Nicotina intranasal o transdérmica para el tratamiento del dolor posoperatorio
Resumen
Antecedentes
Con frecuencia se produce dolor agudo después de los procedimientos quirúrgicos. La nicotina se ha explorado como una medicación coadyuvante para el tratamiento del dolor posoperatorio.
Objetivos
Evaluar el efecto de la administración de nicotina transdérmica o intranasal sobre el dolor posoperatorio, la administración de analgésicos opiáceos y los eventos adversos relacionados con los opiáceos.
Métodos de búsqueda
Se hicieron búsquedas en MEDLINE (1966 hasta 20 marzo 2014), Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL; 2014, número 3), EMBASE (1980 hasta 20 marzo 2014), y también en bases de datos de ensayos en curso (www.controlled‐trials.com/ and http://clinicaltrials.gov/). Se volvió a ejecutar la búsqueda el 28 abril 2015. Cuando se actualice la revisión se evaluará el único estudio de interés.
Criterios de selección
Se incluyeron los ensayos clínicos aleatorios controlados con placebo que evaluaron los efectos de la administración perioperatoria (pre, intra o posoperatoria) de nicotina sobre el dolor posoperatorio, la administración de opiáceos y los eventos adversos relacionados con los opiáceos. Se excluyeron los demás estudios.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, examinaron la elegibilidad de todos los títulos y resúmenes y documentaron las razones para la exclusión. En caso de desacuerdo, un tercer autor decidió la inclusión o la exclusión del informe del ensayo. Cuando se necesitó información adicional para decidir si un ensayo se debía incluir, uno de los autores estableció contacto con el autor correspondiente del ensayo en cuestión.
Resultados principales
Nueve ensayos (666 participantes) evaluaron la nicotina para el dolor posoperatorio. La nicotina puede reducir en una cantidad pequeña las puntuaciones de dolor posoperatorio a las 24 horas en comparación con placebo (ocho ensayos, diferencia de medias ‐0,88 en una escala de 0 a 10, intervalo de confianza [IC] del 95%: ‐1,58 a ‐0,18; pruebas de baja calidad). No estuvo muy claro el efecto sobre el dolor a la hora y a las 12 horas después de la cirugía (pruebas de muy baja calidad). La heterogeneidad estadística fue significativa y no se explicó suficientemente mediante la estratificación de los ensayos según el tipo de procedimiento quirúrgico, la situación con respecto al tabaquismo, la forma de administración de la nicotina, el momento de administración o la evaluación del riesgo de sesgo. La exclusión de un ensayo con alto riesgo de sesgo dio lugar a resultados similares. El efecto de la nicotina sobre la administración posoperatoria de opiáceos fue incierto debido al escaso número de participantes en los estudios. La nicotina probablemente aumenta el riesgo de náuseas posoperatorias (siete ensayos, CR 1,24; IC del 95%: 1,03 a 1,50; pruebas de calidad moderada). Tres ensayos evaluaron la sedación pero el efecto es muy incierto debido a la calidad muy baja de las pruebas. No se encontraron pruebas de que la nicotina aumentara el riesgo de vómitos (siete estudios, diferencia de riesgos [DR] 0,03; IC del 95%: ‐0,04 a 0,09; pruebas de baja calidad). Los resultados de un único ensayo pequeño no fueron suficientes para establecer si la nicotina dio lugar al alta hospitalaria más temprana (pruebas de muy baja calidad).
Conclusiones de los autores
Según pruebas de calidad generalmente baja, la nicotina puede aliviar el dolor posoperatorio a las 24 horas en comparación con placebo, pero los efectos fueron relativamente pequeños (menos de 1 punto en una escala de dolor de 10 puntos) y hubo heterogeneidad significativa en los resultados de los análisis. La nicotina no parece reducir la administración posoperatoria de opiáceos ni los eventos adversos relacionados con los opiáceos, pero probablemente aumenta el riesgo de náuseas. Se necesitan más estudios de investigación para determinar la efectividad de la nicotina para el dolor posoperatorio y para determinar el momento, la dosis y el método de administración óptimos de la nicotina.
PICO
Resumen en términos sencillos
Nicotina para el dolor posoperatorio
Pregunta de la revisión
Esta revisión Cochrane examina si la nicotina administrada antes, durante o inmediatamente después de la cirugía da lugar a menos dolor, administración de opiáceos y efectos secundarios de los opiáceos.
Características de los antecedentes de los estudios
La cirugía mayor generalmente se asocia con dolor significativo. La base del tratamiento para el dolor posterior a la cirugía mayor son los fármacos opiáceos (analgésicos potentes como la morfina). Sin embargo, los opiáceos no siempre son completamente eficaces y se asocian con efectos secundarios que incluyen somnolencia (sedación), respiración superficial (depresión respiratoria), tener deseos de vomitar (náuseas) y vómitos. Los fármacos coadministrados como el paracetamol pueden ayudar a mejorar el control del dolor posoperatorio y reducir la necesidad de opiáceos.
Se incluyeron nueve ensayos clínicos con un total de 666 participantes. Se buscó en varias bases de datos hasta marzo de 2014 para encontrar ensayos aleatorios controlados con placebo (estudios clínicos donde los pacientes se asignan al azar a uno de dos o más grupos de tratamiento, uno de los cuales incluye un grupo simulado [placebo]) de nicotina para el dolor posoperatorio. También se contactó con los autores de los estudios para obtener datos adicionales. No todos los estudios informaron todos los síntomas (resultados) enumerados anteriormente, de manera que lo que se puede señalar acerca de algunos resultados es limitado. Se volvió a ejecutar la búsqueda el 28 abril 2015. Cuando se actualice esta revisión se evaluará un estudio de interés.
Resultados clave
Los resultados indicaron que hay pruebas de calidad muy baja de que la administración de nicotina da lugar a puntuaciones de dolor posoperatorio algo inferiores a las 24 horas después de la cirugía. A la hora y a las 12 horas después de la cirugía el efecto no estuvo muy claro. La nicotina pareció no reducir la administración de opiáceos a los 60 minutos o a las 24 horas, ni hubo pruebas de que redujera la sedación o los vómitos. La nicotina se asoció con un riesgo mayor de náuseas que placebo, lo que puede limitar su uso. No hubo suficientes datos para evaluar los efectos de la administración de nicotina sobre otros efectos secundarios asociados con los opiáceos, incluida la depresión respiratoria, o los efectos de la administración de nicotina sobre la duración de la estancia hospitalaria posterior a la cirugía.
Calidad de la evidencia
La calidad de las pruebas se disminuyó a baja o muy baja debido en gran parte a los problemas con la manera en que se diseñaron los estudios, que podría haber exagerado los resultados porque no hubo datos suficientes en muchos de los análisis para tener seguridad acerca del tamaño promedio del efecto y porque los resultados de algunos de los estudios variaron de manera significativa.
Conclusiones de los autores
Summary of findings
| Main outcomes: Transdermal or intranasal nicotine versus placebo for the treatment of postoperative pain | ||||||
| Patient or population: people being treated for postoperative pain Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Main outcomes: transdermal or intranasalnicotine versus placebo | |||||
| Pain at 60 minutes | The mean pain at 60 minutes in the control groups was | The mean pain at 60 minutes in the intervention groups was | MD ‐0.14 (‐0.94 to 0.65) | 442 | ⊕⊝⊝⊝ | ‐ |
| Pain at 12 hours | The mean pain at 12 hours in the control groups was | The mean pain at 12 hours in the intervention groups was | MD ‐0.00 (‐0.98 to 0.98) | 175 | ⊕⊝⊝⊝ | ‐ |
| Pain at 24 hours | The mean pain at 24 hours in the control groups was | The mean pain at 24 hours in the intervention groups was | MD ‐0.88 (‐1.58 to ‐0.18) | 562 | ⊕⊕⊝⊝ | ‐ |
| Hourly morphine equivalents at 60 minutes | The mean hourly morphine equivalents at 60 minutes in the control groups was | The mean hourly morphine equivalents at 60 minutes in the intervention groups was | MD ‐0.08 (‐0.40 to 0.24) | 168 | ⊕⊕⊝⊝ | ‐ |
| Hourly morphine equivalents at 24 hours | The mean hourly morphine equivalents at 24 hours in the control groups was | The mean hourly morphine equivalents at 24 hours in the intervention groups was | MD ‐6.06 (‐12.91 to 0.79) | 168 | ⊕⊕⊝⊝ | ‐ |
| Sedation score | The mean sedation score in the control groups was | The mean sedation score in the intervention groups was | SMD ‐0.13 (‐0.88 to 0.62) | 148 | ⊕⊕⊝⊝ | ‐ |
| Nausea | Study population | RR 1.24 | 592 | ⊕⊕⊕⊝ | ‐ | |
| 379 per 1000 | 469 per 1000 | |||||
| 400 per 1000 | 496 per 1000 | |||||
| Vomiting | Study population | RD 0.03 (‐0.04 to 0.09) | 602 | ⊕⊕⊝⊝ | ‐ | |
| 150 per 1000 | 176 per 1000 | |||||
| 65 per 1000 | 76 per 1000 | |||||
| Time to hospital discharge | The mean time to hospital discharge in the control groups was | The mean time to hospital discharge in the intervention groups was | MD 1.20 (‐6.19 to 8.59) | 90 | ⊕⊕⊝⊝ | ‐ |
| GRADE Working Group grades of evidence CI: confidence interval; MD: mean difference; SMD: standardized mean difference; RD: risk difference; RR: risk ratio. | ||||||
| 1 Downgraded one level due to serious risk of bias: methodological limitations present in most studies. 4 Downgraded one level due to serious inconsistency: statistical heterogeneity was 75‐100%. 5 Downgraded two levels due very serious imprecision: evidence comes from one small study and the confidence interval around the effect included a clinically meaningful effect with intervention or control. | ||||||
Antecedentes
Para el tratamiento del dolor posoperatorio hay muchos fármacos disponibles. Los opiáceos son la clase de fármacos sistémicos utilizada con más frecuencia para el dolor posoperatorio (Vadivelu 2010), pero no siempre son completamente eficaces y pueden provocar eventos adversos como sedación excesiva, depresión respiratoria, náuseas, vómitos, estreñimiento y erupción cutánea. Un fármaco que se ha explorado para el tratamiento coadyuvante del dolor posoperatorio es la nicotina. Se han realizado pocos estudios sobre la nicotina para el dolor posoperatorio y los resultados de los estudios individuales han sido variables en cuanto a mostrar efectos beneficiosos. En esta revisión sistemática se resumieron las pruebas sobre la nicotina intranasal y transdérmica para el dolor posoperatorio, se exploraron los posibles motivos de los resultados inconsistentes entre los estudios y se destacaron las áreas de interés para los estudios de investigación adicionales.
Descripción de la afección
Después de los procedimientos quirúrgicos con frecuencia ocurre dolor agudo debido al daño tisular como resultado de la cirugía y a la inflamación relacionada. En un estudio (250 participantes), el 82% de los participantes informó algún dolor después de la cirugía y el 39% de estos participantes informó dolor intenso a extremo (Apfelbaum 2003). En otro estudio (200 participantes), la tasa de dolor moderado a extremo en alguna etapa durante las 24 primeras horas después de la cirugía fue del 88% (Svensson 2000). El tratamiento del dolor posoperatorio es un componente importante de la atención quirúrgica, pero los estudios de investigación indican que muchos pacientes informan un control subóptimo del dolor posoperatorio (Owen 1990).
Descripción de la intervención
La práctica clínica habitual en el tratamiento del dolor posoperatorio es la analgesia multimodal. Esta práctica se refiere al uso de combinaciones de fármacos analgésicos (como los opiáceos y el paracetamol [acetaminofén], fármacos antiinflamatorios no esteroideos, gabapentina o pregabalina, u otros) y vías de administración (como regional, intravenosa y epidural), así como formas no farmacológicas, para disminuir las necesidades de opiáceos y los efectos adversos asociados como la sedación, las náuseas, los vómitos, el estreñimiento y el prurito. La analgesia multimodal puede incluir fármacos sistémicos preventivos antes o durante la cirugía, o antes de despertar completamente de la anestesia, así como tratamiento después que el paciente ha recobrado la conciencia.
Una estrategia específica en el tratamiento multimodal del dolor posoperatorio es potenciar los fármacos analgésicos con fármacos adicionales. Estos fármacos adicionales en combinación con los opiáceos pueden aliviar el dolor y reducir la cantidad total de opiáceos necesarios. Algunos posibles agentes que se pueden utilizar de esta manera incluyen la capsaicina, los antagonistas del receptor de N‐metil‐D‐aspartato, o los gabapentinoides (Vadivelu 2010).
La nicotina está disponible en varias formas, incluidas formulaciones transdérmicas (parche) e inhaladas. La nicotina puede aliviar el dolor al reducir directamente el dolor y mejorar el tratamiento general del dolor incluso aunque no proporcione un alivio directo a través de posibles mecanismos que no se comprenden completamente. Los estudios de investigación indican que administrada sola la nicotina aumenta los umbrales de dolor en los pacientes sometidos a la prueba de estimulación por frío (cold pressor test) (inmersión de una mano en agua fría), aunque los resultados no son consistentes con las pruebas de calor o de estimulación eléctrica (Shi 2010). La nicotina puede reducir el riesgo de depresión respiratoria, ya sea por reducción de la dosis de opiáceo necesaria para el control adecuado del dolor o directamente como un estimulante respiratorio. Otros estimulantes han mostrado reducir la depresión respiratoria (Miller 1962). Hay algunas pruebas de que los agonistas nicotínicos pueden bloquear la hiperalgesia asociada con algunos anestésicos inhalados (Flood 2002; Yan 2009).
Uno de los efectos adversos de la nicotina, en particular en los pacientes que no habían recibido nicotina previamente, puede ser las náuseas y los vómitos. Por el contrario, hay algunas pruebas de que los fumadores actuales o los consumidores de rapé tienen menores probabilidades de presentar náuseas y vómitos posoperatorios, debido quizás a los efectos nicotínicos (Brattwall 2010).
Varios factores pueden influir en los efectos analgésicos de la nicotina, que incluyen los antecedentes de fumador actual o exfumador, la vía de administración (p.ej. transdérmica o intranasal), el momento de administración de la nicotina (p.ej. preoperatorio, intraoperatorio o posoperatorio), el sexo y la edad. Por ejemplo, algunas pruebas indican que los fumadores femeninos tienen menor sensibilidad al dolor que los fumadores no femeninos (Girdler 2005). También puede haber variabilidad genética subyacente en la respuesta a la nicotina (Campbell 2006).
De qué manera podría funcionar la intervención
Hay varias hipótesis acerca de cómo la nicotina podría afectar directamente al sistema del dolor. La mayoría incluye el sistema receptor colinérgico nicotínico. Una teoría es que la nicotina estimula los receptores nicotínicos alfa‐4 y beta‐2 y por lo tanto estimula la liberación de noradrenalina espinal (norepinefrina), lo que da lugar a alivio del dolor. También se ha indicado que la actividad presora de la nicotina sobre el sistema cardiovascular puede dar lugar a reducción del dolor. Puede haber un efecto antiinflamatorio de la nicotina a través del receptor colinérgico alfa‐7 (Benowitz 2008; Shi 2010). Los fumadores crónicos experimentan aumento ("upregulation") y desensibilización de los receptores de nicotina, lo que puede dar lugar a los efectos atenuados de la nicotina en esta población.
El sistema opioide también puede participar en los efectos analgésicos de la nicotina. Algunos estudios han encontrado que los animales tratados con naloxona o con deficiencia en el receptor opioide mu no experimentan alivio del dolor con la nicotina, o tienen una respuesta atenuada al dolor (Campbell 2006).
Por qué es importante realizar esta revisión
Aunque algunos estudios han evaluado los efectos de los parches de nicotina o la nicotina inhalada en los pacientes sometidos a cirugía, los resultados de los estudios individuales son hasta cierto punto mixtos (Cheng 2008; Flood 2004; Habib 2008; Hong 2008; Olson 2009; Turan 2008). El objetivo de esta revisión fue sintetizar la bibliografía y, de ser apropiado, combinar los estudios para proporcionar estimaciones agrupadas del efecto y aumentar el poder estadístico para detectar efectos. De haber heterogeneidad estadística significativa en las estimaciones agrupadas, otro objetivo de esta revisión fue evaluar si el tipo de cirugía; el grado de tabaquismo; el sexo; las diferencias en la calidad de los estudios; o las diferencias en la dosis, el momento o la forma de administración de la nicotina pueden ayudar a explicar los resultados divergentes.
Objetivos
Evaluar el efecto de la administración de nicotina transdérmica o intranasal sobre el dolor posoperatorio, la administración de analgésicos opiáceos y los eventos adversos relacionados con los opiáceos.
Métodos
Criterios de inclusión de estudios para esta revisión
Tipos de estudios
Se incluyeron los ensayos clínicos aleatorios controlados con placebo que evaluaron el efecto de la administración perioperatoria (pre, intra o posoperatoria) de nicotina intranasal o transdérmica sobre el dolor posoperatorio o la administración de analgésicos opiáceos. Se excluyeron los demás estudios.
Tipos de participantes
Se incluyeron los participantes sometidos a cualquier cirugía electiva menor o mayor en pacientes hospitalizados o ambulatorios que se asignaron al azar a recibir nicotina o placebo para el dolor posquirúrgico. Se incluyeron hombres y mujeres fumadores o no fumadores de todas las edades, así como niños.
Tipos de intervenciones
Las intervenciones de interés incluyeron la colocación de un parche transdérmico de nicotina o el uso de spray intranasal de nicotina para el control del dolor posoperatorio una o más veces antes, durante o después de la cirugía. La nicotina se incluyó si se administró solamente como coadyuvante a otros tratamientos para el dolor y si se proporcionó pre, intra o posoperatoriamente. Los grupos de comparación recibieron placebo.
Tipos de medida de resultado
Resultados primarios
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Puntuaciones de dolor posoperatorio en reposo, como las informó el participante en una escala de calificación numérica o una escala de calificación categórica a los 60 minutos, las 12 horas y las 24 horas.
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Equivalentes de morfina posoperatoria por hora. Los equivalentes de morfina son una manera de evaluar uniformemente la cantidad administrada en miligramos por kilogramo por hora entre diversos opiáceos.
Resultados secundarios
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Sedación como la informó y la calificó en una escala el participante.
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Náuseas como las informó el participante.
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Vómitos como los informó el participante.
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Tiempo hasta el alta hospitalaria.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Results of the search
We conducted the search on 20 March 2014 (see Appendix 1; Appendix 2; Appendix 3 for full search strategies). We identified 388 studies. We identified two ongoing studies on searches of clinical trials registries (www.controlled‐trials.com/ and www.clinicaltrials.gov). We contacted the authors of the two trials (NCT00790829; NCT01194089), but no data were available yet. After removal of duplicates, there were 347 unique citations for screening. Of those 347 citations, 12 studies appeared to meet inclusion criteria on initial screen and we obtained full‐texts of the articles for further review. After review of full‐text articles and ongoing trials, nine articles met our inclusion criteria (See Figure 1).
We re‐ran the search on 28 April 2015 and found one additional study of interest (Weingarten 2015). We will assess that study when we update the review.
Additional data from primary authors
We obtained additional data from primary authors for four studies (Cheng 2008; Flood 2004; Hong 2008; Turan 2008). Pamela Flood, MD provided pain scores and morphine equivalents at 30 and 60 minutes and one, three, and five days for the Hong 2008 study. Dr Flood also provided the mean and standard deviations for pain scores at 30 minutes, 60 minutes, one day, three days, and five days and morphine equivalents used at these times points for the Cheng 2008 study, and clarified that there were 10 participants per group in the Flood 2004 study. Alparslan Turan, MD provided mean and standard deviation for pain scores at 30 minutes, 60 minutes, one day, three days, and five days as well as the cumulative morphine dose used at each of those time points for the Turan 2008 study.
Included studies
All nine included studies were randomized trials (Cheng 2008; Czarnetzki 2011; Flood 2004; Habib 2008; Hong 2008; Jankowski 2011; Olson 2009; Turan 2008; Yagoubian 2011). Eight were parallel group trials and one was a cross‐over trial (Yagoubian 2011). Sample sizes ranged from 20 to 118 (total n = 666) and duration of follow‐up ranged from one to seven postoperative days.
Four trials focused on gynaecological surgery and included only women (Cheng 2008; Flood 2004; Jankowski 2011; Turan 2008), one trial focused on prostate surgery in men (Habib 2008), and the remainder included both men and women undergoing various surgeries (elective inpatient surgery (Czarnetzki 2011), general surgery (Hong 2008), pelvic or abdominal surgeries (Olson 2009), or third molar extraction (Yagoubian 2011)).
Doses of nicotine ranged from 3 to 17 mg per dose. Nicotine was administered only pre‐ or intra‐operatively, or both, in two trials (Cheng 2008; Yagoubian 2011), only postoperatively in two trials (Flood 2004; Jankowski 2011), and continuously through both time periods in five trials (Cheng 2008; Czarnetzki 2011; Habib 2008; Hong 2008; Olson 2009). Nicotine was administered as a patch in five trials (Czarnetzki 2011; Habib 2008; Hong 2008; Olson 2009; Turan 2008), and as an inhaler in four trials (Cheng 2008; Flood 2004; Jankowski 2011; Yagoubian 2011). Seven studies excluded smokers (Cheng 2008; Czarnetzki 2011; Flood 2004; Habib 2008; Hong 2008; Jankowski 2011; Yagoubian 2011), and one study restricted enrolment to smokers (Olson 2009). One study excluded participants with a history of postoperative nausea and vomiting (Jankowski 2011).
All of the trials were single centre studies. Seven trials were conducted in the USA (Cheng 2008; Flood 2004; Habib 2008; Hong 2008; Jankowski 2011; Olson 2009; Yagoubian 2011), one in Switzerland (Czarnetzki 2011), and one in Turkey (Turan 2008).
Excluded studies
We excluded three studies after full‐text review. One was not a randomized controlled trial (Ionescu 2007), one was an editorial (Benowitz 2008), and one was an abstract of a review (Souzdalnitski 2009) (See Characteristics of excluded studies table).
Ongoing studies
Two studies are ongoing and therefore no data are available yet (NCT00790829; NCT01194089) (see Characteristics of ongoing studies table).
Studies awaiting classification
We re‐ran our search on 28 April 2015. We found one study, which is awaiting classification (Weingarten 2015) (see Characteristics of studies awaiting classification table).
Risk of bias in included studies
See summary of findings Table for the main comparison for an overall assessment of the risk of bias assessment of included studies for each comparison and outcome. See also the 'Risk of bias' graph (see Figure 2) and 'Risk of bias' summary (see Figure 3) for an overview of risk of bias. Details about assessments for specific risk of bias criteria are described below.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Based on the risk of bias assessments, we rated three trials overall as good quality (Czarnetzki 2011; Flood 2004; Jankowski 2011), five as fair quality (Cheng 2008; Habib 2008; Hong 2008; Olson 2009; Turan 2008), and one as poor quality (Yagoubian 2011). The poor quality trial had unclear blinding of participants and study personnel, outcomes assessors, and unclear similarity of intervention groups at baseline (Yagoubian 2011).
Allocation
Three trials reported computerized randomization (Czarnetzki 2011; Olson 2009; Turan 2008), and two reported use of randomization tables (Flood 2004; Hong 2008). The method of random sequence generation was unclear in four trials (Cheng 2008; Habib 2008; Jankowski 2011; Yagoubian 2011).
Two trials reported use of numbered, opaque sealed envelopes for allocation concealment (Cheng 2008; Olson 2009), and two used an opaque container (Czarnetzki 2011; Flood 2004), and one used identical syringes (Jankowski 2011). The method of allocation concealment was unclear in four studies (Habib 2008; Hong 2008; Turan 2008; Yagoubian 2011).
Blinding
Seven trials reported blinded outcomes assessment; in the other two, use of blinded outcome assessment was unclear (Cheng 2008; Yagoubian 2011).
All but one of the studies reported blinding of study participants and personnel. In one other trial, it was unclear whether either personnel or participants were blinded (Yagoubian 2011).
Incomplete outcome data
We did not detect incomplete outcome data in any of the studies.
Selective reporting
We did not detect selective reporting in any of the studies. No trial was available only as an abstract.
Other potential sources of bias
One trial reported significant baseline differences between intervention groups (Olson 2009), and in one trial it was unclear if groups were similar at baseline (Yagoubian 2011). All studies described ITT analysis, withdrawals, co‐interventions were avoided or similar, and timing of outcome assessments were similar.
Effects of interventions
Primary outcome: postoperative pain scores
There was no difference between nicotine and placebo in postoperative pain score at 60 minutes (six trials, MD ‐0.14, 95% CI ‐0.94 to 0.65; Chi2 test = 17.31, degrees of freedom (df) = 5 (P value = 0.72); I2 statistic = 71%, Analysis 1.1) or at 12 hours (two trials, MD ‐0.00, 95% CI ‐0.98 to 0.98, Chi2 test = 4.67, df = 1 (P value = 1.00); I2 statistic = 79%, Analysis 1.2). Sensitivity and subgroup analyses showed no differences when stratified by type of surgery, route of administration, nicotine dose, timing of nicotine, gender, or overall quality.
For pain at 60 minutes, there was a statistically significant difference in the effect of nicotine on pain between studies that recruited smokers and studies recruiting a mix of smokers and non‐smokers, with a more favourable effect with placebo in the studies recruiting smokers (P value = 0.004). However, results should be interpreted with caution because neither trial enrolled only smokers, and there was substantial statistical heterogeneity in the subgroup of trials that focused on non‐smokers (I2 statistic = 53%).
At 24 hours, nicotine was associated with lower pain score than placebo, with a difference of slightly less than 1 on a 0 to 10 point scale (eight trials, MD ‐0.88; 95% CI ‐1.58 to ‐0.18; Chi2 test = 79.23, df = 7 (P value < 0.00001); Figure 4, Analysis 1.3). Results were characterized by a high degree of statistical heterogeneity (I2 statistic = 91%). The Flood 2004 study appeared to be an outlier, reporting a substantially stronger effect for nicotine (MD ‐3.40, 95% CI ‐4.32 to ‐2.48) than the other trials (MD ranged from ‐1.30 to 0.20). Excluding this trial resulted in a difference that was no longer statistically significant (seven trials, MD ‐0.53, 95% CI ‐1.12 to 0.06; Chi2 = 43.85, df = 56 (P value < 0.00001)), but did not eliminate statistical heterogeneity (I2 statistic = 86%). Subgroup analyses showed no clear differences when trials were stratified by type of surgery, route of administration, smoking status, nicotine dose, timing of nicotine, gender, or overall study quality. For a complete overview, see summary of findings Table for the main comparison.
Forest plot of comparison: 1 Main outcomes: Transdermal or intranasal nicotine versus placebo, outcome: 1.3 Pain at 24 hours.
Primary outcome: postoperative opioid use
There was no difference between nicotine and placebo in mean hourly morphine use at 60 minutes (four trials, MD ‐0.08, 95% CI ‐0.40 to 0.24; Chi2 test = 3.41, df = 3 (P value = 0.33); I2 statistic = 12%; Analysis 1.4) or 24 hours (four trials, MD ‐6.06, 95% CI ‐12.91 to 0.79; Chi2 test = 1.10, df = 3 (P value = 0.78); I2 statistic = 0%; Analysis 1.5). There were also no differences in sensitivity or subgroup analyses. For a complete overview, see summary of findings Table for the main comparison.
Secondary outcomes: adverse effects ‐ sedation, nausea, vomiting
There was no difference between nicotine and placebo in sedation scores (three trials, SMD ‐0.13, 95% CI ‐0.88 to 0.62; Chi2 test = 7.68, df = 2 (P value = 0.02); I2 statistic = 74%; Figure 5, Analysis 1.6).
Forest plot of comparison: 1 Main outcomes: Transdermal or intranasal nicotine versus placebo, outcome: 1.6 Sedation score.
Nicotine was associated with higher risk of nausea than placebo (seven trials, RR 1.24, 95% CI 1.03 to 1.50; Chi2 test = 2.63, df = 6 (P value = 0.85); I2 statistic = 0%; Analysis 1.7), but there was no difference in risk of vomiting (seven trials, RD 0.03, 95% CI ‐0.04 to 0.09; Chi2 test = 9.83, df = 6 (P value = 0.13); I2 statistic = 39%; Analysis 1.8). There were also no differences in risk of nausea or vomiting in sensitivity or subgroup analyses.
Secondary outcome: time to hospital discharge
Only one study reported time to hospital discharge. Results did not favour either nicotine or placebo (Analysis 1.9).
Discusión
Resumen de los resultados principales
La revisión sistemática de nueve ensayos controlados aleatorios publicados encontró que la nicotina se asoció con menos dolor que el placebo a las 24 horas después de la cirugía, pero se asoció con ninguna diferencia en las puntuaciones de dolor en puntos temporales más tempranos. La diferencia a las 24 horas fue menor de 1 punto en una escala de dolor de 10 puntos, que es inferior a lo que se considera habitualmente como clínicamente significativo y los resultados se caracterizaron por heterogeneidad estadística significativa. No hubo diferencias entre la nicotina y placebo en la administración posoperatoria de opiáceos. La nicotina se asoció con un aumento del riesgo de náuseas versus placebo.
Compleción y aplicabilidad general de las pruebas
La revisión estuvo limitada por los tamaños de la muestra relativamente pequeños disponibles para muchos de los resultados principales de interés (rango: 90 a 602 participantes), lo que disminuyó la precisión de las estimaciones. El escaso número de ensayos (nueve) limitó la utilidad de los análisis de subgrupos y de sensibilidad. Varios ensayos no informaron algunos resultados como la administración de opiáceos antes de las 24 horas, la sedación y el tiempo hasta el alta hospitalaria. Cuatro de los ensayos se centraron en pacientes sometidas a cirugía ginecológica y uno de los ensayos en hombres sometidos a cirugía de próstata, lo que quizás introduce heterogeneidad y limita la aplicabilidad a otros procedimientos quirúrgicos. Siete ensayos excluyeron a fumadores o fumadores recientes y solamente un ensayo limitó el reclutamiento a fumadores (los otros reclutaron una mezcla de fumadores y no fumadores), lo que impide establecer conclusiones sólidas con respecto a los efectos de la nicotina para el dolor posoperatorio en los fumadores. Además, los equivalentes de morfina (consumo de opiáceos) pueden ser una medición poco sensible de la analgesia (Kissin 2009; McQuay 2008).
Calidad de la evidencia
Tres de los nueve estudios se calificaron de calidad general "buena" según las evaluaciones de los dominios relacionados con el riesgo de sesgo, por lo que se disminuyó la calidad de las pruebas de todos los análisis (Resumen de los hallazgos para la comparación principal).
Algunos análisis se caracterizaron por un grado alto de heterogeneidad estadística (variación en los resultados de los estudios entre los estudios). Una medida estadística utilizada para caracterizar la heterogeneidad es la estadística I2 (mientras más grande el valor, mayor variabilidad en los resultados del estudio). Los resultados con un grado alto de heterogeneidad estadística incluyeron dolor a los 60 minutos (estadística I2 = 71%), a las 12 horas (estadística I2 = 79%), a las 24 horas (estadística I2 = 91%), y las puntuaciones de sedación (estadística I2 = 74%). En general, la heterogeneidad estadística no se redujo significativamente al excluir los ensayos de calidad baja o con valores atípicos, o mediante la estratificación de los ensayos según el tipo de cirugía, el momento de administración, la situación con respecto al tabaquismo y otros factores. Además, los escasos números de ensayos limitaron la utilidad de los análisis de subgrupos. Los resultados basados en los análisis con heterogeneidad estadística significativa se deben interpretar con cuidado.
Con el uso del sistema GRADE se asignaron puntuaciones generales de calidad muy baja a baja debido a las limitaciones metodológicas, la imprecisión y la inconsistencia. Lo anterior indica que es probable que los estudios de investigación adicionales tengan una marcada repercusión sobre las estimaciones de los efectos.
Sesgos potenciales en el proceso de revisión
Dos autores (TD y AM) extrajeron los datos de los estudios. Dos autores (TD y AM) clasificaron de forma independiente el riesgo de sesgo y un tercer autor (RC) resolvió cualquier desacuerdo. AM redactó la revisión pero todos los autores contribuyeron al producto final. No fue posible evaluar formalmente el sesgo de publicación con el uso de métodos gráficos o estadísticos debido a los escasos números de ensayos disponibles para cada análisis. Como se analizó anteriormente, dos estudios cumplieron con los criterios de inclusión pero actualmente reclutaban participantes, por lo que todavía no había datos disponibles (NCT00790829; NCT01194089).
Acuerdos y desacuerdos con otros estudios o revisiones
Se encontraron otras tres revisiones sobre este tema. Una se publicó como resumen (Souzdalnitski 2009). Se consideraron 11 estudios, cuatro fueron ensayos controlados aleatorios. El resumen no señaló cuáles fueron los cuatro ensayos controlados aleatorios utilizados. Al igual que la presente revisión, con el uso de un modelo de efectos aleatorios se encontró que la nicotina se asoció con menos dolor posoperatorio que placebo a las 24 horas (valor de p = 0,031). También se informó una tendencia estadísticamente no significativa hacia el consumo de menos opiáceos (valor de p = 0,054). Otra revisión también presentó resultados consistentes con la presente revisión; encontró que seis de siete estudios analizados apoyaron el uso de la nicotina como tratamiento para el dolor posoperatorio en los participantes que no habían recibido nicotina previamente, pero con un aumento en la incidencia de náuseas posoperatorias (Vibe Nielsen 2012). Los siete estudios incluidos se incluyeron en la presente revisión y todos fueron ensayos controlados aleatorios (Flood 2004; Habib 2008; Hong 2008; Jankowski 2011; Olson 2009; Turan 2008; Yagoubian 2011).
Mishriky 2014 también realizó una revisión que utilizó los mismos estudios incluidos en la presente revisión. Mishriky 2014 encontró que no hubo diferencias en la reducción del dolor en el análisis agrupado en ningún punto temporal y que hubo heterogeneidad significativa, gran parte de la cual parece, según el diagrama de bosque (forest plot), ser causada por el estudio Flood 2004. Como en la presente revisión, Mishriky 2014 encontró de manera similar que cuando se eliminó Flood 2004 todavía no hubo diferencias en el dolor a las 24 horas en los estudios agrupados.
Mishriky 2014 utilizó el consumo acumulativo de morfina a las 24 horas y la presente revisión utilizó los equivalentes de morfina utilizados por hora a las 24 horas. Mishriky 2014 encontró una reducción significativa en el consumo acumulativo de opiáceos a las 24 horas con la administración de nicotina (DM ‐4,85 mg; IC del 95%: ‐9,40 a ‐0,30 [valor de p = 0,04], estadística I2 = 24%), pero en la revisión actual no se encontró una diferencia significativa en los equivalentes de morfina por hora a las 24 horas. Similar al resultado de esta revisión, Mishriky 2014 no encontró diferencias en el dolor o la administración de opiáceos al analizar los subgrupos (participantes que recibieron parche transdérmico versus spray nasal, mujeres versus hombres y no fumadores versus fumadores).
De acuerdo con la presente revisión, Mishriky 2014 también encontró un aumento en las náuseas en el grupo de nicotina (a la hora: cinco ensayos, CR 1,26; IC del 95%: 1,03 a 1,55; estadística I2 = 0%; a las 24 horas: siete ensayos, CR 1,14; IC del 95%: 1,03 a 1,26; estadística I2 = 0%). No se encontraron diferencias en el riesgo de vómitos y Mishriky 2014 decidió no establecer conclusiones acerca de los vómitos debido a los IC amplios.
Study flow diagram. Note: We re‐ran the search on 28 April 2015 and found one additional study of interest. We will assess this study when we update the review.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Main outcomes: Transdermal or intranasal nicotine versus placebo, outcome: 1.3 Pain at 24 hours.
Forest plot of comparison: 1 Main outcomes: Transdermal or intranasal nicotine versus placebo, outcome: 1.6 Sedation score.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 1 Pain at 60 minutes.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 2 Pain at 12 hours.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 3 Pain at 24 hours.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 4 Hourly morphine equivalents at 60 minutes.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 5 Hourly morphine equivalents at 24 hours.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 6 Sedation score.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 7 Nausea.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 8 Vomiting.
Comparison 1 Main outcomes: transdermal or intranasal nicotine versus placebo, Outcome 9 Time to hospital discharge.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 1 Pain at 60 minutes by type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 2 Pain at 60 minutes by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 3 Pain at 60 minutes by smokers or mix of smokers/non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 4 Pain at 60 minutes by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 5 Pain at 60 minutes by timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 6 Pain at 60 minutes by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 7 Pain at 60 minutes by overall quality.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 8 Pain at 12 hours by type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 9 Pain at 12 hours by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 10 Pain at 12 hours by smokers or mix of smokers/non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 11 Pain at 12 hours by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 12 Pain at 12 hours by timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 13 Pain at 12 hours by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 14 Pain at 12 hours by overall quality.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 15 Pain at 24 hours type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 16 Pain at 24 hours by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 17 Pain at 24 hours by smokers or mix of smokers/non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 18 Pain at 24 hours by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 19 Pain at 24 hours by timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 20 Pain at 24 hours by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 21 Pain at 24 hours by overall quality.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 22 Hourly morphine at 60 minutes by type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 23 Hourly morphine at 60 minutes by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 24 Hourly morphine at 60 minutes smokers or mix of smokers/non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 25 Hourly morphine at 60 minutes by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 26 Hourly morphine at 60 minutes timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 27 Hourly morphine at 60 minutes by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 28 Hourly morphine at 60 minutes by overall quality.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 29 Hourly morphine at 24 hours by type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 30 Hourly morphine at 24 hours by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 31 Hourly morphine at 24 hours by smokers or mix of smokers/non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 32 Hourly morphine at 24 hours by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 33 Hourly morphine at 24 hours by timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 34 Hourly morphine at 24 hours by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 35 Hourly morphine at 24 hours overall quality.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 36 Sedation by type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 37 Sedation by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 38 Sedation by smokers or mix of smokers/non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 39 Sedation by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 40 Sedation by timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 41 Sedation by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 42 Sedation by overall quality.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 43 Nausea by type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 44 Nausea by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 45 Nausea by smokers or mix of smokers/non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 46 Nausea by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 47 Nausea by timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 48 Nausea by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 49 Nausea by overall quality.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 50 Vomiting by type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 51 Vomiting by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 52 Vomiting by smokers or mix of smokers/non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 53 Vomiting by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 54 Vomiting by timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 55 Vomiting by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 56 Vomiting by overall quality.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 57 Time to hospital discharge by type of surgery.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 58 Time to hospital discharge by route of administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 59 Time to hospital discharge by smokers or mix of smokers and non‐smokers.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 60 Time to hospital discharge by nicotine dose.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 61 Time to hospital discharge timing of nicotine administration.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 62 Time to hospital discharge by gender.
Comparison 2 Subgroups: transdermal or intranasal nicotine versus placebo, Outcome 63 Time to hospital discharge by overall quality.
| Main outcomes: Transdermal or intranasal nicotine versus placebo for the treatment of postoperative pain | ||||||
| Patient or population: people being treated for postoperative pain Comparison: placebo | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Main outcomes: transdermal or intranasalnicotine versus placebo | |||||
| Pain at 60 minutes | The mean pain at 60 minutes in the control groups was | The mean pain at 60 minutes in the intervention groups was | MD ‐0.14 (‐0.94 to 0.65) | 442 | ⊕⊝⊝⊝ | ‐ |
| Pain at 12 hours | The mean pain at 12 hours in the control groups was | The mean pain at 12 hours in the intervention groups was | MD ‐0.00 (‐0.98 to 0.98) | 175 | ⊕⊝⊝⊝ | ‐ |
| Pain at 24 hours | The mean pain at 24 hours in the control groups was | The mean pain at 24 hours in the intervention groups was | MD ‐0.88 (‐1.58 to ‐0.18) | 562 | ⊕⊕⊝⊝ | ‐ |
| Hourly morphine equivalents at 60 minutes | The mean hourly morphine equivalents at 60 minutes in the control groups was | The mean hourly morphine equivalents at 60 minutes in the intervention groups was | MD ‐0.08 (‐0.40 to 0.24) | 168 | ⊕⊕⊝⊝ | ‐ |
| Hourly morphine equivalents at 24 hours | The mean hourly morphine equivalents at 24 hours in the control groups was | The mean hourly morphine equivalents at 24 hours in the intervention groups was | MD ‐6.06 (‐12.91 to 0.79) | 168 | ⊕⊕⊝⊝ | ‐ |
| Sedation score | The mean sedation score in the control groups was | The mean sedation score in the intervention groups was | SMD ‐0.13 (‐0.88 to 0.62) | 148 | ⊕⊕⊝⊝ | ‐ |
| Nausea | Study population | RR 1.24 | 592 | ⊕⊕⊕⊝ | ‐ | |
| 379 per 1000 | 469 per 1000 | |||||
| 400 per 1000 | 496 per 1000 | |||||
| Vomiting | Study population | RD 0.03 (‐0.04 to 0.09) | 602 | ⊕⊕⊝⊝ | ‐ | |
| 150 per 1000 | 176 per 1000 | |||||
| 65 per 1000 | 76 per 1000 | |||||
| Time to hospital discharge | The mean time to hospital discharge in the control groups was | The mean time to hospital discharge in the intervention groups was | MD 1.20 (‐6.19 to 8.59) | 90 | ⊕⊕⊝⊝ | ‐ |
| GRADE Working Group grades of evidence CI: confidence interval; MD: mean difference; SMD: standardized mean difference; RD: risk difference; RR: risk ratio. | ||||||
| 1 Downgraded one level due to serious risk of bias: methodological limitations present in most studies. 4 Downgraded one level due to serious inconsistency: statistical heterogeneity was 75‐100%. 5 Downgraded two levels due very serious imprecision: evidence comes from one small study and the confidence interval around the effect included a clinically meaningful effect with intervention or control. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain at 60 minutes Show forest plot | 6 | 442 | Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.94, 0.65] |
| 2 Pain at 12 hours Show forest plot | 2 | 175 | Mean Difference (IV, Random, 95% CI) | ‐0.00 [‐0.98, 0.98] |
| 3 Pain at 24 hours Show forest plot | 8 | 562 | Mean Difference (IV, Random, 95% CI) | ‐0.88 [‐1.58, ‐0.18] |
| 4 Hourly morphine equivalents at 60 minutes Show forest plot | 4 | 168 | Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐0.40, 0.24] |
| 5 Hourly morphine equivalents at 24 hours Show forest plot | 4 | 168 | Mean Difference (IV, Random, 95% CI) | ‐6.06 [‐12.91, 0.79] |
| 6 Sedation score Show forest plot | 3 | 148 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.13 [‐0.88, 0.62] |
| 7 Nausea Show forest plot | 7 | 592 | Risk Ratio (M‐H, Random, 95% CI) | 1.24 [1.03, 1.50] |
| 8 Vomiting Show forest plot | 7 | 602 | Risk Difference (M‐H, Random, 95% CI) | 0.03 [‐0.04, 0.09] |
| 9 Time to hospital discharge Show forest plot | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain at 60 minutes by type of surgery Show forest plot | 6 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.1 Type of surgery is gynaecological | 4 | 374 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.89, 0.90] |
| 1.2 Type of surgery is mixed/other | 2 | 68 | Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐2.28, 1.43] |
| 2 Pain at 60 minutes by route of administration Show forest plot | 6 | 442 | Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.94, 0.65] |
| 2.1 Route of administration is patch | 3 | 153 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐1.40, 1.63] |
| 2.2 Route of administration is inhaler | 3 | 289 | Mean Difference (IV, Random, 95% CI) | ‐0.35 [‐1.19, 0.49] |
| 3 Pain at 60 minutes by smokers or mix of smokers/non‐smokers Show forest plot | 6 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 3.1 Non‐smokers only | 4 | 329 | Mean Difference (IV, Random, 95% CI) | ‐0.59 [‐1.38, 0.19] |
| 3.2 Mix of smokers and non‐smokers | 2 | 113 | Mean Difference (IV, Random, 95% CI) | 0.93 [0.27, 1.58] |
| 4 Pain at 60 minutes by nicotine dose Show forest plot | 6 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 4.1 ≤ 5 mg | 6 | 398 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.70, 0.73] |
| 4.2 5‐15 mg | 2 | 35 | Mean Difference (IV, Random, 95% CI) | ‐0.26 [‐3.00, 2.48] |
| 4.3 ≥ 15 mg | 2 | 35 | Mean Difference (IV, Random, 95% CI) | ‐1.07 [‐2.27, 0.13] |
| 5 Pain at 60 minutes by timing of nicotine administration Show forest plot | 6 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 5.1 Pre‐ or intraoperative | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 0.0 [‐1.01, 1.01] |
| 5.2 Postoperative | 2 | 199 | Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐2.22, 0.88] |
| 5.3 Both | 3 | 153 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐1.40, 1.63] |
| 6 Pain at 60 minutes by gender Show forest plot | 6 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 6.1 Women only | 4 | 374 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.89, 0.90] |
| 6.2 Men and women | 2 | 68 | Mean Difference (IV, Random, 95% CI) | ‐0.42 [‐2.28, 1.43] |
| 7 Pain at 60 minutes by overall quality Show forest plot | 6 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 7.1 Good | 2 | 199 | Mean Difference (IV, Random, 95% CI) | ‐0.67 [‐2.22, 0.88] |
| 7.2 Fair | 4 | 243 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.95, 1.14] |
| 8 Pain at 12 hours by type of surgery Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 8.1 Type of surgery is gynaecological | 1 | 85 | Mean Difference (IV, Random, 95% CI) | 0.50 [‐0.14, 1.14] |
| 8.2 Type of surgery is male pelvic | 1 | 90 | Mean Difference (IV, Random, 95% CI) | ‐0.5 [‐1.14, 0.14] |
| 9 Pain at 12 hours by route of administration Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 9.1 Route is patch | 2 | 175 | Mean Difference (IV, Random, 95% CI) | ‐0.00 [‐0.98, 0.98] |
| 10 Pain at 12 hours by smokers or mix of smokers/non‐smokers Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 10.1 Non‐smokers only | 1 | 90 | Mean Difference (IV, Random, 95% CI) | ‐0.5 [‐1.14, 0.14] |
| 10.2 Mix of smokers and non‐smokers | 1 | 85 | Mean Difference (IV, Random, 95% CI) | 0.50 [‐0.14, 1.14] |
| 11 Pain at 12 hours by nicotine dose Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 11.1 ≤ 5 mg | 1 | 85 | Mean Difference (IV, Random, 95% CI) | 0.50 [‐0.14, 1.14] |
| 11.2 5‐15 mg | 1 | 90 | Mean Difference (IV, Random, 95% CI) | ‐0.5 [‐1.14, 0.14] |
| 12 Pain at 12 hours by timing of nicotine administration Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 12.1 Pre‐ or intraoperative | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 12.2 Pre‐ or intraoperative and postoperative | 2 | 175 | Mean Difference (IV, Random, 95% CI) | ‐0.00 [‐0.98, 0.98] |
| 13 Pain at 12 hours by gender Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 13.1 Women only | 1 | 85 | Mean Difference (IV, Random, 95% CI) | 0.50 [‐0.14, 1.14] |
| 13.2 Men and women | 1 | 90 | Mean Difference (IV, Random, 95% CI) | ‐0.5 [‐1.14, 0.14] |
| 14 Pain at 12 hours by overall quality Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 14.1 Fair | 2 | 175 | Mean Difference (IV, Random, 95% CI) | ‐0.00 [‐0.98, 0.98] |
| 15 Pain at 24 hours type of surgery Show forest plot | 8 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 15.1 Type of surgery is gynaecological | 4 | 364 | Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐2.08, 0.26] |
| 15.2 Type of surgery is male pelvic | 1 | 90 | Mean Difference (IV, Random, 95% CI) | ‐0.7 [‐1.36, ‐0.04] |
| 15.3 Type of surgery is mixed/other | 3 | 108 | Mean Difference (IV, Random, 95% CI) | ‐1.25 [‐1.54, ‐0.95] |
| 16 Pain at 24 hours by route of administration Show forest plot | 8 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 16.1 Route is patch | 4 | 243 | Mean Difference (IV, Random, 95% CI) | ‐0.34 [‐0.97, 0.30] |
| 16.2 Route is inhaler | 4 | 319 | Mean Difference (IV, Random, 95% CI) | ‐1.31 [‐2.41, ‐0.21] |
| 17 Pain at 24 hours by smokers or mix of smokers/non‐smokers Show forest plot | 8 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 17.1 Non‐smokers only | 6 | 449 | Mean Difference (IV, Random, 95% CI) | ‐1.08 [‐1.89, ‐0.27] |
| 17.2 Mix of smokers and non‐smokers | 2 | 113 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐1.30, 0.91] |
| 18 Pain at 24 hours by nicotine dose Show forest plot | 8 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 18.1 ≤ 5 mg | 7 | 438 | Mean Difference (IV, Random, 95% CI) | ‐0.70 [‐1.53, 0.12] |
| 18.2 5‐15 mg | 3 | 125 | Mean Difference (IV, Random, 95% CI) | ‐0.69 [‐1.44, 0.06] |
| 18.3 ≥ 15 mg | 2 | 35 | Mean Difference (IV, Random, 95% CI) | ‐1.32 [‐3.28, 0.63] |
| 19 Pain at 24 hours by timing of nicotine administration Show forest plot | 8 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 19.1 Pre‐ or intraoperative | 2 | 120 | Mean Difference (IV, Random, 95% CI) | ‐1.14 [‐1.72, ‐0.56] |
| 19.2 Postoperative | 2 | 199 | Mean Difference (IV, Random, 95% CI) | ‐1.72 [‐4.96, 1.51] |
| 19.3 Both | 4 | 243 | Mean Difference (IV, Random, 95% CI) | ‐0.34 [‐0.97, 0.30] |
| 20 Pain at 24 hours by gender Show forest plot | 8 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 20.1 Women only | 4 | 364 | Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐2.08, 0.26] |
| 20.2 Men and women | 4 | 198 | Mean Difference (IV, Random, 95% CI) | ‐1.06 [‐1.45, ‐0.68] |
| 21 Pain at 24 hours by overall quality Show forest plot | 8 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 21.1 Good | 2 | 199 | Mean Difference (IV, Random, 95% CI) | ‐1.72 [‐4.96, 1.51] |
| 21.2 Fair | 5 | 323 | Mean Difference (IV, Random, 95% CI) | ‐0.36 [‐0.90, 0.18] |
| 21.3 Poor | 1 | 40 | Mean Difference (IV, Random, 95% CI) | ‐1.30 [‐1.61, ‐0.99] |
| 22 Hourly morphine at 60 minutes by type of surgery Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 22.1 Type of surgery is gynaecological | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.62, 0.35] |
| 22.2 Type of surgery is mixed/other | 2 | 68 | Mean Difference (IV, Random, 95% CI) | 0.29 [‐0.70, 1.27] |
| 23 Hourly morphine at 60 minutes by route of administration Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 23.1 Route is patch | 2 | 68 | Mean Difference (IV, Random, 95% CI) | 0.29 [‐0.70, 1.27] |
| 23.2 Route is inhaler | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.62, 0.35] |
| 24 Hourly morphine at 60 minutes smokers or mix of smokers/non‐smokers Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 24.1 Non‐smokers only | 3 | 140 | Mean Difference (IV, Random, 95% CI) | ‐0.09 [‐0.50, 0.32] |
| 24.2 Mix of smokers and non‐smokers | 1 | 28 | Mean Difference (IV, Random, 95% CI) | 0.20 [‐1.11, 1.51] |
| 25 Hourly morphine at 60 minutes by nicotine dose Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 25.1 ≤ 5 mg | 3 | 120 | Mean Difference (IV, Random, 95% CI) | ‐0.11 [‐0.51, 0.28] |
| 25.2 5‐15 mg | 2 | 35 | Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐1.03, 0.75] |
| 25.3 ≥ 15 mg | 2 | 35 | Mean Difference (IV, Random, 95% CI) | ‐0.25 [‐1.39, 0.90] |
| 26 Hourly morphine at 60 minutes timing of nicotine administration Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 26.1 Pre‐ or intraoperative | 1 | 80 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.28, 0.48] |
| 26.2 Postoperative | 1 | 20 | Mean Difference (IV, Random, 95% CI) | ‐0.40 [‐0.85, 0.05] |
| 26.3 Both | 2 | 68 | Mean Difference (IV, Random, 95% CI) | 0.29 [‐0.70, 1.27] |
| 27 Hourly morphine at 60 minutes by gender Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 27.1 Women only | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.62, 0.35] |
| 27.2 Men and women | 2 | 68 | Mean Difference (IV, Random, 95% CI) | 0.29 [‐0.70, 1.27] |
| 28 Hourly morphine at 60 minutes by overall quality Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 28.1 Good | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐0.14 [‐0.62, 0.35] |
| 28.2 Fair | 2 | 68 | Mean Difference (IV, Random, 95% CI) | 0.29 [‐0.70, 1.27] |
| 29 Hourly morphine at 24 hours by type of surgery Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 29.1 Type of surgery is gynaecological | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐5.77 [‐13.02, 1.47] |
| 29.2 Type of surgery is mixed/other | 2 | 68 | Mean Difference (IV, Random, 95% CI) | ‐8.53 [‐29.63, 12.57] |
| 30 Hourly morphine at 24 hours by route of administration Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 30.1 Route is patch | 2 | 68 | Mean Difference (IV, Random, 95% CI) | ‐8.53 [‐29.63, 12.57] |
| 30.2 Route is inhaler | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐5.77 [‐13.02, 1.47] |
| 31 Hourly morphine at 24 hours by smokers or mix of smokers/non‐smokers Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 31.1 Non‐smokers only | 3 | 140 | Mean Difference (IV, Random, 95% CI) | ‐6.05 [‐13.12, 1.01] |
| 31.2 Mix of smokers and non‐smokers | 1 | 28 | Mean Difference (IV, Random, 95% CI) | ‐6.20 [‐34.40, 22.00] |
| 32 Hourly morphine at 24 hours by nicotine dose Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 32.1 ≤ 5 mg | 4 | 129 | Mean Difference (IV, Random, 95% CI) | ‐5.98 [‐12.92, 0.96] |
| 32.2 5‐15 mg | 2 | 35 | Mean Difference (IV, Random, 95% CI) | ‐5.51 [‐28.90, 17.88] |
| 32.3 ≥ 15 mg | 2 | 35 | Mean Difference (IV, Random, 95% CI) | 0.23 [‐25.02, 25.48] |
| 33 Hourly morphine at 24 hours by timing of nicotine administration Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 33.1 Pre‐ or intraoperative | 2 | 108 | Mean Difference (IV, Random, 95% CI) | ‐4.62 [‐12.02, 2.78] |
| 33.2 Postoperative | 1 | 20 | Mean Difference (IV, Random, 95% CI) | ‐16.30 [‐38.38, 5.78] |
| 33.3 Both | 1 | 40 | Mean Difference (IV, Random, 95% CI) | ‐11.5 [‐43.31, 20.31] |
| 34 Hourly morphine at 24 hours by gender Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 34.1 Women only | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐5.77 [‐13.02, 1.47] |
| 34.2 Men and women | 2 | 68 | Mean Difference (IV, Random, 95% CI) | ‐8.53 [‐29.63, 12.57] |
| 35 Hourly morphine at 24 hours overall quality Show forest plot | 4 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 35.1 Good | 2 | 100 | Mean Difference (IV, Random, 95% CI) | ‐5.77 [‐13.02, 1.47] |
| 35.2 Fair | 2 | 68 | Mean Difference (IV, Random, 95% CI) | ‐8.53 [‐29.63, 12.57] |
| 36 Sedation by type of surgery Show forest plot | 3 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 36.1 Type of surgery is gynaecological | 1 | 80 | Std. Mean Difference (IV, Random, 95% CI) | 0.35 [‐0.10, 0.79] |
| 36.2 Type of surgery is mixed/other | 2 | 68 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.45 [‐1.54, 0.64] |
| 37 Sedation by route of administration Show forest plot | 3 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 37.1 Route is patch | 2 | 68 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.45 [‐1.54, 0.64] |
| 37.2 Route is inhaler | 1 | 80 | Std. Mean Difference (IV, Random, 95% CI) | 0.35 [‐0.10, 0.79] |
| 38 Sedation by smokers or mix of smokers/non‐smokers Show forest plot | 3 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 38.1 Non‐smokers only | 2 | 120 | Std. Mean Difference (IV, Random, 95% CI) | 0.27 [‐0.10, 0.65] |
| 38.2 Mix of smokers and non‐smokers | 1 | 28 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.03 [‐1.90, ‐0.16] |
| 39 Sedation by nicotine dose Show forest plot | 3 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 39.1 ≤ 5 mg | 3 | 114 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.03 [‐0.80, 0.75] |
| 39.2 5‐15 mg | 2 | 35 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.74 [‐1.72, 0.24] |
| 39.3 ≥ 15 mg | 2 | 35 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.27 [‐2.41, ‐0.12] |
| 40 Sedation by timing of nicotine administration Show forest plot | 3 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 40.1 Pre‐ or intraoperative | 1 | 80 | Std. Mean Difference (IV, Random, 95% CI) | 0.35 [‐0.10, 0.79] |
| 40.2 Both | 2 | 68 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.45 [‐1.54, 0.64] |
| 41 Sedation by gender Show forest plot | 3 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 41.1 Women only | 1 | 80 | Std. Mean Difference (IV, Random, 95% CI) | 0.35 [‐0.10, 0.79] |
| 41.2 Men and women | 2 | 68 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.45 [‐1.54, 0.64] |
| 42 Sedation by overall quality Show forest plot | 3 | Std. Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 42.1 Fair | 3 | 148 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.13 [‐0.88, 0.62] |
| 43 Nausea by type of surgery Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 43.1 Type of surgery is gynaecological | 3 | 344 | Risk Ratio (M‐H, Random, 95% CI) | 1.21 [0.94, 1.57] |
| 43.2 Type of surgery is male pelvic | 1 | 90 | Risk Ratio (M‐H, Random, 95% CI) | 1.38 [0.95, 1.99] |
| 43.3 Type of surgery is mixed/other | 3 | 158 | Risk Ratio (M‐H, Random, 95% CI) | 1.16 [0.78, 1.73] |
| 44 Nausea by route of administration Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 44.1 Route is patch | 5 | 333 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [1.03, 1.67] |
| 44.2 Route is inhaler | 2 | 259 | Risk Ratio (M‐H, Random, 95% CI) | 1.15 [0.86, 1.54] |
| 45 Nausea by smokers or mix of smokers/non‐smokers Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 45.1 Non‐smokers only | 5 | 479 | Risk Ratio (M‐H, Random, 95% CI) | 1.20 [0.99, 1.47] |
| 45.2 Mix of smokers and non‐smokers | 2 | 113 | Risk Ratio (M‐H, Random, 95% CI) | 1.53 [0.92, 2.57] |
| 46 Nausea by nicotine dose Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 46.1 ≤ 5 mg | 4 | 364 | Risk Ratio (M‐H, Random, 95% CI) | 0.87 [0.45, 1.68] |
| 46.2 5‐15 mg | 3 | 125 | Risk Ratio (M‐H, Random, 95% CI) | 1.41 [1.01, 1.95] |
| 46.3 ≥ 15 mg | 3 | 125 | Risk Ratio (M‐H, Random, 95% CI) | 1.19 [0.79, 1.79] |
| 47 Nausea by timing of nicotine administration Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 47.1 Pre‐ or intraoperative | 1 | 80 | Risk Ratio (M‐H, Random, 95% CI) | 1.0 [0.42, 2.40] |
| 47.2 Postoperative | 1 | 179 | Risk Ratio (M‐H, Random, 95% CI) | 1.17 [0.86, 1.59] |
| 47.3 Both | 5 | 333 | Risk Ratio (M‐H, Random, 95% CI) | 1.31 [1.03, 1.67] |
| 48 Nausea by gender Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 48.1 Women only | 3 | 344 | Risk Ratio (M‐H, Random, 95% CI) | 1.21 [0.94, 1.57] |
| 48.2 Men and women | 4 | 248 | Risk Ratio (M‐H, Random, 95% CI) | 1.27 [0.97, 1.67] |
| 49 Nausea by overall quality Show forest plot | 7 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 49.1 Good | 2 | 269 | Risk Ratio (M‐H, Random, 95% CI) | 1.13 [0.87, 1.47] |
| 49.2 Fair | 5 | 323 | Risk Ratio (M‐H, Random, 95% CI) | 1.36 [1.05, 1.77] |
| 50 Vomiting by type of surgery Show forest plot | 7 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 50.1 Type of surgery is gynaecological | 3 | 354 | Risk Difference (M‐H, Random, 95% CI) | 0.02 [‐0.11, 0.15] |
| 50.2 Type of surgery is male pelvic | 1 | 90 | Risk Difference (M‐H, Random, 95% CI) | 0.12 [‐0.01, 0.24] |
| 50.3 Type of surgery is mixed/other | 3 | 158 | Risk Difference (M‐H, Random, 95% CI) | 0.01 [‐0.08, 0.09] |
| 51 Vomiting by route of administration Show forest plot | 7 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 51.1 Route is patch | 5 | 333 | Risk Difference (M‐H, Random, 95% CI) | 0.05 [‐0.02, 0.12] |
| 51.2 Route is inhaler | 2 | 269 | Risk Difference (M‐H, Random, 95% CI) | 0.00 [‐0.16, 0.17] |
| 52 Vomiting by smokers or mix of smokers/non‐smokers Show forest plot | 7 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 52.1 ≤ 5 mg | 5 | 378 | Risk Difference (M‐H, Random, 95% CI) | 0.01 [‐0.08, 0.10] |
| 52.2 5‐15 mg | 3 | 125 | Risk Difference (M‐H, Random, 95% CI) | 0.06 [‐0.03, 0.16] |
| 52.3 ≥ 15 mg | 3 | 125 | Risk Difference (M‐H, Random, 95% CI) | 0.01 [‐0.10, 0.12] |
| 53 Vomiting by nicotine dose Show forest plot | 7 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 53.1 ≤ 5 mg | 5 | 378 | Risk Difference (M‐H, Random, 95% CI) | 0.01 [‐0.08, 0.10] |
| 53.2 5‐15 mg | 3 | 125 | Risk Difference (M‐H, Random, 95% CI) | 0.06 [‐0.03, 0.16] |
| 53.3 ≥ 15 mg | 3 | 125 | Risk Difference (M‐H, Random, 95% CI) | 0.01 [‐0.10, 0.12] |
| 54 Vomiting by timing of nicotine administration Show forest plot | 7 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 54.1 Pre‐ or intraoperative | 1 | 90 | Risk Difference (M‐H, Random, 95% CI) | ‐0.07 [‐0.15, 0.02] |
| 54.2 Postoperative | 1 | 179 | Risk Difference (M‐H, Random, 95% CI) | 0.08 [‐0.03, 0.18] |
| 54.3 Both | 5 | 333 | Risk Difference (M‐H, Random, 95% CI) | 0.05 [‐0.02, 0.12] |
| 55 Vomiting by gender Show forest plot | 7 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 55.1 Women only | 3 | 354 | Risk Difference (M‐H, Random, 95% CI) | 0.02 [‐0.11, 0.15] |
| 55.2 Men and women | 4 | 248 | Risk Difference (M‐H, Random, 95% CI) | 0.04 [‐0.03, 0.12] |
| 56 Vomiting by overall quality Show forest plot | 7 | Risk Difference (M‐H, Random, 95% CI) | Subtotals only | |
| 56.1 Good | 2 | 269 | Risk Difference (M‐H, Random, 95% CI) | 0.06 [‐0.03, 0.16] |
| 56.2 Fair | 5 | 333 | Risk Difference (M‐H, Random, 95% CI) | 0.02 [‐0.07, 0.10] |
| 57 Time to hospital discharge by type of surgery Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 57.1 Type of surgery is male pelvic | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
| 58 Time to hospital discharge by route of administration Show forest plot | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
| 58.1 Route is patch | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
| 59 Time to hospital discharge by smokers or mix of smokers and non‐smokers Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 59.1 Non‐smokers only | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
| 60 Time to hospital discharge by nicotine dose Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 60.1 5‐15 mg | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
| 61 Time to hospital discharge timing of nicotine administration Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 61.1 Pre‐ or intraoperative | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
| 62 Time to hospital discharge by gender Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 62.1 Men and women | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
| 63 Time to hospital discharge by overall quality Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 63.1 Fair | 1 | 90 | Mean Difference (IV, Random, 95% CI) | 1.20 [‐6.19, 8.59] |
