Preventive analgesia and early postoperative period in ambulatory orthopedic surgeries in children. Anesteziologiia i Reanimatologiia 2004; 1: 29-31.

Sen 2001 {published data only}

Sen I, Mitra S, Gombar KK. Fatal anaphylactic reaction to oral diclofenac sodium (1). Canadian Journal of Anesthesia 2001; 48(4): 421.

Swanepoel 1999 {published and unpublished data}

Swanepoel A, Semple P. Oral versus rectal diclofenac for postoperative tonsillectomy pain in children. Anaesthesia 1999; 54(3): 298-9.

Sylaidis 1998 {published data only}

Sylaidis P, Neill TJ. Diclofenac analgesia following cleft palate surgery. Cleft Palate-Craniofacial Journal 1998; 35(6): 544-5.

Tawalbeh 2001 {published data only}

Tawalbeh MI, Nawasreh OO, Husban AM. Comparative study of diclofenac sodium and paracetamol for treatment of pain after adenotonsillectomy in children. Saudi Medical Journal 2001; 22(2): 121-3.

Tay 2002 {published data only}

Tay CLM, Tan S. Diclofenac or paracetamol for analgesia in paediatric myringotomy outpatients. Anaesthesia and Intensive Care 2002; 30(1): 55-9.

Tewary 1993 {published data only}

Tewary AK, Curry AR. Same-day tonsillectomy. The Journal of Laryngology and Otology 1993; 107: 706-8.

Thiagarajan 1993 {published and unpublished data}

Thiagarajan J, Bates S, Hitchcock M, Morgan H. Blood loss following tonsillectomy in children. A blind comparison of diclofenac and papaveretum. Anaesthesia 1993; 48(2): 132-5.

van der Marel 2004 {published data only}

van der Marel , Anderson BJ, Romsing J, Jacqz A, Tibboel D. Diclofenac and metabolite pharmacokinetics in children. Paediatric Anaesthesia 2004; 14(6): 443-51.

Varvinski 2001 {published data only}

Varvinski A, McGill FJ, Judd V, Hodzovic I. Soto's syndrome - A rare challenge?. Anaesthesia 2001; 56(8): 809.

Viitanen 2000 {published data only}

Viitanen H, Baer G, Annila P. Recovery characteristics of sevoflurane or halothane for day-case anaesthesia in children aged 1-3 years. Acta Anaesthesiologica Scandinavica 2000; 44(1): 101-6.

Vuori 2004 {published data only}

Vuori A, Salo M, Viljanto J, Pajulo O, Pulkki K, Nevalainen T. Effects of post-operative pain treatment using non-steroidal anti- inflammatory analgesics, opioids or epidural blockade on systemic and local immune responses in children. Acta Anaesthesiologica Scandinavica 2004; 48(6): 738-49.

Walmsley 1997 {published data only}

Walmsley AJ. Peri-operative use of nonsteroidal anti-inflammatory drugs in children. Anaesthesia 1997; 52(11): 1120.

Watters 1988 {published data only}

Watters CH, Patterson CC, Mathews HML, Campbell W. Diclofenac sodium for post-tonsillectomy pain in children. Anaesthesia 1988; 43(8): 641-3.

Wennstrom 2002 {published data only}

Wennstrom B, Reinsfelt B. Rectally administered diclofenac (Voltaren) reduces vomiting compared with opioid (morphine) after strabismus surgery in children. Acta Anaesthesiologica Scandinavica 2002; 46(4): 430-4.

Willey 2005 {published data only}

Willey SE, Griffiths DM, Nightingale JJ. Prospective randomised controlled trial comparing rectal versus oral paracetamol and diclofenac in children following appendicectomy. Acute Pain 2005; 7: 33-5.

Williams 2002 {published data only}

Williams DG, Patel A, Howard RF. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability. British Journal of Anaesthesia 2002; 89(6): 839-45.

Yamamoto 1994 {published data only}

Yamamoto I, Yukioka H, Fujimori M. Clinical study of postoperative sedation in pediatric patients. Effects of inhalation anesthetics and postoperative analgesics. Japanese Journal of Anesthesiology 1994; 43: 1191-5.

Yoo 1999 {published data only}

Yoo JW, Shin OY, Kang WJ, Choi YK, Kwon MI, Cho JS. Comparison of diclofenac or fentanyl for pain following tonsillectomy [In Korean characters]. Korean Journal of Anaesthesiology 1999; 36: 679-84.

Referencias de los estudios excluidos de esta revisión

Anon 2005 {published data only}

Anonymous . Tramadol oral solution: new drug. Poorly evaluated and potentially dangerous in children. Prescrire International 2005; 77(14): 83-5.

Arundel 2007 {published data only}

Arundel C, Lewis JH. Drug-induced liver disease in 2006. Current Opinion in Gastroenterology 2007; 23(3): 244-54.

Bano 2004 {published data only}

Bano F, Haider S, Sultan ST. Comparison of caudal bupivacaine and bupivacaine-midazolam for peri and postoperative analgesia in children. Journal of the College of Physicians and Surgeons Pakistan 2004; 14(2): 65-8.

Baroni 1983 {published data only}

Baroni L, Grossi E, Trombetta N. Multicenter study on the use of injectable diclofenac in pain states: analysis of the clinical data on 1873 patients. La Clinica terapeutica 1983; 106(6): 447-56.

Berry 1992b {published data only}

Berry CB, Morton NS. Venous sequelae of diclofenac. British Journal of Anaesthesia 1992; 69(3): 332.

Bertin 1991 {published data only}

Bertin L, Pons G, d'Athis P, Lasfargues G, Maudelonde C, Duhamel JF, Olive G. Randomized, double-blind, multicenter, controlled trial of ibuprofen versus acetaminophen (paracetamol) and placebo for treatment of symptoms of tonsillitis and pharyngitis in children. Journal of Pediatrics 1991; 119(5): 811-4.

Bruce 2006 {published data only}

Bruce E, Franck L, Howard RF. The efficacy of morphine and Entonox analgesia during chest drain removal in children. Paediatric Anaesthesia 2006; 16(3): 302-8.

Camera 1992 {published data only}

Camara PR, Lins B. Diclofenac in microgranules of planned release: evaluation of its effectiveness and tolerability in patients with traumatic injuries and rheumatic conditions extra-to articulate [Diclofenaco em microgranulos de liberacao planejada: avaliacao da sua eficacia e tolerabilidade em pacientes com lesoes traumaticas e condicoes reumaticas extra-articulares.]. Folha Medica 1992; 104: 31-4.

Campbell 1990 {published data only}

Campbell WI, Kendrick R, Patterson C. Intravenous diclofenac sodium: does its administration before operation suppress postoperative pain?. Anaesthesia 1990; 45: 763-6.

Castro 1995 {published data only}

Castro MCD. Action of potassium diclofenac in the inflammatory processes of various etiologies [Acao do diclofenaco potassico nos processos inflamatorios de varias etiologias – estuto multicentrico]. Folha Medica 1995; 111: 87-91.

Courtney 2001 {published data only}

Courtney MJ, Cabraal D. Tramadol vs diclofenac for posttonsillectomy analgesia. Archives of Otolaryngology - Head and Neck Surgery 2001; 127: 385-8.

Cuvellier 2005 {published data only}

Cuvellier JC, Joriot S, Auvin S, Vallee L. Pharmacologic treatment of acute migraine attack in children. Archives de Pediatrie 2005; 12(3): 316-25.

Farsi 2007 {published data only}

Farsi M, Gitto L. A statistical analysis of pain relief after surgical operations. Health Policy 2007; 83(2-3): 382-90.

Fender 1992 {published data only}

Fender P, Juillard J, Schubert B, Sengler J. Nicaulau's syndrome. Annales de Readaptation et de Medecine Physique 1992; 35(3): 255-7.

Garcia-Alonso 1991 {published data only}

Garcia-Alonso F, Gonzalez de Suzo MJ, Lopez-Alvarez M, Palop R. Comparative study of the efficacy of dipyrone, diclofenac sodium and pethidine in acute renal colic. European Journal of Clinical Pharmacology 1991; 40: 543-6.

Gold 2007 {published data only}

Gold BD, Scheiman JM, Sabesin SM, Vitat P. Updates on the management of upper gastrointestinal disorders in the primary care setting: NSAID-related gastropathies and pediatric reflux disease. Journal of Family Practice 2007; 56(3): S1-S11.

Han 2005 {published data only}

Han S, Baldemir M, Kose SK, Erdem D, Sakinci U. The time course of recovery following mild thoracic trauma. Heart Lung and Circulation 2005; 14(4): 252-4.

Hernandez 1997 {published data only}

Hernandez L, Barrientos B, Lopez DF. Comparison of analgesia provided by diclofenac and dipyrone in postoperated patients with abdominal surgery. Anestesia en Mexico 1997; 9(4): 137-42.

Hicklin 1999 {published data only}

Hicklin L, Tostevin PMJ, Wyatt ME. Parental satisfaction with paediatric day-case ENT surgery. The Journal of Laryngology and Otology 1999; 113: 1072-5.

Karachalios 1992 {published data only}

Karachalios GN, Fotiadou A, Chrisikos N, Karabetsos A, Kehagioglou K. Treatment of acute migraine attack with diclofenac sodium: a double- blind study. Headache 1992; 32: 98-100.

Keohane 1995 {published data only}

Keohane M, McAuley D, Ardill AC. Peripheral nerve blocks for paediatric day-stay surgery: One year's experience in a district general hospital. Ulster Medical Journal 1995; 64(1): 39-41.

Kokki 1994 {published data only}

Kokki H, Hendolin H, Maunuksela EL, Vainio J, Nuutinen L. Ibuprofen in the treatment of postoperative pain in small children. A randomized double-blind-placebo controlled parallel group study. Acta Anaesthesiologia Scandinavica 1994; 38(5): 467-72.

Kurimoto 1993 {published data only}

Kurimoto N, Yamamoto S, Enomoto M, Murayama M. Thoracoscopic surgery by use of endo-GIA. Kyobu geka 1993; 46(6): 489-93.

Kuzelova 2004 {published data only}

Kuzelova M, Plackova S. Analysis of accidental drug intoxications in children hospitalized at the Children's Faculty Hospital in Bratislava in the years 1996 - 2000. Cesko-Slovenska Pediatrie 2004; 59: 341-7.

Lankinen 2006 {published data only}

Lankinen U, Avela R, Tarkkila P. The prevention of emergence agitation with tropisetron or clonidine after sevoflurane anesthesia in small children undergoing adenoidectomy. Anesthesia & Analgesia 2006; 102(5): 1383-6.

Lau 2002 {published data only}

Lau H, Wong C, Goh LC, Patil NG, Lee F. Prospective randomized trial of pre-emptive analgesics following ambulatory inguinal hernia repair: intravenous ketorolac versus diclofenac suppository. ANZ Journal of Surgery 2002; 72: 704-7.

Leaper 2006 {published data only}

Leaper M, Mahadevan M, Vokes D, Sandow D, Anderson BJ, West T. A prospective randomised single blinded study comparing harmonic scalpel tonsillectomy with bipolar tonsillectomy. International Journal of Pediatric Otorhinolaryngology 2006; 70(8): 1389-96.

Lemelle 1998 {published data only}

Lemelle I, Crance J, Sommelet D. Uveitis in children. Journal de Pediatrie et de Puericulture 1998; 11: 215-21.

Machida 2004 {published data only}

Machida M, Imamura Y, Usui T, Asai T. Effects of preemptive analgesia using continuous subcutaneous morphine for postoperative pain in scoliosis surgery: A randomized study. Journal of Pediatric Orthopaedics 2004; 24(5): 576-80.

Majid 2004 {published data only}

Majid Y, Mohammad K. A comparison of caudally administered single dose bupivacaine and bupivacaine-tramadol combination for postoperative analgesia in children. JK Science 2004; 6: 19-22.

Mannion 1994 {published data only}

Mannion D, Armstrong C, O'Leary G, Casey W. Paediatric post orchidopexy analgesia - effect of diclofenac combined with ilioinguinal/iliohypogastric nerve block. Paediatric Anaesthesia 1994; 4: 327-30.

Marczyk 1992 {published data only}

Marczyk LRS. Comparative study of maleate of flupirtine versus diclofenac potassium in musculoskeletal diseases. Arquivos Brasileiros de Medicina 1992; 66: 269-75.

Maunuksela 1991 {published data only}

Maunuksela EL, Olkkola KT. Pediatric pain management. International Anesthesiology Clinics 1991; 29: 37-55.

McEwan 2000 {published data only}

McEwan A, Sigston PE, Andrews KA, Hack HA, Jenkins AMC, May L, et al. A comparison of rectal and intramuscular codeine phosphate in children following neurosurgery. Paediatric Anaesthesia 2000; 10(2): 189-93.

Miralles 1987 {published data only}

Miralles R, Cami J, Gutierrez J, Torne J, Garces JM, Badenas JM. Diclofenac versus dipyrone in acute renal colic: a double-blind controlled trial. European Journal of Clinical Pharmacology 1987; 33: 527-8.

Mitic 2007 {published data only}

Mitic S, Tvinnereim M, Lie E, Saltyte BJ. A pilot randomized controlled trial of coblation tonsillectomy versus dissection tonsillectomy with bipolar diathermy haemostasis. Clinical Otolaryngology 2007; 32(4): 261-7.

Moore 1985 {published data only}

Moore PA, Acs G, Hargreaves JA. Postextraction pain relief in children: a clinical trial of liquid analgesics. International Journal of Clinical Pharmacology Therapy and Toxicology 1985; 23(11): 573-7.

Mostaque 1998 {published data only}

Mostaque AK, Rasul G. Appendicectomy under local infiltration anaesthesia. Journal of Institute of Postgraduate Medicine and Research 1998; 13: 9-13.

Nordbladh 1991 {published data only}

Nordbladh I, Ohlander B, Bjorkman BOR. Analgesia in tonsillectomy: a double-blind study on pre and post- operative treatment with diclofenac. Clinical Otolaryngology and Allied Sciences 1991; 16: 554-8.

Ozcan 2002 {published data only}

Ozcan S, Yilmaz E, Buyukkocak U, Basar H Apan A. Comparison of three analgesics for extracorporeal shock wave lithotripsy. Scandinavian Journal of Urology and Nephrology 2002; 36: 281-5.

Parker 1986 {published data only}

Parker DA, Gibbin KP, Noyelle RM. Syrup formulations for post-tonsillectomy analgesia: a double-blind study comparing ibuprofen, aspirin and placebo. J-Laryngol-Otol 1986; 100(9): 1055-60.

Pendeville 2001 {published data only}

Pendeville PE, Kabongo F, Veyckemans F. Use of remifentanil in combination with desflurane or propofol for ambulatory oral surgery. Acta anaesthesiologica Belgica 2001; 52(2): 181-6.

Roelofse 1993 {published data only}

Roelofse JA, van der Bijl P, Joubert JJ. An open comparative study of the analgesic effects of tenoxicam and diclofenac sodium after third molar surgery. Anesthesia & Pain Control in Dentistry 1993; 2: 217-22.

Roelofse 1996 {published data only}

Roelofse JA, van der Bijl P, Joubert JJ. Analgesic and anti-inflammatory efficacy of tenoxicam and diclofenac sodium after third molar surgery. Anesthesia Progress 1996; 43: 103-7.

Romej 1996 {published data only}

Romej M, Voepel L, Merkel SI, Reynolds PI, Quinn P. Effect of preemptive acetaminophen on postoperative pain scores and oral fluid intake in pediatric tonsillectomy patients. AANA Journal 1996; 64: 535-40.

Romsing 2001 {published data only}

Romsing J, Ostergaard D, Senderovitz T, Drozdziewicz D, Sonne J, Ravn G. Pharmacokinetics of oral diclofenac and acetaminophen in children after surgery. Paediatric Anaesthesia 2001; 11(2): 205-13.

Rozhkova 1983 {published data only}

Rozhkova VN, Biberman I. Comparative evaluation of the action of nonsteroid anti-inflammatory agents in experiments and clinic states. Farmakologiia i Toksikologiia 1983; 46: 79-82.

Schachtel 1993 {published data only}

Schachtel BP, Thoden WR. A placebo-controlled model for assaying systemic analgesics in children. Clinical Pharmacology and Therapeutics 1993; 53(5): 593-601.

Schaller 1998 {published data only}

Schaller S, Kaplan BS. Acute nonoliguric renal failure in children associated with nonsteroidal anti-inflammatory agents. Pediatric Emergency Care 1998; 14: 416-8.

Schwentner 2006 {published data only}

Schwentner C, Oswald J, Lunacek A, Deibl M, Koerner I, Bartsch G, et al. Lich-Gregoir reimplantation causes less discomfort than Politano-Leadbetter technique: Results of a prospective, randomized, pain scale-oriented study in a pediatric population. European Urology 2006; 49(2): 388-95.

Shah 2001 {published data only}

Shah C, Shahab R, Robb P, Roy D. Role of a home care team in paediatric day-case tonsillectomy. The Journal of Laryngology and Otology 2001; 115: 39-43.

Sheppard 1993 {published data only}

Sheppard IJ, Moir AA, Thomas RSA, Narula AA. Organization of day-case adenoidectomy in the management of chronic otitis media with effusion - Preliminary results. Journal of the Royal Society of Medicine 1993; 86(2): 76-8.

Silvasti 1999 {published data only}

Silvasti M, Tarkkila P, Tuominen M, Svartling N, Rosenberg PH. Efficacy and side effects of tramadol versus oxycodone for patient-controlled analgesia after maxillofacial surgery. European Journal of Anaesthesiology 1999; 16(2): 834-9.

Stanley 2002 {published data only}

Stanley TV. Idiopathic intracranial hypertension presenting as hemiplegic migraine. Acta Paediatrica, International Journal of Paediatrics 2002; 91(8): 980-2.

Taneja 2004 {published data only}

Taneja MK. Blunt dissection to bipolar forcep tonsillectomy - a comparison. Indian Journal of Otolaryngology and Head and Neck Surgery 2004; 56: 67-70.

Teiria 1994 {published data only}

Teiria H, Meretoja OA. PCA in paediatric orthopaedic patients: influence of a NSAID on morphine requirement. Paediatric Anaesthesia 1994; 4: 87-91.

Thomaser 2004 {published data only}

Thomaser EG, Tschopp K. Influence of intraoperatively applied current of coagulation on the postoperative course in tonsillectomy. Laryngo- Rhino- Otologie 2004; 83: 501-6.

Tuzuner 2007 {published data only}

Tuzuner AM, Ucok C, Kucukyavuz Z, Alkis N, Alanoglu Z. Preoperative diclofenac sodium and tramadol for pain relief after bimaxillary osteotomy. Journal of Oral & Maxillofacial Surgery 2007; 65(12): 2453-8.

Valladares 2004 {published data only}

Valladares G, Martinez N, Vazquez G, Merino S, Reina M, Echevarrea M. Postoperative analgesia in foot and ankle surgery through lateral popliteal sciatic blockade with ropivacaine. Revista de la Sociedad Espanola del Dolor 2004; 11: 82-6.

van den Berg 1999 {published data only}

van den Berg , Montoya P, Halliday EM, Hassan I, Baloch M. Analgesia for adenotonsillectomy in children and young adults: A comparison of tramadol, pethidine and nalbuphine. European Journal of Anaesthesiology 1999; 16(3): 186-94.

Verheggen 1994 {published data only}

Verheggen R, Jansen J. Fractures of the odontoid process: analysis of the functional results after surgery. European Spine Journal 2004; 3: 146-50.

Walton 1993 {published data only}

Walton GM, Rood JP, Snowdon AT, Rickwood D. Ketorolac and diclofenac for postoperative pain relief following oral surgery. British Journal of Oral and Maxillofacial Surgery 1993; 31: 158-60.

Weber 2007 {published data only}

Weber T, Matzl J, Rokitansky A, Klimscha W, Neumann K, Deusch E. Superior postoperative pain relief with thoracic epidural analgesia versus intravenous patient-controlled analgesia after minimally invasive pectus excavatum repair. Journal of Thoracic & Cardiovascular Surgery 2007; 134(4): 865-70.

Referencias adicionales

AAP 2001

American Academy of Pediatrics. Committee on Psychosocial Aspects of Child and Family Health & Task Force on Pain in Infants, Children , Adolescents . The assessment and management of acute pain in infants, children, and adolescents. Pediatrics 2001; 108(3): 793-7.

Abraham 2006

Abraham J, Davis C. Testing times: the emergence of the practolol disaster and its challenges to British drug regulation in the modern period. Social History of Medicine 2006; 19: 127-47.

Aronson 2005

Aronson JK. Unity from diversity: the evidential use of anecdotal reports of adverse drug reactions and interactions. Journal of Evaluation in Clinical Practice 2005; 11(2): 195-208.

Barden 2004

Barden J, Edwards J, Moore RA, McQuay HJ. Single dose oral diclofenac for postoperative pain. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD004768]

Cardwell 2005

Cardwell M, Siviter G, Smith A. Non-steroidal anti-inflammatory drugs and perioperative bleeding in paediatric tonsillectomy. Cochrane Database of Systematic Reviews 2005, Issue 2. [DOI: 10.1002/14651858.CD003591.pub2]

Cashman 1995

Cashman J, McAnulty G. Nonsteroidal anti-inflammatory drugs in perisurgical pain management. Mechanisms of action and rationale for optimum use. Drugs 1995; 49(1): 51-70.

Choonara 2002

Choonara I, Conroy S. Unlicensed and off-label drug use in children: implications for safety. Drug Safety 2002; 25(1): 1-5.

Collins 2004

Collins SL, Moore RA, McQuay HJ, Wiffen PJ, Edwards JE. Single dose oral ibuprofen and diclofenac for postoperative pain. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD001548]

Conroy 2001

Conroy S, Peden V. Unlicensed and off label analgesic use in paediatric pain management. Paediatric Anaesthesia 2001; 11(4): 431-6.

Garcia 2004

Garcia Rodriguez L A, Hernandez-Diaz S. Risk of uncomplicated peptic ulcer among users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs. American Journal of Epidemiology 2004; 159(1): 23-31.

Holdgate 2004

Holdgate A, Pollock T. Nonsteroidal anti-inflammatory drugs (NSAIDs) versus opioids for acute renal colic. Cochrane Database of Systematic Reviews 2004, Issue 3. [DOI: 10.1002/14651858.CD004137.pub3]

Howard 2003

Howard RF. Current status of pain management in children. JAMA 2003; 290(18): 2464-9.

Ioannidis 2002

Ioannidis JPA, Lau J. Improving safety reporting from randomised trials. Drug Safety 2002; 25(2): 77-84.

Kearns 2003

Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology - drug disposition, action, and therapy in infants and children. New England Journal of Medicine 2003; 349(12): 1157-67.

Kirchheiner 2003

Kirchheiner J, Meineke I, Steinbach N, Meisel C, Roots I, Brockmoller J. Pharmacokinetics of diclofenac and inhibition of cyclooxygenases 1 and 2: no relationship to the CYP2C9 genetic polymorphism in humans. British Journal of Clinical Pharmacology 2003; 55(1): 51-61.

Krishna 2003

Krishna S, Hughes LF, Lin SY. Postoperative hemorrhage with nonsteroidal anti-inflammatory drug use after tonsillectomy: a meta-analysis. Archives of Otolaryngology - Head & Neck Surgery 2003; 129(10): 1086-9.

Lloyd-Thomas 1999

Lloyd-Thomas AR. Modern concepts of paediatric analgesia. Pharmacology & Therapeutics 1999; 83(1): 1-20.

McQuay 1998

McQuay HJ, Moore RA. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review. Health Technology Assessment 1998; Vol. 2: 1-236.

Michaloliakou 1996

Michaloliakou C, Chung F, Sharma S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesthesia and Analgesia 1996; 82: 44-51.

Morselli 1980

Morselli PL, Franco-Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants. Age-related differences and therapeutic implications. Clinical Pharmacokinetics 1980; 5(6): 485-527.

Romsing 1997

Romsing J, Walther-Larsen S. Peri-operative use of nonsteroidal anti-inflammatory drugs in children: analgesic efficacy and bleeding. Anaesthesia 1997; 52(7): 673-83.

Sweetman 2002

Sweetman SC (Editor). Martindale: the complete drug reference. . London: Pharmaceutical Press, 2002.

Todd 1988

Todd PA, Sorkin EM. Diclofenac sodium. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1988; 35(3): 244-85.

Turner 1998

Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off label drug use in paediatric wards: prospective study. BMJ 1998; 316(7128): 343-5.

Van 2000

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Tablas

Características de los estudios

Características de los estudios incluidos [ordenados por ID del estudio]

Akinci 2005

Methods

Randomized controlled trial

Participants

22 children needing ventilation after orthopedic spinal surgery

Interventions

  1. remifentanil infusion ( 11)

  2. fentanyl infusion (11) for postop analgesia/sedation in PICU. All patients received IM diclofenac 1 mg/kg before extubation

Outcomes

  1. Pain

  2. PONV

Notes

Asthmatics: not clear. Safety quality: moderate

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Andrzejowski 2002

Methods

Randomised controlled trial.

Participants

133 children (ASA 1-2) undergoing dental surgery.

Interventions

  1. Swab soaked in bupivacaine 0.25% (60)

  2. Swab soaked in saline (60). All patients received rectal diclofenac 1 mg/kg.

Outcomes

  1. Pain

  2. Bleeding

Notes

13 dropouts due to inability to self-score pain. Wrote to authors: all these patients received diclofenac and none had any serious adverse events. Adverse events monitored for, no serious adverse events occurred in the 133 receiving diclofenac. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Azuma 1982

Methods

Comparative trial of analgesia, diclofenac pharmacokinetics. Not randomised or blinded.

Participants

40 children post-tonsillectomy.

Interventions

  1. Rectal diclofenac 1 mg/kg (20)

  2. Non-NSAID group (20).

Outcomes

  1. Analgesia

  2. Pharmacokinetics

  3. Adverse events.

Notes

Not enough information to include in comparative study. Adverse events monitored for, no serious adverse events occurred in the 20 receiving diclofenac. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Baer 1992

Methods

Randomised controlled trial, investigator blind.

Participants

44 children (ASA 1) undergoing adenoidectomy.

Interventions

  1. Rectal diclofenac 12.5 mg (19)

  2. Rectal paracetamol 125 mg (25).

Outcomes

  1. Pain

  2. Bleeding

  3. Behaviour

  4. Post-operative complications

Notes

Adverse events monitored for, no adverse events in either group and no serious adverse events. States is blinded study but no details on how blinding done. Asthmatics: excluded. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Bebawy 2005

Methods

Randomised controlled trial

Participants

80 children, 2-6 years old undergoing inguinal hernia repair

Interventions

  1. Sevoflurane ( 40)

  2. Halothane (40). All patients received rectal diclofenac sodium 2 mg/kg as pre-med. Post-op local wound infiltration using ropivacaine.

Outcomes

  1. Pain

Notes

Asthmatics: excluded (C/Is to NSAIDs). Safety quality: moderate

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Berry 1992a

Methods

Randomised controlled trial, investigator blind.

Participants

40 children (ASA 1-2) undergoing adenotonsillectomy.

Interventions

  1. Intravenous diclofenac 1 mg/kg (20)

  2. Intravenous papaveretum 0.2 mg/kg (20).

Outcomes

  1. Pain

  2. Bleeding

  3. Vomiting

  4. Venous irritation.

Notes

Wrote to author of letter on venous sequelae of diclofenac in children which mentioned a clinical study - directed to paper in The Journal of the Pain Society. Blinding centralised with hospital pharmacy prepared doses. Papaveretum and paracetamol rescue analgesia used. Adverse events monitored for, 20 children had diclofenac, no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Bhattacharya 2005

Methods

Randomised controlled trial. Assessor (nurse) blind

Participants

50 children aged 8-12 undergoing tonsillectomy and/or adenoidectomy

Interventions

  1. rectal diclofenac 2 mg/kg post induction (25)

  2. IV pethidine 0.5 mg/kg (25)

Outcomes

  1. Pain

  2. Adverse events

Notes

Asthmatics: excluded. Safety quality: moderate

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Bone 1988

Methods

Randomised controlled trial, investigator blind.

Participants

60 children undergoing tonsillectomy.

Interventions

  1. Rectal diclofenac 2 mg/kg (20)

  2. Intramuscular papaveretum 0.2 mg/kg (20). 3. No treatment (20).

Outcomes

  1. Pain

  2. Nausea and vomiting

  3. Respiratory rate

  4. Restlessness

Notes

Paracetamol and papaveretum rescue analgesia used. Risk of bias as no placebo injection/suppositories used. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Borkar 2005

Methods

Randomised controlled trial

Participants

50 children aged 3-13 years undergoing laparoscopy

Interventions

  1. caudal block (25)

  2. rectal diclofenac (25) All children also received metoclopramide and pentazocine post-induction

Outcomes

  1. Pain

  2. PONV

Notes

Study said to be randomised but blinding not mentioned. Adverse events monitored; 25 children received diclofenac; no reports of serious adverse events

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Duarte 1997

Methods

Randomised comparative open study.

Participants

60 children with swollen glands, with and without sore throat and laryngitis

Interventions

1. nimesulide (n = 21), 2.5 mg/kg bd; 2. dipyrone 25 mg/kg qds (n = 19) 3. diclo 0.5 mg/kg bd (21); all for 4-10 days

Outcomes

1. Pain 2. Adverse events

1. Pain 2. Adverse events

Notes

Adverse events monitored for; 21 children received diclofenac; 1 case of palpebral oedema, treatment stopped. Asthmatics: no information. Safety quality: moderate

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Elhakim 2003

Methods

Randomised controlled trial.

Participants

50 children (ASA 1-2) undergoing tonsillectomy.

Interventions

1. Intramuscular ketamine 0.1 mg/kg (25). 2. Intramuscular saline, equivalent volume to ketamine dose (25). All children received rectal diclofenac 2 mg/kg.

Outcomes

1. Pain. 2. Adverse events.

Notes

Evidence of monitoring for adverse events, no serious adverse events reported. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Engelhardt 2001

Methods

Randomised controlled trial.

Participants

29 children undergoing adenotonsillectomy.

Interventions

1. Sublingual morphine 0.1mg/kg (14). 2. Intravenous morphine 0.1 mg/kg (15). All patients received rectal diclofenac 1 mg/kg.

Outcomes

  1. Pain

  2. Sedation

  3. Adverse events.

Notes

Adverse events monitored for, 29 patients received diclofenac, no reports of serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Engelhardt 2003

Methods

Randomised controlled trial.

Participants

60 children undergoing tonsillectomy +/- adenoidectomy.

Interventions

1. Intravenous morphine 0.1mg/kg (20). 2. Intravenous tramadol 1mg/kg (20). 3. Intravenous tramadol 2mg/kg (20). All (60) received rectal diclofenac 1mg/kg.

Outcomes

1. Pain. 2. Adverse events until discharge.

Notes

Adverse events monitored for, 60 patients received diclofenac, no reports of serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Ericsson 2006

Methods

Randomized open comparative study of two surgical methods.

Participants

Ninety-two children (5-15 years) with sleep-disordered breathing

Interventions

1. Rectal diclo 1-2.5 mg/kg end of op, repeated after 8 hours. 2. post-op paracet and diclo for at least 3 days; route not clear

Outcomes

1. Pain 2. Adverse events

Notes

Evidence of monitoring for adverse events over 4-10 days. 1 report of pain and nausea at day 3; diclofenac stopped needing change in analgesic medication

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Filatov 2000

Methods

Randomised controlled trial.

Participants

126 children (ASA 1) undergoing adenoidectomy.

Interventions

  1. Rectal diclofenac 12.5 mg, rectal diazepam 0.5 mg/kg, intravenous glycopyrrolate 5µg/kg, topical EMLA® to hand (20)

  2. Rectal diclofenac 12.5 mg, rectal diazepam 0.5 mg/kg topical EMLA® to hand (21)

  3. Oral ketamine in cola drink 6 mg/kg, intravenous glycopyrrolate 5 µg/kg (30)

  4. Oral ketamine in cola drink 6 mg/kg (29). Placebo local anaesthetic cream, suppository, rectal fluid, oral cola drink and injection used.

Outcomes

  1. Pain

  2. Adverse events

Notes

Wrote to authors as 26 patients excluded causing risk of bias, no reply therefore cannot include in comparative analysis. Adverse events monitored for, 41 patients received diclofenac, no reports of serious adverse events. Asthmatics: unknown. Safety quality: Low

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Findlow 1997

Methods

Randomised controlled trial.

Participants

40 boys undergoing orchidopexy.

Interventions

  1. Caudal bupivacaine 0.25% 0.5 mL/kg and ketamine 0.5 mg/kg. (20)

  2. Ilioinguinal block bupivacaine 0.25% 0.5 mL/kg (20). All (40) received rectal diclofenac 1-2 mg/kg.

Outcomes

  1. Pain

  2. Adverse events including follow-up

Notes

Drop-outs: two did not undergo surgery or receive diclofenac, two no follow-up was possible but received diclofenac. Adverse events monitored for, 38 patients received diclofenac, no reports of serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Fischer 1992

Methods

Randomised controlled trial.

Participants

60 children undergoing orthopaedic surgery.

Interventions

1. Oral diclofenac 50 mg twice or three times daily (50). 2. Oral serrapeptase 5 mg 1-2 tablets three times daily (50).

Outcomes

1. Pain. 2. Swelling. 3. Adverse events.

Notes

Cannot use for comparative analysis - five serrapeptase and three diclofenac drop-outs, unaccounted for and no blinding. Adverse events monitored for, 47 patients received diclofenac, one event rated by patient as severe but unclear which one from table, could be: vomiting, headache, stomach pain or erythema. Asthmatics: unknown. Safety quality: Low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Fosel 2005

Methods

Prospective cohort

Participants

100 children aged between 6 and 14 years post tonsillectomy

Interventions

Combined regime including an opioid (piritramid), and rectal paracetamol 1 mg/kg diclofenac orally 3 times a day from 2nd postop day

Outcomes

1. Pain 2. Vomiting 3. Bleeding

Notes

Adverse events monitored for, 100 patients received diclofenac, no reports of serious adverse events. Asthmatics: excluded. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Funk 2008

Methods

Randomised placebo-controlled trial. Nurse giving drug blinded.

Participants

40 children (1-5 yr) undergoing ENT, hernia repair, and urology surgery

Interventions

1. Physostigmine 30 mcg/kg IV (20) 2. Saline (20) All children received. rectal diclo 1-2 mg/kg post induction as part of combined regime including regional/local bupivacaine

Outcomes

1. Agitation 2. PONV 3. Sleep disturbances

Notes

Adverse events monitored for post-operation and at day 7 and 28. 20 children r received diclofenac. No reports of severe adverse events. Asthmatics: unknown. Safety quality: moderate

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Gadiyar 1995

Methods

Randomised controlled trial, investigator blinded.

Participants

39 children (ASA 1 or 2) undergoing day case surgery.

Interventions

1. Rectal diclofenac 1 mg/kg plus caudal bupivacaine 0.125% plus adrenaline 1:400 000 1 mL/kg (19). 2. Caudal bupivacaine 0.125% plus adrenaline 1:400 000 1 mL/kg only (20).

Outcomes

1. Pain. 2. Sedation. 3. Time to passing urine. 4. Time to eating/drinking. 5. Excessive bleeding.

Notes

Paracetamol rescue analgesia used. Adverse events monitored for including post-discharge follow-up. No mention of nausea and vomiting but subjectively looked at bleeding, no increase in the diclofenac group. No reports of serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Gananca 1991

Methods

Randomised controlled trial.

Participants

58 children with pharyngo-tonsillitis.

Interventions

1. Oral diclofenac resinate 0.5 mg/kg (29). 2. Oral nimesulide 5 mg/kg (29). Seven day treatment, all patients also received oral amoxicillin 30 mg/kg/day.

Outcomes

1. Pain. 2. Adverse events. 3. Taste of medication.

Notes

Include in comparative study but open study with no blinding so risk of bias. Specifically mentions no other medicines used during treatment course, adverse events monitored for, 29 patients received diclofenac, no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Hanafy 2004

Methods

Randomised controlled trial.

Participants

51 children (ASA 1-2) undergoing adenotonsillectomy.

Interventions

1. Intravenous dexmedetomidine 0.5 µg/kg (23). 2. Intravenous saline (23). All patients received rectal diclofenac 1 mg/kg.

Outcomes

1. Post-operative agitation. 2. Adverse events.

Notes

Wrote to authors (as 5 patients excluded - risk of bias) no response. Adverse events monitored for, 46 patients received diclofenac, no reports of serious adverse events. Asthmatics: unknown. Safety quality: Low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Holder 1997

Methods

Randomised controlled trial.

Participants

45 boys (ASA 1-2) undergoing circumcision.

Interventions

1. Subcutaneous ring block with bupivacaine 0.25% 2 mg/kg (16). 2. Subpubic penile block using bupivacaine 0.5% 0.2 mL/kg (24). Seven patients received diclofenac 1 mg/kg rescue analgesia.

Outcomes

1. Pain. 2. Adverse events.

Notes

Adverse events monitored for, seven patients received diclofenac, no reports of serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Homer 2002

Methods

Audit.

Participants

100 children undergoing tonsillectomy.

Interventions

77 received diclofenac.

Outcomes

1. Pain. 2. Haemorrhage rate.

Notes

Retrospective audit, adverse events monitored for, 77 patients received diclofenac, no reports of serious adverse events (mentions one patient with reactionary haemorrhage settled with conservative treatment). Asthmatics: unknown. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Hultcrantz 2004

Methods

Randomised controlled trial.

Participants

150 children undergoing tonsillectomy.

Interventions

1. Radiofrequency technique (49). 2. Standard technique (43). All children received diclofenac (route not stated) 0.7-1 mg/kg/dose.

Outcomes

1. Pain. 2. Adverse events including follow-up.

Notes

Only 92 of the 150 randomised were operated on. Five were excluded for not accepting randomisation, five operated on without being randomised and the rest had surgery cancelled. Adverse events monitored for, 92 patients received diclofenac, no reports of serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Kierszenbaum 1991

Methods

Randomised comparative study.

Participants

60 children aged 1-12 years with upper respiratory tract infections

Interventions

1. diclofenac resinate orally 0.5 mg/kg tid for 7 days (30) 2. nimesulide 1% oral suspension 5 mg/kg bd for 7 days (30)

Outcomes

1. Throat pain 2. Dysphagia 3. Adverse events

Notes

Adverse events monitored for; 30 children received diclofenac; treatment stopped in two cases because of hypothermia. Asthmatics: unknown. Safety quality: moderate

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Kokinsky 1999

Methods

Audit.

Participants

200 children undergoing day case surgery.

Interventions

68 children received rectal diclofenac 0.8-2 mg/kg intra-operatively, and 10 post-operatively

Outcomes

1. Pain. 2. Adverse events.

Notes

Wrote to authors for clarification on adverse events. Two patients who received diclofenac had serious adverse events (one protracted vomiting requiring prolonged admission, one re-operated due to bleeding in penile surgery). Asthmatics: unknown. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Korpela 1990

Methods

Pharmacokinetic study.

Participants

10 children undergoing minor surgery.

Interventions

1. Intravenous diclofenac 0.5 mg/kg infused over five minutes (5). 2. Intravenous diclofenac 0.5 mg/kg infused over 15 minutes (5).

Outcomes

1. Pharmacokinetics. 2. Adverse events.

Notes

Adverse events monitored for and contacted authors, 10 patients received diclofenac, no serious adverse events. Asthmatics: excluded. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Kurokawa 2002

Methods

Case series.

Participants

Girls undergoing laparoscopic nephroureterectomy.

Interventions

Laparoscopic nephroureterectomy, two received rectal diclofenac 12.5 mg.

Outcomes

1. Post-operative complications. 2. Pain.

Notes

Adverse events monitored for, two patients received diclofenac, no serious adverse events. Asthmatics: unknown. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Lai 2005

Methods

Comparative study.

Participants

19 children and 23 adults undergoing appendicectomy.

Interventions

Standardised analgesia including diclofenac 1.5 mg/kg in children.

Outcomes

1. Pain measured by PCA morphine consumption. 2. Adverse events.

Notes

Some evidence of monitoring for adverse events, contacted author for confirmation, no serious adverse events occurred in the paediatric patients. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Lambert 2000

Methods

Comparative study.

Participants

19 children and 23 adults undergoing appendicectomy.

Interventions

Standardised analgesia including diclofenac 1.5 mg/kg in children.

Outcomes

1. Pain measured by PCA morphine consumption. 2. Adverse events.

Notes

Some evidence of monitoring for adverse events, contacted author for confirmation, no serious adverse events occurred in the paediatric patients. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Leontev 2004

Methods

Comparative study.

Participants

57 children undergoing minor surgery.

Interventions

1. Rectal or intramuscular diclofenac 1 mg/kg (47). 2. Analgin and Promedol (10).

Outcomes

1. Pain. 2. Adverse events.

Notes

Some evidence of monitoring for adverse events, no serious adverse events in 47 patients receiving diclofenac. no mention of blinding. Asthmatics: unknown. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Leontev 2005

Methods

Open comparative study

Participants

92 children aged 11-15 years undergoing minor surgical procedures

Interventions

1. diclofenac 1.5-2.0 mg/kg, rectally (n=22) 2. diclofenac IM injection 1-1.5 mg/kg (n=21) 3. rectal paracetamol 25-30 mg/kg ( 20 ) ; 4. IM promedol (meperidine) dose not clear (12) ; 5. dipyrone 5-10 mg/kg (14)

Outcomes

1. Pain 2. PONV 3. Bleeding 4. Allergy

Notes

Adverse events monitored for; 43 children received diclofenac; 5 cases of allergic skin rash, reverse d with chlorpyramine

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Littlejohn 1996

Methods

Randomised controlled trial, investigator blind.

Participants

60 children undergoing day case dental extractions.

Interventions

1. Rectal diclofenac 1-2 mg/kg (19). 2. Intravenous nalbuphine 0.3 mg/kg (21). 3. No analgesia (20).

Outcomes

1. Pain. 2. Subjective bleeding. 3. Time to waking. 4. Nausea.

Notes

Paracetamol rescue analgesia. Adverse events monitored for and no serious adverse events. Asthmatics: excluded. Safety quality: moderate, no evidence of follow-up.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Mak 2001

Methods

Randomised controlled trial, investigator blind.

Participants

187 boys undergoing circumcision.

Interventions

1. Rectal diclofenac 1 mg/kg and intravenous fentanyl 0.5 µg/kg (61). 2. Dorsal penile nerve block with 0.5% bupivacaine (63). 3. Caudal block with bupivacaine 0.5 mL/kg (61).

Outcomes

1. Pain. 2. Adverse events.

Notes

Cannot use in comparative section as comparison was diclofenac plus fentanyl (one patient in each group suffered bleeding, three in each of the local block groups vomited versus one in diclofenac/fentanyl group). Drop-outs in caudal group due to inability to perform caudal block. Adverse events monitored for, 61 patients received diclofenac, no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Martindale 2004

Methods

Randomised controlled trial.

Participants

60 children undergoing day case surgery.

Interventions

1. Caudal bupivacaine 0.25% 1 mL/kg (20). 2. Caudal bupivacaine 0.25% 1 mL/kg plus S(+)-ketamine 0.5mg/kg (20). 3. Caudal bupivacaine 0.25% 1 mL/kg plus intravenous S(+)-ketamine 0.5 mg/kg. All patients received rectal diclofenac 1 mg/kg.

Outcomes

1. Pain. 2. Adverse events.

Notes

One patient was withdrawn - did not have surgery so 59 received diclofenac. Adverse events monitored for, no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



McGowan 1998

Methods

Randomised controlled trial.

Participants

61 boys (ASA 1-2) undergoing circumcision.

Interventions

1. Rectal diclofenac 2-2.5 mg/kg plus penile block with bupivacaine 0.5% 0.3 mL/kg (20). 2. Penile block with bupivacaine 0.5% 0.3 mL/kg (18). 3. Rectal diclofenac 2-2.5 mg/kg (20).

Outcomes

1. Pain. 2. Bleeding. 3. Nausea and vomiting.

Notes

Got raw data. Include the diclofenac plus penile block vs penile block in the comparative analysis. Three dropouts - penile block failed. Adverse events monitored for and two diclofenac patients had serious adverse events, both late haemorrhage requiring overnight hospitalisation and reoperation in one case. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Mendham 1996

Methods

Randomised controlled trial, investigator blind.

Participants

127 children undergoing tonsillectomy or adenotonsillectomy.

Interventions

1. Rectal diclofenac 1 mg/kg (25). 2. Rectal diclofenac 1 mg/kg plus intravenous fentanyl 0.75µg/kg (33). 3. Intravenous tenoxicam 0.4 mg/kg (35). 4. Intravenous tenoxicam 0.4 mg/kg plus intravenous fentanyl 0.75 µg/kg (28).

Outcomes

1. Pain. 2. Bleeding. 3. Sedation.

Notes

Wrote to author for more detail on exclusions and drop-outs. Six patients excluded - two from group 1, one from group 2 and two from group 3 returned to theatre with post-operative bleeding, one from group 2 was excluded due to insufficient data. Morphine rescue analgesia used. Adverse events monitored for, 62 patients received diclofenac, three serious adverse events. Asthmatics: excluded severe. Safety quality: Moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Menezes 2002

Methods

Comparative study.

Participants

100 children (ASA 1-3) undergoing orthopaedic surgery.

Interventions

1. Rectal diclofenac 1 mg/kg (20). 2. Caudal bupivacaine 0.25% plus adrenaline (1:400000) 0.5-1 mL/kg (20). 3. Caudal fentanyl 1.5 ?g/kg (20). 4. Caudal morphine 30 ?g/kg (20). 5. Caudal sulfentanil 0.3 ?g/kg (20).

Outcomes

1. Pain. 2. Adverse events.

Notes

Randomisation by order of admission and no blinding. Some patients received midazolam pre-medication but cannot tell who - exclude from comparative analysis. Adverse events monitored for, 20 patients received diclofenac with no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Mikawa 1995

Methods

Randomised placebo controlled trial.

Participants

140 children (ASA 1) undergoing strabismus surgery.

Interventions

1. Diazepam 0.4 mg/kg (35). 2. Clonidine 2µg/kg (35). 3. Clonidine 4 µg/kg (35) all dissolved in apple juice. 4. Placebo (35). All patients received rectal diclofenac 12.5 or 25 mg.

Outcomes

1. Vomiting. 2. Adverse events.

Notes

Adverse events monitored for, 140 patients received diclofenac, no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Miniti 1993

Methods

Open randomised comparative study

Participants

60 children with tonsillitis attending a walk-in ENT clinic

Interventions

1. nimesulide 5% oral suspension 2.5 mg/kg bd for 7 days (30) 2. diclofenac resinate 0.5 mg/kg tds for 7 days. All children also received amoxicillin

Outcomes

1. Throat pain 2. Dysphagia 3. Adverse events

Notes

Include in quantitative adverse events comparison but not blind so risk of bias. Adverse events monitored for; 30 children received diclofenac, no reports of serious adverse events

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Moores 1990

Methods

Randomised controlled trial, investigator blinded.

Participants

43 children undergoing day case herniotomy.

Interventions

1. Rectal diclofenac 2.5 mg/kg (20). 2. Caudal bupivacaine 0.25% 1 mL/kg (18).

Outcomes

1. Pain. 2. Vomiting. 3. Oral intake. 4. Mobility. 5. Passing urine. 6. Sleep disturbance.

Notes

Paracetamol rescue analgesia used. Wrote to authors, no response. Five dropouts, three incomplete questionnaires, one discharged early, one surgical complications caused overnight admission, original allocation unclear. Blinding maintained by placing gauze over sacral hiatus for all patients. Asthmatics: unknown. Safety quality: Low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Morton 1999

Methods

Randomised controlled trial.

Participants

80 children undergoing appendicectomy.

Interventions

1. Rectal diclofenac 1 mg/kg 8 hourly (20). 2. Rectal paracetamol 20 mg/kg loading dose than 15 mg/kg 6 hourly (20). 3. Diclofenac plus paracetamol in the doses above (20). 4. No simple analgesic (20). All patients on patient controlled morphine infusions.

Outcomes

1. Pain. 2. Adverse events.

Notes

No information on blinding. Differential morphine consumption used as efficacy measure. Cannot compare number of adverse events between groups. Adverse events monitored for, 40 patients received diclofenac, no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Mukherjee 2001

Methods

Randomised controlled trial.

Participants

60 children (ASA 1-2) undergoing tonsillectomy or adenotonsillectomy.

Interventions

1. Intramuscular morphine 100 µg/kg (27). 2. Intravenous fentanyl 1µg/kg (29). All patients received rectal diclofenac 1-1.5 mg/kg.

Outcomes

1. Pain. 2. Adverse events.

Notes

Wrote to authors, four drop-outs did receive diclofenac and did not suffer any serious adverse events. Adverse events monitored for, 60 patients received diclofenac, no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Murphy 2000

Methods

Pharmacokinetic study.

Participants

20 children undergoing adenotonsillectomy.

Interventions

Rectal diclofenac 2 mg/kg.

Outcomes

1. Pharmacokinetics. 2. Adverse events.

Notes

Conference abstract, little detail but does mention no patients suffered any adverse effects. Asthmatics: unknown. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Nakayama 1982

Methods

Prospective cohort.

Participants

40 children undergoing tonsillectomy.

Interventions

Rectal diclofenac 25 mg.

Outcomes

1. Pain. 2. Adverse events.

Notes

Adverse events monitored for, 40 patients received diclofenac, no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Nikolic 2001

Methods

Case series.

Participants

28 children admitted with acute tubulointerstitial nephritis.

Interventions

None.

Outcomes

1. Description of treatment and outcome

Notes

One case was attributed to diclofenac, no details on length of treatment given. Child made a full recovery with supportive therapy.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Nishina 2000

Methods

Randomised controlled trial, investigator blind.

Participants

125 children (ASA 1) undergoing ophthalmological surgery.

Interventions

1. Rectal diclofenac 2 mg/kg (25). 2. Intravenous flurbiprofen 1 mg/kg (25). 3. Oral clonidine 4 µg/kg (25). 4. Rectal diclofenac plus oral clonidine (25). 5. Intravenous flurbiprofen plus oral clonidine (25). Placebos used for pre-medication where patient was awake.

Outcomes

1. Pain. 2. Vomiting. 3. Time to eye opening. 4. NSAID complications (rash, pruritus, bronchospasm, convulsions).

Notes

Paracetamol and diclofenac rescue analgesia used. NSAID complications looked for. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Nordman 2006

Methods

Randomised controlled trial. Observer blind

Participants

54 children (ASA 1 and 2) aged 4 months-12 years having elective surgery

Interventions

1. isoflurane (27) 2. desflurane (27) All received oral paracetamol 20 mg/kg with pre-med and diclofenac 1 mg/kg rectally during operation

Outcomes

1. Anaesthetic recovery 2. Adverse events

Notes

Evidence of monitoring for adverse events. 54 children received diclofenac, no serious events reported. Asthmatics: unknown. Safety quality:moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Nze 2006

Methods

Randomised placebo-controlled trial

Participants

74 children aged 1-7 years day-case adenoidectomy

Interventions

1. 1 mg/kg i.v. after induction of anaesthesia followed by an infusion of diclofenac 1 mg/kg over 2 hours (74) 2. placebo 0.9% saline (76)

Outcomes

1. pain 2. Bleeding 3. Adverse events

Notes

Evidence of monitoring for adverse events. Cannot use for comparative analyses as blinding is unclear and placebo data is missing from Table in paper. Authors contacted but no response. Asthmatics excluded. safety quality:moderate

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



O'Donnell 2007

Methods

Prospective cohort study with three groups

Participants

210 children (ASA 1 or 2) aged between 3 and 12 years, having routine extractions of primary teeth in three hospitals using three different pain regimes

Interventions

"Usual care" for the hospital concerned 1. Voltarol suppository (70) 2. Paracetamol (70) 3. No analgesia (70)

Outcomes

1. Pain

Notes

This was a tri-site study with each hospital using its usual pain regime. Children compared on gender only; no data on ages. 70 children received diclofenac; adverse event monitoring unclear; no adverse events reported. Asthmatics: unknown. Safety quality: low

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Oztekin 2002

Methods

Randomised controlled trial, investigator blind.

Participants

40 children (ASA 1-2) undergoing tonsillectomy.

Interventions

1. Rectal diclofenac 1 mg/kg (20). 2. No treatment (20).

Outcomes

1. Pain. 2. Adverse events.

Notes

Morphine as rescue analgesia. Adverse events monitored for, 20 patients received diclofenac, one serious adverse event from each group required nasal packaging and prolonged hospitalisation. Asthmatics: excluded. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Riad 2007

Methods

Randomised controlled trial. Assessors blinded

Participants

108 children (ASA 1) aged 3-8 undergoing inguinal hernia repair

Interventions

1. rectal diclofenac 1 mg/kg 1 hr pre-op (36) 2. rectal paracetamol 40 mg/kg (36) 3. both drugs (36)

Outcomes

1. Pain

Notes

Differential morphine consumption used as efficacy measure. Adverse event monitoring unclear; no adverse events reported. Asthmatics: excluded. Safety quality: low

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Robinson 1994

Methods

Retrospective cohort (case note review)

Participants

366 patients undergoing tonsillectomy.

Interventions

Cases of post-tonsillectomy haemorrhage reviewed, not all received diclofenac.

Outcomes

Four children identified to have had post-tonsillectomy haemorrhage, three received diclofenac.

Notes

Include in qualitative review - authors state that they believe the incidence of post-operative bleeding increases with diclofenac use and these cases were likely to be caused by diclofenac.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Romsing 2000

Methods

Randomised controlled trial, investigator blind.

Participants

52 children undergoing tonsillectomy.

Interventions

1. Oral diclofenac 2-3 mg/kg/24 hours (24). 2. Paracetamol 90 mg/kg/24 hours (24). Placebo tablets and oral liquid used to maintain blinding.

Outcomes

1. Pain. 2. Bleeding. 3. Nausea and vomiting.

Notes

Four patients (two from each group) excluded as unwilling to take oral analgesics - no risk of bias as patients did not receive study medication. Asthmatics: excluded. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Ryhanen 1994

Methods

Randomised controlled trial, investigator blind.

Participants

299 children (ASA 1) undergoing herniotomy or orchidopexy.

Interventions

1. Intramuscular diclofenac 1 mg/kg (70). 2. No analgesia (73). 3. Caudal bupivacaine 0.25% 1 mL/kg (57). 4. Caudal bupivacaine 0.25% with adrenaline 5µg/mL 1 mL/kg (50).

Outcomes

1. Pain. 2. Adverse events. 3. Diclofenac pharmacokinetics.

Notes

Wrote to author, original data destroyed. 49 drop-outs cannot account for all but author states no patients had serious adverse events. Cannot compare post-operative complication rates as no numbers given (overall percentages). Gauze placed over sacral hiatus to maintain blinding. Adverse events monitored for, 70 patients received diclofenac with no serious adverse events. Asthmatics: excluded. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Sahajananda 2003

Methods

Case report.

Participants

Eight year old boy with Kartagener's syndrome.

Interventions

Lobectomy, received diclofenac for acute pain.

Outcomes

Post-operative complications.

Notes

Description of anaesthesia in difficult case. Received diclofenac, no serious adverse events. Asthmatic: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Samarkandi 2005

Methods

Randomised controlled trial, investigator blind.

Participants

92 children (ASA 1) undergoing herniotomy.

Interventions

1. Rectal diclofenac 1 mg/kg (32). 2. Caudal bupivacaine 0.25% 0.75 mL/kg (30). 3. Combination of the above (30).

Outcomes

1. Pain. 2. Vomiting. 3. Urinary retention. 4. Time to ambulation. 5. Sleep on night after operation.

Notes

Pethidine and paracetamol rescue analgesia used. Gauze covering sacral hiatus used for all patients to maintain blinding. Adverse events monitored for, 63 patients received diclofenac with no serious adverse events. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Schiffmann 2005

Methods

Case report.

Participants

16 year-old girl two weeks post wisdom teeth removal.

Interventions

Oral diclofenac 75 mg twice daily for five days and clindamycin 300 mg three times daily for 10 days.

Outcomes

Colon perforation causing peritonitis and requiring peritoneal lavage and colostomy formation, closed after three months with no further complications.

Notes

Include in qualitative review. Diclofenac implicated as lesions typical of NSAID-associated damage and showed no signs of pseudomembranous colitis possibly induced by clindamycin.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Seaton 2000

Methods

Case report.

Participants

15 year old boy with meningococcaemia.

Interventions

Received diclofenac for arthralgia.

Outcomes

Developed widespread limb purpura, protracted immunological phenomena and late-onset gastrointestinal vasculitis.

Notes

Include as case report but note causality uncertain. Contacted author, unsure as to the most likely cause for gastrointestinal pathology - either diclofenac or meningococcal related arthropathy.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Selin 2004

Methods

Comparative study.

Participants

86 children undergoing orthopaedic surgery.

Interventions

1. Intramuscular diclofenac 50-75 mg (50). 2. No additional treatment (36).

Outcomes

1. Pain. 2. Bleeding.

Notes

No information on randomisation or blinding. Some evidence adverse events monitored for, 50 patients received diclofenac with no serious adverse events. Asthmatics: unknown. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Sen 2001

Methods

Case report.

Participants

Nine year-old girl hospitalised for transient synovitis.

Interventions

Discharge medication: oral diclofenac 25 mg twice daily.

Outcomes

On the first dose at home patient developed body aches, rash, itching, cutaneous flushing and became febrile. A second dose was administered two hours later (to treat these symptoms) and developed generalised rash and choking. Prompt hospitalisation with haemodynamic and respiratory support, but resuscitation failed.

Notes

Include in qualitative review.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Swanepoel 1999

Methods

Randomised trial, investigator blinded.

Participants

80 children undergoing tonsillectomy.

Interventions

1. Rectal diclofenac 1 mg/kg on induction of anaesthesia (40). 2. Oral diclofenac suspension 1 mg/kg two hours before surgery (40).

Outcomes

1. Pain.

Notes

Letter describing study, unclear whether adverse events looked for but states all patients discharged home the following day and no problems with haemostasis occurred. Wrote to author who confirmed no serious adverse events occurred. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Sylaidis 1998

Methods

Prospective cohort

Participants

20 children undergoing cleft palate repair.

Interventions

Rectal diclofenac 1 mg/kg in theatre and further post-operative doses if required.

Outcomes

1. Post-operative complications.

Notes

Two non-serious adverse events noted, neither attributed to diclofenac. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Tawalbeh 2001

Methods

Randomised controlled trial.

Participants

80 children undergoing tonsillectomy.

Interventions

1. Rectal diclofenac 0.5-1.5 mg/kg/dose (41). 2. Oral paracetamol 10-15 mg/kg (39).

Outcomes

1. Pain. 2. Prolonged hospitalisation. 3. Bleeding requiring surgical intervention. 4. Nausea and vomiting.

Notes

Uses rescue analgesia. Risk of bias as treatment allocation known. Two serious adverse events (re-hospitalisation) one in each group. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Tay 2002

Methods

Randomised controlled trial, investigator blind.

Participants

63 children (ASA 1-2) undergoing bilateral myringotomy.

Interventions

1. Oral diclofenac resinate 0.5 mg/kg (30). 2. Oral paracetamol 15 mg/kg (33).

Outcomes

1. Pain. 2. Vomiting.

Notes

Fentanyl rescue analgesia used, some evidence of adverse event monitoring, no serious adverse events reported. Asthmatics: unknown. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Tewary 1993

Methods

Retrospective case record review.

Participants

363 children undergoing tonsillectomy.

Interventions

All patients received rectal diclofenac 25 mg on induction of anaesthesia.

Outcomes

1. Reactionary haemorrhage. 2. Return to hospital due to bleeding.

Notes

Six patients either had prolonged hospitalisation or were rehospitalised within 24 hours for reactionary haemorrhage. Five patients returned to hospital with bleeding between days two and eight (11 serious adverse events in total). Asthmatics: unknown. Safety quality: low.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Thiagarajan 1993

Methods

Randomised controlled trial, investigator and anaesthetist blinded.

Participants

198 children (ASA 1-2) undergoing tonsillectomy.

Interventions

1. Intramuscular diclofenac 1 mg/kg (91). 2. Intramuscular papaveretum 0.2 mg/kg (92).

Outcomes

1. Pain. 2. Bleeding requiring surgical intervention. 3. Subjective blood loss. 4. Nausea and vomiting.

Notes

15 withdrawals, 10 did not receive the study drug and record sheets of five were incomplete. Wrote to authors - none of these five excluded patients had a serious adverse event, but unclear whether they received diclofenac. Can use recovery area adverse events for comparative analysis without rescue analgesia. Evidence of monitoring for adverse events, 91 patients definitely received diclofenac, one serious adverse event - bleeding requiring re-operation. Asthmatics: excluded. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



van der Marel 2004

Methods

Pharmacokinetic study

Participants

26 children undergoing tonsillectomy.

Interventions

Rectal diclofenac 2 mg/kg followed by 1 mg/kg eight hourly.

Outcomes

1. Pharmacokinetics.

Notes

Wrote to authors, no serious adverse events. Study also pooled pharmacokinetic data from 11 patients from Romsing 2000. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Varvinski 2001

Methods

Case report.

Participants

13 year old girl with Soto's syndrome.

Interventions

Orthopaedic surgery, rectal diclofenac (2 mg/kg) for acute pain.

Outcomes

Post-operative complications.

Notes

Description of anaesthesia in difficult case. Child received diclofenac and did not have a serious adverse event. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Viitanen 2000

Methods

Randomised controlled trial.

Participants

80 children (ASA 1-3) undergoing adenoidectomy with or without myringotomy.

Interventions

1. Sevoflurane 8% (40). 2. Halothane 5% (40). All received rectal diclofenac 12.5 mg.

Outcomes

1. Recovery characteristics. 2. Adverse events.

Notes

Evidence of monitoring for adverse events, 80 patients received diclofenac, no serious adverse events. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Vuori 2004

Methods

Randomised controlled trial.

Participants

51 children (ASA 1-2) undergoing elective major abdominal, thoracic or orthopaedic surgery.

Interventions

1. Intravenous diclofenac1.5 mg/kg followed by rectal diclofenac 2mg/kg twice daily (17). 2. Intravenous oxycodone 0.1 mg/kg followed by a continuous infusion of 0.03 mg/kg/hr (16). 3. Epidural bupivacaine 0.25% 0.1-0.2 mL/kg followed by an epidural infusion of bupivacaine 0.125% plus fentanyl 50 µg (15). Each treatment lasted for three days after the operation.

Outcomes

1. Systemic and local immune response. 2. Pain. 3. Diclofenac pharmacokinetics. 4. Adverse events.

Notes

Main study focus on immune response to surgery, no detail on adverse events. However, adverse events were monitored for and one serious adverse event (bleeding requiring transfusion) occurred in diclofenac group. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Walmsley 1997

Methods

Audit

Participants

30 children undergoing ENT surgery.

Interventions

Soluble oral diclofenac 12.5 mg or 25 mg.

Outcomes

1. Pain.

Notes

Wrote to author, no serious adverse events occurred. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Watters 1988

Methods

Randomised controlled trial, investigator blind.

Participants

75 children (ASA 1-2) undergoing tonsillectomy.

Interventions

1. Intramuscular diclofenac 1 mg/kg (25). 2. Pethidine 1 mg/kg (25). 3. No analgesia (25).

Outcomes

1. Pain. 2. Drowsiness. 3. Vomiting.

Notes

Pethidine rescue analgesia used. Adverse events monitored for and no serious adverse events occurred. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Yes

A - Adequate



Wennstrom 2002

Methods

Randomised controlled trial.

Participants

50 children (ASA 1-2) undergoing strabismus surgery.

Interventions

1. Rectal diclofenac 1 mg/kg (25). 2. Intravenous morphine 0.05 mg/kg (25).

Outcomes

1. Pain. 2. Nausea and vomiting.

Notes

Risk of bias as no allocation blinding, morphine used for rescue analgesia. Cannot include in comparative analysis as gives number of episodes not number of patients with vomiting. Adverse events monitored for and no serious adverse events occurred. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

No

C - Inadequate



Willey 2005

Methods

Randomised comparative study. Not blind

Participants

31 children aged 4-16 years admitted to two hospitals with a diagnosis of appendicitis

Interventions

Postoperative paracetamol 90 mg/kg/24 hours and diclofenac 3 mg/kg/24 hours via 1. rectal route (11) 2. oral route (18). All children received one diclofenac suppository pre-op.

Outcomes

1. Pain 2. PONV

Notes

Allocation to oral or rectal treatment said to be randomised but marked imbalance of numbers. Evidence of monitoring for adverse events. Asthmatics:unknown. Safety quality: medium

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Williams 2002

Methods

Randomised controlled trial.

Participants

98 children (ASA 1-2) undergoing adenotonsillectomy.

Interventions

1. Intramuscular codeine 1.5 mg/kg (48). 2. Intramuscular morphine (0.15 mg/kg) (48). All patients received rectal diclofenac 1 mg/kg.

Outcomes

1. Pain. 2. Adverse events. 3. CYP2D6 genotype.

Notes

Two withdrawals, neither received diclofenac. Adverse events monitored for, 96 received diclofenac and no serious adverse events occurred. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Yamamoto 1994

Methods

Comparative study.

Participants

74 children undergoing minor surgery.

Interventions

1. Sevoflurane. 2. Isoflurane. 3. Halothane. Rectal diclofenac 1 mg/kg was given to 23 patients.

Outcomes

1. Pain. 2. Adverse events.

Notes

Adverse events monitored for and no serious adverse events occurred. Asthmatics: unknown. Safety quality: moderate.

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

D - Not used



Yoo 1999

Methods

Randomised placebo-controlled trial

Participants

60 patients, aged 3-13 years, day-case tonsillectomy with or without adenoidectomy.

Interventions

1. IV fentanyl 1 mcg/kg (20) ; 2. IM diclofenac 1 mg.kg (20) 3. PLACEBO injection (20) route not stated. Post-induction

Outcomes

1. Pain 2. PONV 3. Bleeding

Notes

Study translated from Korean; blinding unclear. Evidence of monitoring for adverse events but cannot use for comparative analysis as not known if post-op bleeds required surgical intervention. Asthmatics: unknown. safety quality:moderate

Risk of bias

Item

Authors' judgement

Description

Allocation concealment?

Unclear

B - Unclear



Características de los estudios excluidos [ordenados por ID del estudio]

Study

Reason for exclusion

Anon 2005

(French) No mention of diclofenac use of adverse effects

Arundel 2007

Review. No cases involving diclofenac-induced liver disease in children

Bano 2004

Diclofenac as rescue analgesia, cannot tell number who received it

Baroni 1983

(Italian) Adult and paediatric patients, cannot separate out paediatric data

Berry 1992b

Letter relating to Berry 1992a

Bertin 1991

Diclofenac not used

Bruce 2006

Some children probably received diclofenac but individual cases cannot be identified

Camera 1992

Adult and paediatric patients, cannot separate out data on children

Campbell 1990

Adult patients only

Castro 1995

Translated from Spanish - adult patients

Courtney 2001

Adult and paediatric patients, cannot separate out data on children

Cuvellier 2005

(French) Clinical review. No case reports involving diclofenac use

Farsi 2007

Data relates to patients over 17 years old

Fender 1992

Translated from French - adult patient

Garcia-Alonso 1991

Adult patients only

Gold 2007

Clinical update. No specific cases involving diclofenac in children

Han 2005

Adult patients only

Hernandez 1997

Translated from Spanish - adult patients

Hicklin 1999

'Most' children given diclofenac, wrote to authors, no response

Karachalios 1992

Adult patients only

Keohane 1995

Not all patients received diclofenac, cannot separate out those who did

Kokki 1994

Diclofenac not used

Kurimoto 1993

Translated from Japanese - not all patients received diclofenac, cannot separate out those who did

Kuzelova 2004

Accidental intoxications, not a study of acute pain in children

Lankinen 2006

Diclofenac use is mentioned in abstract but there is no mention at all in the main paper

Lau 2002

Adult patients only

Leaper 2006

Spme children received diclofenac but not possible to identify data on individual cases

Lemelle 1998

Translated from French - review article

Machida 2004

Adult and paediatric patients, cannot separate out data on children

Majid 2004

Number of patients receiving diclofenac unclear, wrote to authors, no response

Mannion 1994

No mention of adverse events or blinding, wrote to authors, no response

Marczyk 1992

Translated from Portugese - adult patients

Maunuksela 1991

Review article

McEwan 2000

Diclofenac as rescue analgesia, not all patients received it and cannot separate out adverse event data in the ones that did

Miralles 1987

Adult patients only

Mitic 2007

Some patients received diclofenac but not possible to identify data on specific cases

Moore 1985

Diclofenac not used

Mostaque 1998

No mention of adverse events, wrote to authors, no response

Nordbladh 1991

Adult and paediatric patients, cannot separate out data on children

Ozcan 2002

Adult patients only

Parker 1986

Diclofenac not used

Pendeville 2001

Adult and paediatric patients, cannot separate out data on children

Roelofse 1993

Adult patients only

Roelofse 1996

Adult patients only

Romej 1996

Paitients did not receive diclofenac

Romsing 2001

Pharmacokinetic data from Romsing 2000 - further analysis on same study/patients

Rozhkova 1983

Translated from Russian - adult patients only

Schachtel 1993

Does not fit criteria for this review (Diclofenac not used for treating acute pain in children)

Schaller 1998

Case reports of NSAID renal toxicity in children - none were diclofenac

Schwentner 2006

Cannot determine number of patients receiving diclofenac

Shah 2001

Number of patients receiving diclofenac unclear, wrote to authors, no response

Sheppard 1993

Not all patients received diclofenac, cannot separate out those who did

Silvasti 1999

Adult patients

Stanley 2002

Case report, child received diclofenac but cannot ascertain when or what dose. Adverse events mentioned but no link to diclofenac made in text

Taneja 2004

Adult and paediatric patients, not all received diclofenac and cannot separate out data on children

Teiria 1994

Patients received diclofenac or ibuprofen, cannot tell numbers receiving diclofenac

Thomaser 2004

Translated from German - 70 dropouts, cannot tell total number of children exposed to diclofenac

Tuzuner 2007

Adult patients only

Valladares 2004

Adult and paediatric patients, cannot separate out data on children

van den Berg 1999

Adult and paediatric patients, cannot separate out paediatric data

Verheggen 1994

Adult and paediatric patients, not all received diclofenac and cannot separate out data on children

Walton 1993

Adult patients only

Weber 2007

Mix of children and adults. Cannot separate out data on children



Table 1. Quality analysis of safety study papers

Quality categories

High

Moderate

Low

Study design

Prospective, number of patients exposed to diclofenac given

Prospective, number of patients exposed to diclofenac given

Prospective or retrospective, number of patients exposed to diclofenac given

Adverse event monitoring

Evidence of monitoring for adverse events

Evidence of monitoring for adverse events

Spontaneous reporting of adverse events

Adverse event reporting

Specific adverse events reported

Adverse events may be grouped by system

Adverse events may be grouped by system

Assessment of causality linking adverse events and adverse drug reactions

Use of causality algorithm or difference versus placebo in double-blind RCT

Causality may be attributed by clinical judgement or difference versus placebo in double-blind RCT

Causality may be attributed by clinical judgement or difference versus placebo in double-blind RCT

Follow-up

Post-discharge follow-up on at least one occasion

No evidence of follow-up

No evidence of follow-up



Table 2. Serious adverse events in 3611 participants given diclofenac for acute pain

Study

Number of Events

Description

Duarte 1997*

1

Palpebral oedema "of serious intensity". Diclofenac stopped

Fischer 1992

1

Unclear as refers to table grouping moderate/severe as rated by patient. Reaction is one of: vomiting, headache, stomach pain or erythema.

Kierszenbaum 1991*

2

Hypothermia "obliging the suspension of treatment"

Kokinsky 1999

1

Protracted vomiting requiring prolonged hospitalisation.

Kokinsky 1999

1

Bleeding after penile surgery requiring re-operation.

Leontev 2005

5

Allergic skin reaction, reversed with injected chlorpyramine

McGowan 1998

2

Late haemorrhage after day-case circumcision requiring hospital admission.

Mendham 1996

3

Haemorrhage after tonsillectomy requiring re-operation.

Oztekin 2002

1

Bleeding after tonsillectomy requiring prolonged hospitalisation.

Tawalbeh 2001

1

Bleeding requiring re-hospitalisation after tonsillectomy.

Tewary 1993

6

Bleeding causing prolonged or re-hospitalisation after tonsillectomy.

Thiagarajan 1993

1

Bleeding requiring re-operation after tonsillectomy.

Vuori 2004

1

Bleeding requiring blood transfusion following major surgery.

TOTAL

26

NOTE: Only two studies * reported that they considered these serious adverse events to be adverse drug reactions caused by diclofenac.



Table 3. Summary of case reports sorted by indication

Reaction type

Chronic treatment

Indication unknown

Acute pain

Acute allergic-type reaction

0

1

4

Cardiovascular

0

0

1

Central nervous system

5

2

5

Dermatological

7

4

3

Endocrine

1

1

0

Genitourinary

3

0

1

Gastrointestinal - bleeding

3

3

7

Gastrointestinal - general

3

1

5

Haematological

1

0

5

Hepatic

2

0

0

Injection site reactions

0

0

6

Muscular

0

0

2

Renal

0

1

0

Respiratory

4

1

3



Figuras

Figure 1

Forest plot of comparison: 1 Diclofenac vs no treatment/placebo, outcome: 1.1 Number of patients requiring rescue analgesia.


Figure 1


Figure 2

Forest plot of comparison: 2 Diclofenac vs paracetamol, outcome: 2.1 Number of patients requiring rescue analgesia.


Figure 2


Figure 3

Forest plot of comparison: 3 Diclofenac vs any other treatment, outcome: 3.1 Nausea and/or vomiting.


Figure 3


Figure 4

Forest plot of comparison: 3 Diclofenac vs any other treatment, outcome: 3.2 Bleeding requiring surgical intervention.


Figure 4


Figure 5

Forest plot of comparison: 4 Diclofenac vs other NSAIDs, outcome: 4.1 Nausea and/or vomiting.


Figure 5


Analysis 1.1

Comparison 1 Diclofenac vs no treatment/placebo, Outcome 1 Number of patients requiring rescue analgesia.


Analysis 1.1


Analysis 2.1

Comparison 2 Diclofenac vs paracetamol, Outcome 1 Number of patients requiring rescue analgesia.


Analysis 2.1


Analysis 3.1

Comparison 3 Diclofenac vs any other treatment, Outcome 1 Nausea and/or vomiting.


Analysis 3.1


Analysis 3.2

Comparison 3 Diclofenac vs any other treatment, Outcome 2 Bleeding requiring surgical intervention.


Analysis 3.2


Analysis 4.1

Comparison 4 Diclofenac vs other NSAIDs, Outcome 1 Nausea and/or vomiting.


Analysis 4.1


Analysis 4.2

Comparison 4 Diclofenac vs other NSAIDs, Outcome 2 Bleeding requiring surgical intervention.


Analysis 4.2