BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions.
OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache).
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022.
SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm. DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal.
MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes.
AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.
ANTECEDENTES: El tratamiento del dolor es una gran prioridad para los pacientes con artritis reumatoide (AR). Los antidepresivos se utilizan en ocasiones como agentes coadyuvantes para aumentar el alivio del dolor, ayudar con el sueño y reducir la depresión. Estos antidepresivos incluyen los antidepresivos tricíclicos (ATC), los inhibidores de la monoaminooxidasa (IMAO), los inhibidores selectivos de la recaptación de serotonina (ISRS), los inhibidores selectivos de la recaptación de serotonina noradrenalina (ISRSN) y los inhibidores de la recaptación de norepinefrina (IRN). Desafortunadamente la prescripción de antidepresivos en esta población aún es polémica debido a las pruebas científicas contradictorias.
OBJETIVOS: El objetivo de esta revisión fue determinar la eficacia y la seguridad de los antidepresivos para el tratamiento del dolor en pacientes con AR.
MÉTODOS DE BÚSQUEDA: Se realizó una búsqueda electrónica en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials, CENTRAL) ( Cochrane Library 2010, cuarto trimestre); MEDLINE (1950 hasta noviembre, semana 1, 2010); EMBASE (2010, semana 44); y en PsycINFO (1806 hasta noviembre, semana 2, 2010). También se buscó en los resúmenes del American College of Rheumatology (ACR) de 2008 a 2009 y de la European League Against Rheumatism (EULAR) y se realizó una búsqueda manual de las listas de referencias de los artículos.
CRITERIOS DE SELECCIÓN: Se incluyeron ensayos controlados con asignación aleatoria (ECAs) que compararon un tratamiento antidepresivo con otro tratamiento (activo o placebo, incluidos los tratamientos no farmacológicos) en pacientes adultos con AR que tenían al menos una medida de resultado clínicamente relevante. Las medidas de resultado de interés fueron dolor, efectos adversos, función, sueño, depresión y calidad de vida.
OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos revisores cegados extrajeron los datos y evaluaron el riesgo de sesgo de los ensayos de forma independiente. Se realizaron metanálisis para examinar la eficacia de los antidepresivos en el dolor, la depresión y la función, así como su seguridad.
RESULTADOS PRINCIPALES: Se incluyeron ocho ECAs (652 participantes) en esta revisión. Todos los ensayos evaluaron los ATC y dos ensayos evaluaron un ISRS como comparador. Siete de los ocho ensayos tuvieron un alto riesgo de sesgo. No hubo datos suficientes para calcular el número necesario a tratar para un resultado beneficioso adicional (NNTB) para el resultado primario de dolor. Los análisis cualitativos no encontraron pruebas de un efecto de los antidepresivos sobre la intensidad del dolor ni la depresión a corto plazo (menos de una semana) y encontraron pruebas contradictorias de un efecto beneficioso a medio (de una a seis semanas) o largo plazo (más de seis semanas). Hubo significativamente más eventos adversos leves en los pacientes que recibieron ATC comparados con los que recibieron placebo (cociente de riesgos [CR] 2,27; intervalo de confianza [IC] del 95%: 1,17 a 4,42), pero no hubo un aumento significativo de los retiros debido a un evento adverso (CR 1,09; IC del 95%: 0,49 a 2,42).
CONCLUSIONES DE LOS AUTORES: Actualmente no hay pruebas suficientes para apoyar la prescripción habitual de antidepresivos como analgésicos en los pacientes con AR, ya que no es posible establecer conclusiones confiables acerca de su eficacia a partir de ocho ECAs con placebo. El uso de estos agentes se puede asociar con eventos adversos que son generalmente leves y no dan lugar a la interrupción del tratamiento. Se necesitan más ensayos de alta calidad en esta área.
Esta revisión estructurada se refiere a la cuestión de si los antidepresivos tienen un antinociceptivo (analgésico) el efecto para el dolor crónico independiente de su efecto antidepresivo. Con el fin de responder a esta pregunta, los estudios de dolor agudo humanos, individuales estudios controlados con placebo para el tratamiento de determinados síndromes de dolor crónico, y los estudios metaanalytic fueron revisados y se coloca en forma de tabla. El análisis de esta evidencia llevó a las siguientes conclusiones: La evidencia fue consistente en lo que indica que los antidepresivos en general puede tener un efecto antinociceptivo en el dolor crónico, y que estos fármacos son eficaces para el dolor neuropático. También hubo cierta evidencia de que estos fármacos podrían ser eficaces para el dolor psicógeno o trastorno somatomorfo asociada. Esta evidencia también sugiere fuertemente que serotoninérgico-noradrenérgico antidepresivos pueden tener un efecto antinociceptivo más consistente que los antidepresivos serotoninérgicos. Por último, esta evidencia indica que los antidepresivos pueden ser eficaces para el dolor asociado con algunos síndromes de dolor específicos, tales como el dolor lumbar crónico, la osteoartritis o artritis reumatoide, fibrositis o fibromialgia, y la cicatrización de la úlcera. Las posibles razones de los resultados contradictorios de estudios en esta área se presentan, y los problemas que podrían limitar la validez de las conclusiones de esta revisión se discuten.
Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions.
OBJECTIVES:
To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache).
SEARCH METHODS:
We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022.
SELECTION CRITERIA:
We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm.
DATA COLLECTION AND ANALYSIS:
Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal.
MAIN RESULTS:
This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes.
AUTHORS' CONCLUSIONS:
Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.
