Pregabalin for pain in fibromyalgia in adults

  • Review
  • Intervention

Authors

  • Sheena Derry,

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
  • Malene Cording,

    1. University of Copenhagen, Copenhagen, Denmark
  • Philip J Wiffen,

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
  • Simon Law,

    1. The Churchill Hospital, Pain Relief Unit, Oxford, UK
  • Tudor Phillips,

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
  • R Andrew Moore

    Corresponding author
    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
    • R Andrew Moore, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, OX3 7LE, UK. andrew.moore@ndcn.ox.ac.uk.


Abstract

Background

This review updates part of an earlier Cochrane review on 'Pregabalin for acute and chronic pain in adults' (Moore 2009), and considers only fibromyalgia pain.

Antiepileptic drugs have been used in pain management since the 1960s. Pregabalin is an antiepileptic drug also used in management of chronic pain conditions, including fibromyalgia. Pain response with pregabalin is associated with major benefits for other symptoms, and improved quality of life and function in people with chronic painful conditions.

Objectives

To assess the analgesic efficacy and adverse events of pregabalin for pain in fibromyalgia in adults, compared with placebo or any active comparator.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE for randomised controlled trials from inception to May 2009 for the original review and to 16 March 2016 for this update. We also searched the reference lists of retrieved studies and reviews, and online clinical trial registries.

Selection criteria

We included randomised, double-blind trials of eight weeks' duration or longer, comparing pregabalin with placebo or another active treatment for relief of pain in fibromyalgia, and reporting on the analgesic effect of pregabalin, with subjective pain assessment by the participant.

Data collection and analysis

Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with moderate pain relief (at least 30% pain relief over baseline or much or very much improved on Patient Global Impression of Change scale (PGIC)) or substantial pain relief (at least 50% pain relief over baseline or very much improved on PGIC). Where pooled analysis was possible, we used dichotomous data to calculate risk ratio and number needed to treat (NNT), using standard methods. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 'Summary of findings' tables.

Main results

Our searches identified two new published studies with classic design, and one new published study with an enriched enrolment randomised withdrawal (EERW) design.

We included eight studies. Five (3283 participants) had a classic design in which participants were randomised at the start of the study to pregabalin (150, 300, 450, or 600 mg daily) or placebo, with assessment after 8 to 13 weeks of stable treatment. No studies included active comparators. Studies had low risk of bias, except that the last observation carried forward (LOCF) imputation method used in analyses of the primary outcomes could overestimate treatment effect.

Pregabalin increased the number of participants experiencing substantial benefit (at least 50% pain intensity reduction after 12 or 13 weeks' stable treatment (450 mg: RR 1.8, 95% CI 1.4 to 2.1, 1874 participants, 5 studies, high quality evidence)). Substantial benefit with pregabalin 300 to 600 mg was experienced by about 14% of participants with placebo, but about 9% more with pregabalin 300 to 600 mg (22% to 24%) (high quality evidence). Pregabalin increased the number of participants experiencing moderate benefit (at least 30% pain intensity reduction after 12 or 13 weeks' stable treatment) (450 mg: RR 1.5, 95% CI (1.3 to 1.7), 1874 participants, 5 studies, high quality evidence). Moderate benefit with pregabalin 300 to 600 mg was experienced by about 28% of participants with placebo, but about 11% more with pregabalin 300 to 600 mg (39% to 43%) (high quality evidence). A similar magnitude of effect was found using PGIC of 'very much improved' and 'much or very much improved'. NNTs for these outcomes ranged between 7 and 14 (high quality evidence).

A small study (177 participants) compared nightly with twice-daily pregabalin, and concluded there was no difference in effect.

Two studies (1492 participants began initial dose titration, 687 participants randomised) had an EERW design in which those with good pain relief after titration were randomised, double blind, to continuing the effective dose (300 to 600 mg pregabalin daily) or a short down-titration to placebo for 13 or 26 weeks. We calculated the outcome of maintained therapeutic response (MTR) without withdrawal, equivalent to a moderate benefit. Of those randomised, 40% had MTR with pregabalin and 20% with placebo (high quality evidence). The NNT was 5, but normalised to the starting population tested it was 12. About 10% of the initial population would have achieved the MTR outcome, similar to the result from studies of classic design. MTR had no imputation concerns.

The majority (70% to 90%) of participants in all treatment groups experienced adverse events. Specific adverse events were more common with pregabalin than placebo, in particular dizziness, somnolence, weight gain, and peripheral oedema, with number needed to harm of 3.7, 7.4, 18, and 19 respectively for all doses combined (high quality evidence). Serious adverse events did not differ between active treatment groups and placebo (very low quality evidence). Withdrawals for any reason were more common with pregabalin than placebo only with the 600 mg dose in studies of classic design. Withdrawals due to adverse events were about 10% higher with pregabalin than placebo, but withdrawals due to lack of efficacy were about 6% lower (high quality evidence).

Authors' conclusions

Pregabalin 300 to 600 mg produces a major reduction in pain intensity over 12 to 26 weeks with tolerable adverse events for a small proportion of people (about 10% more than placebo) with moderate or severe pain due to fibromyalgia. The degree of pain relief is known to be accompanied by improvements in other symptoms, quality of life, and function. These results are similar to other effective medicines in fibromyalgia (milnacipran, duloxetine).

Résumé scientifique

La prégabaline contre la douleur dans la fibromyalgie de l’adulte

Contexte

Cette revue est une mise à jour partielle d’une revue Cochrane précédente sur la prégabaline contre la douleur aiguë et chronique chez l’adulte (Moore 2009 ) et porte seulement sur la douleur dans la fibromyalgie.

L’utilisation de médicaments antiépileptiques pour traiter la douleur remonte aux années 1960. La prégabaline est un anticonvulsivant qui est également utilisé pour le traitement des troubles douloureux chroniques et notamment de la fibromyalgie. La réduction de la douleur par la prégabaline est associée à des bénéfices majeurs pour d’autres symptômes et à l’amélioration de la qualité de vie et des fonctions des personnes souffrant d’affections chroniques douloureuses.

Objectifs

Évaluer l’efficacité analgésique et les effets indésirables de la prégabaline contre la douleur dans la fibromyalgie chez l’adulte, par rapport à un placebo ou à un agent actif de comparaison.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL), MEDLINE et EMBASE pour trouver des essais contrôlés randomisés, de leur date de création respective à mai 2009, pour la revue originale, et au 16 mars 2016 pour la présente mise à jour. Nous avons également effectué des recherches dans les références bibliographiques des études trouvées et de revues, ainsi que dans les registres d’essais cliniques en ligne.

Critères de sélection

Nous avons inclus des essais randomisés en double aveugle, d’une durée de huit semaines ou plus, comparant la prégabaline à un placebo ou à un autre traitement actif pour le traitement de la douleur dans la fibromyalgie et rapportant l’effet analgésique de la prégabaline, avec une évaluation subjective de la douleur par les patients.

Recueil et analyse des données

Deux auteurs de la revue ont extrait indépendamment les données et évalué la qualité des essais et des biais potentiels. Les critères d’évaluation principaux étaient le nombre de participants dont la douleur était modérément soulagée (diminution d’au moins 30 % de la douleur par rapport à l’inclusion ou douleur « très améliorée » ou « vraiment très améliorée » sur l’échelle de changement global subjectif ressenti par le patient (PGIC)) ou notablement soulagée (diminution d’au moins 50 % par rapport à l’inclusion ou douleur « vraiment très améliorée » sur l’échelle PGIC). Lorsqu’une analyse groupée était possible, nous avons utilisé des données dichotomiques pour calculer le risque relatif et le nombre de sujets à traiter (NST), au moyen de méthodes standard. Nous avons évalué la qualité des données en utilisant le système GRADE (Grading of Recommendations Assessment, Development and Evaluation) et créé des tableaux de résumés des résultats.

Résultats principaux

Nos recherches ont identifié deux nouvelles études publiées de conception classique et une nouvelle étude « enriched enrolment randomised withdrawal » (EERW).

Nous avons inclus huit études. Cinq (3283 participants) avaient un plan classique, dans lequel les participants étaient randomisés au début de l’étude entre la prégabaline (150, 300, 450 ou 600 mg par jour) et un placebo, avec une évaluation après 8 à 13 semaines de traitement à dose stable. Aucune étude n’incluait d’agents de comparaison actifs. Les études présentaient un faible risque de biais, à ceci près que l’analyse des principaux critères d’évaluation par la méthode LOCF (imputation par report de la dernière observation reportée) pourrait surestimer l’effet du traitement.

La prégabaline a augmenté le nombre de participants ressentant un bénéfice substantiel (au moins 50 % de réduction de l'intensité de la douleur après 12 ou 13 semaines de traitement à dose stable (450 mg : RR 1,8, IC à 95 % de 1,4 à 2,1, 1874 participants, 5 études, données de bonne qualité)). Avec un dosage de 300 à 600 mg, un bénéfice subjectif substantiel a été ressenti par près de 14 % des participants avec un placebo, mais environ 9 % de plus sous prégabaline (22 % à 24 %) (données de bonne qualité). La prégabaline a augmenté le nombre de participants ressentant un bénéfice modéré (au moins 30 % de réduction de l'intensité de la douleur après 12 ou 13 semaines de traitement à dose stable) (450 mg : RR 1,5, IC à 95 % (de 1,3 à 1,7), 1874 participants, 5 études, données de bonne qualité). Un bénéfice modéré a été ressenti par près de 28 % des participants avec un placebo, mais environ 11 % de plus sous prégabaline entre 300 et 600 mg (39 % à 43 %) (données de bonne qualité). Un effet de même ampleur a été trouvé en utilisant les niveaux « très amélioré » et « très amélioré à vraiment très amélioré » de l’échelle PGIC. Le NST pour ces critères d’évaluation variait entre 7 et 14 (données de bonne qualité).

Une petite étude (177 participants) comparait des prises de prégabaline deux fois par jour et le soir et a conclu qu’il n’y avait pas de différence en termes d’effet.

Deux études (1492 participants au moment de la titration initiale, 687 participants randomisés) présentaient une conception EERW dans laquelle les personnes dont la douleur était bien soulagée après la titration étaient randomisées, en double aveugle, entre la poursuite à la dose efficace (300 à 600 mg de prégabaline par jour) et un court sevrage avec un placebo pendant 13 ou 26 semaines. Nous avons calculé le critère d’évaluation de la réponse thérapeutique maintenue (RTM) sans abandon, qui équivaut à un bénéfice modéré. Chez les patients randomisés, 40 % avaient une RTM avec la prégabaline et 20 % avec le placebo (données de bonne qualité). Le NST était de 5, mais après normalisation sur la population initiale testée, il passait à 12. Environ 10 % de la population initiale aurait atteint le critère d’évaluation de RTM, ce qui concorde avec les résultats d’études de conception classique. La RTM ne posait pas de problème d’imputation.

La majorité (70 % à 90 %) des participants de tous les groupes de traitement ont rapporté des événements indésirables. Les événements indésirables spécifiques ont été plus fréquents avec la prégabaline qu’avec le placebo, en particulier des vertiges, une somnolence, une prise de poids et un œdème périphérique. Le nombre de sujets à traiter pour observer un effet indésirable supplémentaire était de 3,7, 7,4, 18 et 19 respectivement pour toutes les doses combinées (données de bonne qualité). Les événements indésirables graves n’étaient pas différents entre les groupes de traitement actif et placebo (données de très mauvaise qualité). Les arrêts prématurés pour toute cause étaient plus fréquents avec la prégabaline qu’avec un placebo, uniquement avec la dose de 600 mg et dans les études de conception classiques. Les arrêts prématurés en raison d’événements indésirables étaient d’environ 10 % plus élevés avec la prégabaline qu’avec le placebo, mais ceux motivés par un manque d’efficacité étaient inférieurs d’environ 6 % (données de bonne qualité).

Conclusions des auteurs

La prégabaline dosée entre 300 et 600 mg produit une réduction importante de l’intensité de la douleur pendant 12 à 26 semaines, avec des événements indésirables tolérables, pour un petit nombre de patients (environ 10 % de plus que le placebo) souffrant de douleurs modérées ou sévères causées par une fibromyalgie. On sait que le degré de réduction de la douleur est accompagné d’améliorations d’autres symptômes, de la qualité de vie et des fonctions. Ces résultats sont similaires à ceux d’autres médicaments efficaces dans la fibromyalgie (milnacipran, duloxétine).

Resumen

Pregabalina para el dolor de la fibromialgia en adultos

Antecedentes

Esta revisión actualiza parte de una revisión Cochrane anterior sobre "Pregabalina para el dolor agudo y crónico en adultos" (Moore 2009) y sólo considera el dolor de la fibromialgia.

Los fármacos antiepilépticos se utilizan para el tratamiento del dolor desde la década de los sesenta. La pregabalina es un fármaco antiepiléptico que también se utiliza en el tratamiento de afecciones de dolor crónico como la fibromialgia. La respuesta del dolor con la pregabalina se asocia con efectos beneficiosos importantes en otros síntomas y una mejoría en la calidad de vida y la función en pacientes con afecciones dolorosas crónicas.

Objetivos

Evaluar la eficacia analgésica y los eventos adversos de la pregabalina para el dolor de la fibromialgia en adultos, comparada con placebo o cualquier comparador activo.

Métodos de búsqueda

Se hicieron búsquedas de ensayos controlados aleatorios en el Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials) (CENTRAL), MEDLINE, y en EMBASE, desde su inicio hasta mayo 2009 para la revisión original y el 16 marzo 2016 hasta para esta actualización. También se realizaron búsquedas en las listas de referencias de estudios y revisiones recuperados y en registros de ensayos clínicos en línea.

Criterios de selección

Se incluyeron los ensayos aleatorios doble ciego con una duración de ocho semanas o más que compararon pregabalina con placebo u otro tratamiento activo para el alivio del dolor de la fibromialgia e informaron el efecto analgésico de la pregabalina, con la evaluación subjetiva del dolor por el participante.

Obtención y análisis de los datos

Dos autores de la revisión, de forma independiente, extrajeron los datos y evaluaron la calidad de los ensayos y el sesgo potencial. Los resultados primarios fueron participantes con alivio moderado del dolor (alivio del dolor de al menos el 30% sobre el valor inicial o mejoría importante o muy importante en la escala Patient Global Impression of Change [PGIC]) o alivio significativo del dolor (alivio del dolor de al menos el 50% sobre el valor inicial o muy importante en la PGIC). Cuando fue posible realizar el análisis agrupado se utilizaron los datos dicotómicos para calcular el cociente de riesgos y el número necesario a tratar (NNT), mediante métodos estándar. Se evaluó la calidad de la evidencia utilizando GRADE (Grading of Recommendations Assessment, Development and Evaluation) y se crearon las tablas "Resumen de los hallazgos".

Resultados principales

Las búsquedas identificaron dos estudios nuevos publicados con diseño clásico y un estudio nuevo publicado con un diseño de retiros aleatorios e inclusión enriquecida (EERW, su sigla en inglés).

Se incluyeron ocho estudios. Cinco estudios (3283 participantes) tuvieron un diseño clásico en el cual los participantes se asignaron al azar al comienzo del estudio a pregabalina (150, 300, 450 ó 600 mg diarios) o placebo, y la evaluación se realizó después de ocho a 13 semanas de tratamiento estable. Ningún estudio incluyó comparadores activos. Los estudios tuvieron bajo riesgo de sesgo, excepto que el método de imputación utilizado, la última observación realizada (LOCF, por su sigla en inglés), utilizado en el análisis de los resultados primarios podría sobrestimar el efecto del tratamiento.

La pregabalina aumentó el número de participantes que presentaron un efecto beneficioso significativo (reducción en la intensidad del dolor de al menos el 50% después de 12 ó 13 semanas de tratamiento estable (450 mg: CR 1,8; IC del 95%: 1,4 a 2,1; 1874 participantes, cinco estudios, pruebas de alta calidad)). Alrededor del 14% de los participantes con placebo presentaron un efecto beneficioso significativo con 300 a 600 mg de pregabalina, pero alrededor del 9% más con 300 a 600 mg de pregabalina (22% al 24%) (pruebas de alta calidad) La pregabalina aumentó el número de participantes que presentaron un efecto beneficioso moderado (reducción en la intensidad del dolor de al menos el 30% después de 12 ó 13 semanas de tratamiento estable) (450 mg: CR 1,5; IC del 95%: 1,3 a 1,7), 1874 participantes, cinco estudios, pruebas de alta calidad). Alrededor del 28% de los participantes con placebo presentaron un efecto beneficioso moderado con 300 a 600 mg de pregabalina, pero alrededor del 11% más con 300 a 600 mg de pregabalina (39% a 43%) (pruebas de alta calidad) Al utilizar la PGIC se encontró una magnitud similar del efecto de "mejoría muy importante" y "mejoría importante o muy importante". Los NNT de estos resultados variaron entre 7 y 14 (pruebas de alta calidad)

Un estudio pequeño (177 participantes) comparó pregabalina en la noche con pregabalina dos veces al día y concluyó que no hubo diferencias en el efecto.

Dos estudios (1492 participantes comenzaron con el ajuste inicial de la dosis, 687 participantes se asignaron al azar) tuvieron un diseño EERW en el que los pacientes con alivio adecuado del dolor después del ajuste se asignaron al azar de manera doble ciego a continuar con la dosis efectiva (300 a 600 mg diarios de pregabalina) o a una disminución gradual pequeña de la dosis hasta placebo durante 13 ó 26 semanas. Se calculó el resultado respuesta terapéutica mantenida (RTM) sin retiro, equivalente a un efecto beneficioso moderado. De los pacientes que se asignaron al azar, el 40% tuvo una RTM con pregabalina y el 20% con placebo (pruebas de alta calidad) El NNT fue 5, pero normalizado a la población inicial estudiada, fue 12. Alrededor del 10% de la población inicial habría logrado el resultado de RTM, similar al resultado de los estudios con diseño clásico. No hubo inquietudes con respecto a la imputación para la RTM.

La mayoría (del 70% al 90%) de los participantes en todos los grupos de tratamiento presentaron eventos adversos. Los eventos adversos específicos fueron más frecuentes con pregabalina que con placebo, en particular mareos, somnolencia, aumento de peso y edema periférico, con un número necesario para dañar de 3,7; 7,4; 18 y 19 respectivamente para todas las dosis combinadas (pruebas de alta calidad) Los eventos adversos graves no difirieron entre los grupos de tratamiento activo y placebo pruebas de muy baja calidad). Los retiros por cualquier motivo fueron más frecuentes con pregabalina que con placebo solamente con la dosis de 600 mg en los estudios con diseño clásico. Los retiros debido a eventos adversos fueron alrededor del 10% mayores con pregabalina que con placebo, pero los retiros debido a la falta de eficacia fueron alrededor de un 6% menos (pruebas de alta calidad)

Conclusiones de los autores

La pregabalina a dosis de 300 a 600 mg produce una reducción importante en la intensidad del dolor a las 12 a 26 semanas, con eventos adversos tolerables en una proporción pequeña de pacientes (alrededor del 10% más que con placebo) con dolor moderado o intenso debido a la fibromialgia. Se sabe que el grado de alivio del dolor se acompaña de mejorías en otros síntomas, en la calidad de vida y en la función. Estos resultados son similares a los de otros fármacos efectivos para la fibromialgia (milnaciprán, duloxetina).

Plain language summary

Pregabalin for treating fibromyalgia pain in adults

Bottom line

We found high quality evidence that pregabalin at daily doses of 300 to 600 mg produces a large fall in pain in about 1 in 10 people with moderate or severe pain from fibromyalgia. Pain reduction comes with improvements in other symptoms, in quality of life, and in ability to function.

Background

Fibromyalgia is characterised by persistent, widespread pain and tenderness, sleep problems, and fatigue. Common pain-relieving medicines such as paracetamol and ibuprofen are not usually considered effective. Medicines used to treat epilepsy or depression can be effective in some people with fibromyalgia and other forms of chronic (persistent, long-lasting) pain where there may be nerve damage. Pregabalin is an antiepileptic licensed to treat fibromyalgia in some parts of the world, in particular the USA.

This review is an update of one originally published in 2009, which examined the effects of pregabalin on all types of pain. In this review we have only examined fibromyalgia pain. The earlier review showed that pregabalin worked in a small proportion of people with fibromyalgia. This is the same as all other fibromyalgia treatments to date, and for chronic pain conditions generally. Our definition of 'worked' involved both a high level of pain relief and being able to take the medication over a longer period without intolerable side effects.

Study characteristics

We searched scientific databases for studies that looked at the effects of pregabalin in adults with fibromyalgia who had moderate or severe pain. The treatment had to last at least eight weeks. The evidence is current to March 2016.

Eight studies satisfied the inclusion criteria, including three new studies for this update. Five studies randomised 3283 participants to immediate treatment with pregabalin or placebo. Two studies identified 687 out of 1492 participants who had a good pain response and could take the medicine, and then randomised them to continued treatment with pregabalin or placebo. Study quality was good. One other had no useful data.

Key results

High quality evidence showed that 1 in 10 people with moderate or severe fibromyalgia pain reported a large fall in pain by a third to a half over 12 to 26 weeks. This is an outcome that people with fibromyalgia consider to be useful. The dose of pregabalin was 300 to 600 mg daily.

Side effects occurred in 8 or 9 people in 10, often while adjusting to the medicine. Particular side effects were dizziness (affecting 1 in 4 participants), drowsiness (1 in 7), weight gain (1 in 18), and peripheral oedema (1 in 19) (high quality evidence). Serious side effects were no more common with pregabalin than with placebo, affecting 1 or 2 in 100. About 1 in 10 more participants taking pregabalin withdrew from the study because of side effects, and 1 in 17 fewer withdrew because the medicine was not working.

Quality of the evidence

The evidence was mostly of high quality, which means we are very confident that the true effect lies close to that of the estimate of the effect in this review. Concern about how information was handled when people left the studies was offset by other information showing that results were not impacted by this to any important degree.

Laički sažetak

Pregabalin za liječenje boli kod fibromijalgije u odraslih osoba

Zaključak

U ovom Cochrane sustavnom pregledu literature pronašli smo dokaze visoke kvalitete koji potvrđuju da pregabalin u dozama od 300 do 600 mg, primijenjenim u jednom danu, dovodi do velikog ublažavanja boli u približno jedne od 10 osoba s umjerenom ili teškom boli uzrokovane fibromijalgijom. Smanjenje boli dolazi s poboljšanjima u drugim simptomima, kvaliteti života, te u sposobnosti funkcioniranja.

Dosadašnje spoznaje

Fibromijalgija je bolest obilježena trajnom, raširenom boli i osjetljivošću, problemima spavanja te umorom. Lijekovi koji se često koriste za ublažavanje boli, kao što su paracetamol i ibuprofen, obično nisu djelotvorni za ublažavanje boli koju uzrokuje fibromijalgija. Lijekovi koji se koriste za liječenje epilepsije ili depresije mogu biti djelotvorni kod nekih ljudi s fibromijalgijom ili nekim drugim oblikom kronične (uporne, dugotrajne) boli odnosno tamo gdje je došlo do oštećenja živca. Pregabalin je antiepileptik odobren za liječenje fibromijalgije u nekim dijelovima svijeta, posebice u SAD-u.

Ovaj Cochrane sustavni pregled literature je obnovljena verzija izvornog pregleda objavljenog u 2009. godini, a u kojem su ispitani učinci pregabalina na sve vrste boli. U ovom smo pregledu ispitivali samo bol uzrokovanu fibromijalgijom. Ranijim pregledom je utvrđeno da pregabalin djeluje kod malog broja ljudi s fibromijalgijom. To također vrijedi i za sve druge postupke liječenja fibromijalgije koji se danas koriste, kao i za stanja kronične boli općenito. Naša definicija za djelotvornost uključuje istovremeno i visoku razinu smanjenja boli i mogućnosti da se lijekovi uzimaju duži period bez ozbiljnih nuspojava.

Obilježja uključenih istraživanja

Pretraživali smo znanstvene baze podataka kako bi pronašli studije koje su ispitivale učinke pregabalina kod odraslih s fibromijalgijom, a koji su imali umjerenu ili tešku bol. Liječenje je moralo trajati najmanje osam tjedana. Obuhvaćena su sva istraživanja dostupna do ožujka 2016.

Osam studija je zadovoljilo kriterije za uključivanje, uključujući i tri nove studije koje obuhvaća ovo ažuriranje. Pet je istraživanja nasumično rasporedilo ukupno 3283 sudionika na hitno liječenje s pregabalinom ili na placebo. Dvije studije su utvrdile da je 687 od ukupno 1492 sudionika imalo dobar odgovor na bol i koji su mogli uzimati lijek, a zatim su ih nasumično rasporedili u skupine za nastavak liječenja s pregabalinom ili na placebo. Kvaliteta studija je bila dobra. Preostala osma studija nije imala korisne podatke.

Ključni rezultati

Dokazi visoke kvalitete pokazali su da je jedna od 10 osoba s umjerenom ili teškom boli uzrokovane fibromijalgijom opisala veliko smanjenje boli za trećinu do polovice tijekom 12 do 26 tjedana. To je ishod koji ljudi s fibromijalgijom smatraju korisnim. Doza pregabalina je bila od 300 do 600 mg na dan.

Nuspojave su se dogodile kod 8 ili 9 od ukupno 10 osoba, često tijekom prilagođavanja na lijek. Karakteristične nuspojave su omaglica (koja pogađa jednog od četiri sudionika), omamljenost (jednog od sedam), debljanje (jednog od 18) i periferni edem (jednog od 19) (visoka kvaliteta dokaza). Ozbiljne nuspojave nisu bile mnogo češće s pregabalinom nego s placebom. Zabilježene su kod jednog ili dvoje sudionika od ukupno 100. Približno je jedan od 10 i više sudionika koji su uzimali pregabalin morao odustati od sudjelovanja u istraživanju zbog nuspojava, a jedan od ukupno 17 sudionika je odustao zbog nedjelotvornosti lijeka.

Kvaliteta dokaza

Dokazi su uglavnom visoke kvalitete, što znači da smo vrlo uvjereni da je stvarni učinak blizu učinku procijenjenom u ovom pregledu. Dvojbu oko toga kako su podaci bili obrađeni nakon što su ljudi napustili studije umanjuju drugi podaci koji pokazuju da rezultati nisu time značajno pogođeni.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Jasna Safić
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Résumé simplifié

La prégabaline pour le traitement de la douleur dans la fibromyalgie de l’adulte

Bilan

Nous avons trouvé des données de bonne qualité prouvant que la prégabaline, prise à des doses quotidiennes de 300 à 600 mg, réduisait fortement la douleur chez environ 1 personne sur 10 souffrant de douleurs modérées ou sévères causées par une fibromyalgie. La réduction de la douleur est associée à des améliorations d’autres symptômes, de la qualité de vie et de la capacité fonctionnelle.

Contexte

La fibromyalgie est caractérisée par des douleurs et des sensibilités étendues et persistantes, des troubles du sommeil et une fatigue. Les médicaments antalgiques courants, comme le paracétamol et l’ibuprofène, ne sont généralement pas considérés comme efficaces. Certains médicaments utilisés pour traiter l’épilepsie ou la dépression peuvent être efficaces chez certaines personnes souffrant de fibromyalgie et d’autres formes de douleurs chroniques (persistantes et de longue durée) qui peuvent être associées à des lésions nerveuses. La prégabaline est un anticonvulsivant autorisé pour traiter la fibromyalgie dans certaines parties du monde, en particulier aux États-Unis.

Ceci est une mise à jour d’une revue publiée pour la première fois en 2009, qui examinait les effets de la prégabaline sur tous les types de douleur. Dans la présente revue, nous nous sommes concentrés sur les douleurs dans la fibromyalgie. La revue précédente a montré que la prégabaline était efficace sur un petit pourcentage des personnes atteintes de fibromyalgie, dans la même mesure que les autres traitements de la fibromyalgie et autant que pour les pathologies douloureuses chroniques plus généralement. Notre définition de l’efficacité impliquait à la fois un bon soulagement de la douleur et la possibilité de prendre le médicament pendant une longue durée sans effets secondaires intolérables.

Caractéristiques de l'étude

Nous avons recherché dans des bases de données scientifiques des études examinant les effets de la prégabaline chez des adultes souffrant de fibromyalgie avec des douleurs modérées ou sévères. Le traitement devait durer au moins huit semaines. Les preuves sont à jour à la date de mars 2016.

Huit études remplissaient les critères d’inclusion, dont trois nouvelles études par rapport à la première version de la revue. Cinq études randomisaient 3283 participants entre un traitement immédiat avec la prégabaline et un placebo. Deux études ont identifié 687 participants sur 1492 dont la douleur répondait bien et qui toléraient le médicament, qui ont ensuite été randomisés entre la poursuite du traitement avec la prégabaline et un placebo. Ces études étaient de bonne qualité. Aucune autre n’a livré de données utiles.

Principaux résultats

Des données probantes de bonne qualité ont montré qu’une personne sur dix souffrant de douleurs fibromyalgiques modérées à sévères rapportait une forte diminution des douleurs, d’un tiers à la moitié, sur 12 à 26 semaines. Ceci constitue un paramètre de résultat que les personnes atteintes de fibromyalgie jugent utile. La dose de prégabaline était de 300 à 600 mg par jour.

Des effets secondaires ont été observés chez 8 ou 9 personnes sur 10, souvent pendant l’ajustement de la dose. Les effets secondaires spécifiques comprenaient des étourdissements (1 participant sur 4), une la somnolence (1 sur 7), une prise de poids (1 sur 18) et un œdème périphérique (1 sur 19) (données de bonne qualité). Les effets secondaires graves n’étaient pas plus fréquents avec la prégabaline qu’avec le placebo, à 1 ou 2 sujets sur 100. Environ 1 participant sur 10 de plus sous prégabaline a abandonné l’étude en raison d’effets secondaires, et 1 sur 17 de moins parce que le médicament était inefficace.

Qualité des données probantes

Les données probantes étaient généralement de bonne qualité, ce qui signifie que nous sommes très certains que l’effet réel est proche de son estimation dans cette revue. Les doutes concernant la manière dont les informations étaient gérées après l’abandon de patients étaient contrebalancés par d’autres informations montrant que cela n’avait eu aucune incidence notable sur les résultats.

Notes de traduction

Traduction réalisée par Suzanne Assénat et révisée par Cochrane France

Resumen en términos sencillos

Pregabalina para el tratamiento del dolor de la fibromialgia en adultos

Conclusión

Se encontraron pruebas de alta calidad de que la pregabalina a dosis diarias de 300 a 600 mg produce una disminución importante del dolor en alrededor de uno de cada diez pacientes con dolor moderado o intenso por fibromialgia. La reducción del dolor se acompaña de mejorías en otros síntomas, en la calidad de vida y en la capacidad de funcionar.

Antecedentes

La fibromialgia se caracteriza por dolor y sensibilidad persistentes y diseminados, trastornos del sueño y fatiga. En general los fármacos habituales que alivian dolor como el paracetamol y el ibuprofeno no se consideran efectivos. Los fármacos utilizados para tratar la epilepsia o la depresión pueden ser efectivos en algunos pacientes con fibromialgia y otras formas de dolor crónico (persistente y duradero) en las que puede haber daño nervioso. La pregabalina es un antiepiléptico autorizado para tratar la fibromialgia en algunas partes del mundo, en particular en los EE.UU.

Esta revisión es una actualización de otra revisión publicada originalmente en 2009 que examinó los efectos de la pregabalina sobre todos los tipos de dolor. En esta revisión sólo se examinó el dolor de la fibromialgia. La revisión anterior indicó que la pregabalina funcionó en una proporción pequeña de pacientes con fibromialgia. Lo anterior es similar a todos los otros tratamientos para la fibromialgia hasta la fecha, así como para las afecciones de dolor crónico en general. La presente definición de "funcionó" incluyó un nivel alto de alivio del dolor y la posibilidad de tomar la medicación durante un período más largo sin efectos secundarios intolerables.

Características de los estudios

Se buscaron en las bases de datos científicas los estudios que analizaron los efectos de la pregabalina en adultos con fibromialgia que tenían dolor moderado o intenso. El tratamiento tuvo que durar al menos ocho semanas. Las pruebas están actualizadas hasta marzo 2016.

Ocho estudios cumplieron los criterios de inclusión y se incluyeron tres estudios nuevos en esta actualización. Cinco estudios asignaron al azar a 3283 participantes a tratamiento inmediato con pregabalina o placebo. Dos estudios identificaron 687 de 1492 participantes que tuvieron una buena respuesta del dolor y podían recibir el fármaco y luego los asignaron al azar a tratamiento continuo con pregabalina o placebo. La calidad de los estudios fue buena. Otro estudio no tuvo datos útiles.

Resultados clave

Pruebas de alta calidad indicaron que uno de cada diez pacientes con dolor de la fibromialgia moderado o intenso informó una disminución importante del dolor a una tercera parte o a la mitad a las 12 a 26 semanas. Los pacientes con fibromialgia consideran que este resultado es útil. La dosis de pregabalina fue de 300 a 600 mg diarios.

En ocho o nueve pacientes de cada diez ocurrieron efectos secundarios, a menudo durante el ajuste del fármaco. Los efectos secundarios particulares fueron mareos (que afectaron a uno de cuatro pacientes), somnolencia (uno de siete), aumento de peso (uno de 18) y edema periférico (uno de 19) (pruebas de alta calidad) Los efectos secundarios graves no fueron más frecuentes con pregabalina que con placebo y afectaron a uno o dos de 100. Alrededor de uno de diez participantes más que recibieron pregabalina se retiró del estudio debido a los efectos secundarios, y uno de 17 menos se retiró porque el fármaco no funcionaba.

Calidad de la evidencia

En su mayoría las pruebas fueron de alta calidad, lo que significa que existe mucha seguridad en que el verdadero efecto está alrededor de la estimación del efecto de esta revisión. Las inquietudes con respecto a cómo se procesó la información cuando los pacientes abandonaron los estudios estuvieron compensadas por otra información que muestra que dicho procesamiento no afectó los resultados en un grado importante.

Notas de traducción

La traducción y edición de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripción efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Si detecta algún problema con la traducción, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.

Резюме на простом языке

Прегабалин для лечения боли при фибромиалгии у взрослых

Суть

Мы нашли доказательства высокого качества, что прегабалин в дозе от 300 до 600 мг в день приводит к значительному уменьшению боли у 1 человека из 10, страдающих от умеренных или сильных болей при фибромиалгии. Уменьшение боли сопровождается уменьшением других симптомов и улучшением качества жизни и функционирования.

Актуальность

Фибромиалгия характеризуется постоянными, распространенными болями, повышенной чувствительностью, проблемами со сном и усталостью/утомляемостью. Часто применяемые болеутоляющие средства, такие как парацетамол и ибупрофен, обычно не считают эффективными. Лекарства, применяемые для лечения эпилепсии или депрессии, могут быть эффективны у некоторых людей с фибромиалгией и другими формами хронической (постоянной, долго продолжающейся) боли, когда могут быть повреждены нервные клетки. Прегабалин это противоэпилептическое средство, лицензированное для лечения фибромиалгии в некоторых частях мира, в частности, в США.

Этот обзор является обновлением первоначального обзора, опубликованного в 2009 году, в котором изучали влияние прегабалина на все типы боли. В этом обзоре мы изучали только боль, связанную с фибромиалгией. В ранее проведенном обзоре было показано, что прегабалин был эффективен у небольшой пропорции людей с фибромиалгией. То же самое относится и к другим видам лечения фибромиалгии на сегодняшний день и к состояниям хронической боли в целом. Наше определение «эффективен» включало как высокий уровень облегчения боли, так и возможность принимать лекарство в течение более длительного периода без непереносимых побочных эффектов.

Характеристика исследований

Мы провели поиск в научных базах данных на предмет исследований, в которых изучали эффекты прегабалина у взрослых с фибромиалгией, сопровождающейся умеренными и сильными болями. Лечение продолжалось, по меньшей мере, в течение восьми недель. Доказательства актуальны на март 2016 года.

Восемь исследований отвечали критериям включения, включая три новых исследования в этом обновлении. В пяти исследованиях рандомизировали (распределили в случайном порядке) 3283 участника в группы для немедленного начала лечения прегабалином или плацебо. В двух исследованиях выявили, что у 687 человек из 1492 участников был хороший болевой ответ и они могли принимать лекарство, и затем они были рандомизированы для продолжения лечения прегабалином или плацебо. Качество исследований было хорошим. Другое исследование не содержало полезной информации.

Основные результаты.

Доказательства высокого качества показали, что 1 человек из 10 с сильными или умеренными болями, связанными с фибромиалгией, сообщил о значительном снижении боли на треть или на половину на протяжении от 12 до 26 недель. Это исход, который можно считать приемлемым у людей с фибромиалгией. Доза прегабалина составила от 300 от 600 мг в день.

Побочные эффекты возникали у 8 или 9 человек из 10, часто в процессе адаптации к лечению. Основными побочными эффектами были головокружение (у 1 из 4 участников), сонливость (у 1 из 7), увеличение веса (у 1 из 18), а также периферические отеки (у 1 из 19) (доказательства высокого качества). Серьезные побочные эффекты прегабалина были отмечены не чаще, чем у плацебо, только в 1 или 2 случаях из 100. Примерно 1 из 10 участников, принимавших прегабалин, выбыл из исследования по причине развития побочных эффектов, и 1 из 17 - из-за неэффективности лечения.

Качество доказательств

Доказательства, в основном, были высокого качества, а это означает, что мы уверены в том, что истинный эффект близок к оценке эффекта в этом обзоре. Есть опасения в отношении обработки информации при выбывании людей от исследований, как это было компенсировано другой информацией, указывающей, на то, что это не повлияло на результаты в какой-либо значимой степени.

Заметки по переводу

Перевод: Сагитова Динара. Редактирование: Курбатова Ольга Геннадьевна, Юдина Екатерина Викторовна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Summary of findings(Explanation)

Summary of findings for the main comparison. Pregabalin compared with placebo for fibromyalgia in studies of classic design
  1. 1: We decided not to downgrade for LOCF imputation because LOCF NNT and BOCF NNT similar in magnitude with no clinical implications in the differences

Pregabalin compared with placebo for fibromyalgia in studies of classic design

Patient or population: adults with fibromyalgia enrolled in studies of classic design

Settings: community

Intervention: pregabalin 450 mg

Comparison: placebo

Outcomes

(follow up: 8-14 weeks)

Probable outcome with pregabalin Probable outcome with placebo

RR, NNT, NNH, NNTp

(95% CI)

No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
‘Substantial benefit’ (at least 50% reduction in pain)240 per 1000140 per 1000

RR 1.8 (1.4 to 2.1)

NNT 9.7 (7.2 to 15)

1874 participants

(5 studies)

High quality1
‘Substantial benefit’ (PGIC very much improved)170 per 100090 per 1000

RR 1.9 (1.5 to 2.4)

NNT 12 (9.0 to 20)

1869 participants

(5 studies)

High quality1
‘Moderate benefit’ (at least 30% reduction in pain)430 per 1000290 per 1000

RR 1.5 (1.3 to 1.7)

NNT 7.2 (5.5 to 10)

1874 participants

(5 studies)

High quality1
‘Moderate benefit’ (PGIC much or very much improved)360 per 1000270 per 1000

RR 1.3 (1.2 to 1.5)

NNT 11 (7.8 to 22)

1869 participants

(5 studies)

High quality1
Withdrawals due to lack of efficacy40 per 1000100 per 1000

RR 0.4 (0.2 to 0.5)

NNTp 15 (11 to 24)

1874 participants

(5 studies)

High qualityLarge number of participants and events, clearly reported
Withdrawals due to adverse events170 per 100090 per 1000

RR 2.0 (1.6 to 2.6)

NNH 11 (8.4 to 17)

1874 participants

(5 studies)

High qualityLarge number of participants and events, clearly reported
Serious adverse events21 per 100011 per 1000RR 1.9 (0.8 to 4.6)

1238 participants

(3 studies)

Very low qualityDowngraded 3 levels due to small numbers of events. Number of events too small to make any reliable judgement about differences between pregabalin and placebo
DeathNo deaths recorded at any dose of pregabalin or placebo in any studyNot calculated

3460 participants

(6 studies)

Very low qualityNo data because no events were reported
BOCF: baseline observation carried forward; CI: confidence interval; LOCF: last observation carried forward; NNH: number needed to harm; NNT: number needed to treat; NNTp: number needed to treat to prevent; PGIC: Patient Global Impression of Change; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Pregabalin compared with placebo for fibromyalgia in enriched enrolment randomised withdrawal (EERW) studies

Summary of findings 2. Pregabalin compared with placebo for fibromyalgia in enriched enrolment randomised withdrawal (EERW) studies
Pregabalin compared with placebo for fibromyalgia in enriched enrolment randomised withdrawal (EERW) studies

Patient or population: adults with fibromyalgia enrolled in EERW studies

Settings: community

Intervention: pregabalin 300 to 600 mg

Comparison: placebo

Outcomes

(follow up: 13-26 weeks)

Probable outcome with pregabalin Probable outcome with placebo

RR, NNT, NNH

(95% CI)

No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Maintenance of initial therapeutic response of at least 30% pain intensity reduction over baseline and continued treatment at 13 or 26 weeks

(equivalent to 'moderate benefit')

400 per 1000200 per 1000

RR 1.9 (1.5 to 2.4)

NNT 5.3 (3.9 to 8.2)

687 participants

(2 studies)

High quality

Fully defined outcomes, without imputation.

Consistent effects in both studies.

Note that the population in these studies was enriched (46% of initial enrolled)

Participants experiencing at least 1 adverse event650 per 1000490 per 1000

RR 1.3 (1.2 to 1.5)

NNH 6.2 (4.3 to 11)

687 participants

(2 studies)

High qualityAdequate numbers of participants and events
Serious adverse events23 per 10006 per 1000Not calculated

687 participants

(2 studies)

Very low qualitySmall numbers of events
Death1 death1 deathNot calculated

687 participants

(2 studies)

Very low qualitySmall numbers of events
CI: confidence interval; NNH: number needed to harm; NNT: number needed to treat; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

This protocol is based on a template for reviews of drugs used to relieve fibromyalgia. The aim is for all reviews to use the same methods, based on new criteria for what constitutes reliable evidence in chronic pain (Moore 2010a; Appendix 1).

The earlier review of 'Pregabalin for acute and chronic pain in adults' has been split into separate titles (Moore 2009). This review looked at pregabalin for pain in fibromyalgia, and a separate review will look at pregabalin for neuropathic pain. These new titles will serve to update the original.

Description of the condition

Fibromyalgia symptoms can be assessed by self-report of the patient using the fibromyalgia criteria and severity scales for clinical and epidemiological studies, a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia (so-called Fibromyalgia Symptom Questionnaire) (Wolfe 2011). Fibromyalgia was previously defined by the American College of Rheumatology (ACR) 1990 classification criteria as widespread pain lasting for longer than three months with tenderness on palpation at 11 or more of 18 specified tender points (Wolfe 1990). For a clinical diagnosis, the ACR 1990 classification criteria and the ACR 2010 preliminary diagnostic criteria can both be used (Wolfe 1990; Wolfe 2010). Lacking a specific laboratory test, diagnosis is established by a history of the key symptoms and the exclusion of somatic diseases sufficiently explaining the key symptoms (Wolfe 2010). The indexing of fibromyalgia within the International Classification of Diseases is under debate. While some rheumatologists have thought of it as a specific pain disorder and central sensitivity syndrome (Clauw 2014; Yunus 2008), recent research points at small fibre pathology in a subgroup of fibromyalgia patients that may be of pathophysiological importance (Oaklander 2013; Üçeyler 2013a) though this is regarded as speculative. In psychiatry and psychosomatic medicine, fibromyalgia symptoms are categorised as a functional somatic syndrome, a bodily distress syndrome, a somatic physical symptom disorder, or a somatoform disorder (Häuser 2014).

Fibromyalgia is a heterogenous condition. The definite aetiology (causes) of this syndrome remains unknown. A model of interacting biological and psychosocial variables in the predisposition, triggering, and development of the chronicity of fibromyalgia symptoms has been suggested (Sommer 2012). Depression (Forseth 1999), genetics (Arnold 2013; Lee 2012), obesity combined with physical inactivity (Mork 2010), physical and sexual abuse in childhood (Häuser 2011), sleep problems (Mork 2010), and smoking (Choi 2010), predict future development of fibromyalgia. Psychosocial stress (working place and family conflicts) and physical stress (infections, surgery, accidents) might trigger the onset of chronic widespread pain and fatigue (Clauw 2014; Sommer 2012). Depression and post-traumatic stress disorder worsen fibromyalgia symptoms (Häuser 2013a; Lange 2010).

Several factors are associated with the pathophysiology (functional changes associated with or resulting from disease) of fibromyalgia, but the relationship is unclear. The functional changes include alteration of sensory processing in the brain, reduced reactivity of the hypothalamus-pituitary-adrenal axis to stress, increased pro-inflammatory and reduced anti-inflammatory cytokine profiles (produced by cells involved in inflammation), disturbances in neurotransmitters such as dopamine and serotonin, and pathology (Oaklander 2013; Sommer 2012; Üçeyler 2013a). Prolonged exposure to stress, as outlined above, may contribute to these functional changes in predisposed individuals (Bradley 2009). There are similarities to, and differences from, neuropathic pain (Koroschetz 2011).

Patients often report high disability levels and poor quality of life along with extensive use of medical care (Häuser 2015). Many people with fibromyalgia are significantly disabled, and experience moderate or severe pain for many years (Bennett 2007). Chronic painful conditions comprised five of the 11 top-ranking conditions for years lived with disability in 2010 (Vos 2012), and are responsible for considerable loss of quality of life, and employment, and increased health costs (Moore 2014a).

Fibromyalgia is common. One component of fibromyalgia, chronic widespread pain, is not only associated with other symptoms such as poor sleep, fatigue, and depression (Wolfe 2014), but also estimated to affect 11% of the general population (Mansfield 2016). Numerous studies have investigated prevalence of fibromyalgia in different settings and countries. A review gives a global mean prevalence of potential cases of fibromyalgia of 2.7% (range 0.4% to 9.3%), with a mean in the Americas of 3.1%, in Europe of 2.5%, and in Asia of 1.7% (Queiroz 2013). Changes in diagnostic criteria do not appear to have significantly affected estimates of prevalence (Wolfe 2013). A survey using a modification of the 2010 ACR criteria found a prevalence of 1.8% in a large US survey, but 73% of these were given a different diagnosis by their physician (Walitt 2015). Estimates of prevalence in specific populations vary greatly, but have been reported to be as high as 9% in female textile workers in Turkey and 10% in metal workers in Brazil (59% in those with repetitive strain injury; Queiroz 2013). Women are more frequently diagnosed with the disorder when the 1990 ACR criteria are used for clinical surveys. Using these criteria, the women-to-men ratio has ranged from 8:1 to 30:1 in patients who were studied in clinical institutions and surveys. However, with criteria that do not use tender point examination, the sex ratio can be close to equal. The sex ratio has ranged from 4:1 to 1:1 in studies that were conducted in the general population using the research criteria for fibromyalgia (Häuser 2015; Queiroz 2013).

Fibromyalgia pain is known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any intervention. Recent evidence-based guidelines recommend a multidisciplinary approach, with pharmacological treatment being combined with physical or cognitive training, or both. Interventions aim to reduce the key symptoms of fibromyalgia (pain, sleep problems, fatigue) and the associated symptoms (depression, disability) and to improve daily functioning (Eich 2012; Fitzcharles 2013). Conventional analgesics are usually not effective. Patients are often offered treatment with antidepressants like serotonin and noradrenaline reuptake inhibitors (Häuser 2013b; Lunn 2014), tricyclic agents such as amitriptyline (Moore 2012a), or anticonvulsants like gabapentin or pregabalin (Moore 2014b; Wiffen 2013; Üçeyler 2013b). The proportion of patients who achieve worthwhile pain relief (typically at least 50% reduction in pain intensity) is small (Moore 2013b), and generally reaches only 10% to 25% more than with placebo, with numbers needed to treat (NNTs) between 9.8 and 14 in fibromyalgia (Wiffen 2013), somewhat higher (worse) than for neuropathic pain (Kalso 2013; Wiffen 2013). Those who do experience good levels of pain relief, however, also benefit from substantial reductions in other symptoms, such as fatigue, function, sleep, depression, anxiety, and ability to work, with significant improvement in quality of life (Moore 2010c; Straube 2011). Fibromyalgia is not particularly different from other chronic pain with regard to a small proportion of trial participants having a good response to analgesic treatment (Moore 2013b).

Description of the intervention

Pregabalin is marketed under different trademarks worldwide and is also manufactured in combination with vitamin B12; we have not included the combination in this review. Pregabalin is licensed for the treatment of epilepsy, generalised anxiety disorder, and peripheral and central neuropathic pain in adults; in the USA and some other jurisdictions it is additionally licensed for treatment of fibromyalgia. Guidance suggests that pregabalin treatment can be started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after an interval of three to seven days and, if needed, to a maximum dose of 600 mg per day after an additional seven-day interval (EMC 2016). Pregabalin is approved for fibromyalgia in the USA and Canada, and in a number of countries in South America, the Middle East, and Asia.

A particular issue with pregabalin is that of dose and dose escalation, with different upper limits used in different trials. In standard clinical trials in neuropathic pain there is known to be a significant dose-response (Straube 2008). Another issue is the possible impact of enriched enrolment on the efficacy reported in trials, although the rather small amount of partial enrichment that could occur in most trials is without any significant effect (Straube 2008). More interesting is the publication of the results of trials with a complete enrichment, randomised withdrawal (EERW) design in fibromyalgia. These offer a potential challenge to interpretation of clinical trial data (McQuay 2008; Moore 2015).

How the intervention might work

Pregabalin has a mechanism of action similar to gabapentin, binding to calcium channels and reducing calcium influx as well as influencing GABAergic neurotransmission (Taylor 2007). This mode of action confers antiepileptic, analgesic, and anxiolytic effects. It is more potent than gabapentin due to a higher affinity for calcium channels and is therefore used at lower doses, with substantial differences in gastrointestinal absorption (Bockbrader 2010). The dosing regimen for pregabalin is two times daily.

Why it is important to do this review

Pregabalin can be used to treat pain associated with fibromyalgia in adults, and is licensed for this condition in the USA and some other countries, but not in Europe.

In addition, the standards used to assess evidence in chronic pain trials have changed substantially, with particular attention being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is the move from using average pain scores, or average change in pain scores, to the number of people who have a large decrease in pain (by at least 50% or 30%) and who continue in treatment, ideally in trials of 8 to 12 weeks or longer. Pain intensity reduction of 50% or more has been shown to correlate with improvements in comorbid symptoms, function, and health-related quality of life generally for acute and chronic pain (Moore 2013a), and specifically for fibromyalgia (Moore 2010b). These standards are set out in the reference guide for pain studies (PaPaS 2012).

This Cochrane review assessed the evidence using methods that make both statistical and clinical sense, and used developing criteria for what constitutes reliable evidence in chronic pain (Moore 2010a). The studies included and analysed needed to meet a minimum of reporting quality (blinding, randomisation), validity (duration, dose and timing, diagnosis, outcomes, etc.), and size (ideally at least 500 participants in a comparison in which the NNT is 4 or above (Moore 1998)). This approach sets high standards and marks a departure from how reviews were conducted previously. The use of unbiased studies reduces the chances of overestimating treatment effects (Mills 2015).

Objectives

To assess the analgesic efficacy and adverse events of pregabalin for pain in fibromyalgia in adults, compared with placebo or any active comparator.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) with double-blind assessment of participant outcomes and a duration of eight weeks or longer. We required full journal publication, with the exception of online clinical trial results summaries of otherwise unpublished clinical trials, and abstracts with sufficient data for analysis. We did not include short abstracts (usually meeting reports). We excluded studies that were non-randomised, studies of experimental pain, case reports, and clinical observations.

Trials had to have at least 20 participants per treatment arm. This is based on growing evidence of bias in small studies (Dechartres 2013; Dechartres 2014; Moore 1998).

Types of participants

Studies included adult participants aged 18 years and above, with pain due to fibromyalgia, diagnosed using the 1990 or 2010 criteria (Wolfe 1990; Wolfe 2010).

Types of interventions

Pregabalin at any dose, by any route, administered for the relief of fibromyalgia pain, and compared to placebo or any active comparator.

Types of outcome measures

We anticipated that studies would use a variety of outcome measures, with the majority of studies using a visual analogue scale (VAS) for pain intensity or pain relief, or both. We were particularly interested in Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) definitions for moderate and substantial benefit in chronic pain studies (Dworkin 2008). These are defined as:

  1. at least 30% pain relief over baseline (moderate);

  2. at least 50% pain relief over baseline (substantial);

  3. much or very much improved on Patient Global Impression of Change scale (PGIC) (moderate);

  4. very much improved on PGIC (substantial).

These outcomes are analytically relevant, concentrating as they do on dichotomous outcomes where pain responses do not follow a normal (Gaussian) distribution. They are also clinically relevant; people with chronic pain desire high levels of pain relief, ideally more than 50%, and ideally no worse than mild pain (Moore 2013a; O'Brien 2010).

Primary outcomes
  1. Participant-reported pain relief of 30% or greater.

  2. Participant-reported pain relief of 50% or greater.

  3. PGIC much or very much improved.

  4. PGIC very much improved.

Secondary outcomes
  1. Any pain-related outcome indicating some improvement.

  2. Withdrawals due to lack of efficacy, adverse events, and for any cause.

  3. Participants experiencing any adverse event.

  4. Participants experiencing any serious adverse event. Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an 'important medical event' that may jeopardise the patient, or may require an intervention to prevent one of the above characteristics or consequences.

  5. Specific adverse events, particularly somnolence and dizziness.

Search methods for identification of studies

Electronic searches

We searched the following databases, without language restrictions.

  • Cochrane Central Register of Controlled Trials (CENTRAL, via the Cochrane Register of Studies Online database (CRSO)) to 16 March 2016.

  • MEDLINE (via Ovid) from 1946 to 16 March 2016.

  • EMBASE (via Ovid) from 1974 to 16 March 2016.

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

Searching other resources

We reviewed the bibliographies of any RCTs identified and review articles, and searched clinical trial databases (ClinicalTrials.gov (ClinicalTrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/)) to identify additional published or unpublished data. We did not contact investigators or study sponsors for this update.

Data collection and analysis

Selection of studies

Two review authors read the abstract of each study identified by the search, eliminated studies that clearly did not satisfy the inclusion criteria, and obtained full copies of the remaining studies. The same review authors then independently read these studies to determine eligibility; any disagreements or uncertainty were settled by discussion, with a third review author if necessary. Studies were not anonymised in any way before assessment. We have included a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow chart (Figure 1).

Figure 1.

Study flow diagram.

Data extraction and management

Two review authors independently extracted data using a standard form and checked these for agreement before entry into Review Manager 5 (RevMan 2014), or any other analysis tool. We included information about the pain condition and number of participants treated, drug and dosing regimen, study design (placebo or active control, standard design or EERW), study duration and follow-up, analgesic outcome measures and results, withdrawals, and adverse events (participants experiencing any adverse event, or serious adverse event).

Assessment of risk of bias in included studies

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

Two review authors independently assessed risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8, Higgins 2011), and adapted from those used by the Cochrane Pregnancy and Childbirth Group, resolving any disagreements by discussion. We assessed the following for each study.

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

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

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

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

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

Measures of treatment effect

We calculated NNTs as the reciprocal of the absolute risk reduction (McQuay 1998). For unwanted effects, the NNT becomes the number needed to harm (NNH) and is calculated in the same manner. We used dichotomous data to calculate risk ratio with 95% confidence intervals using a fixed-effect model unless we found significant statistical heterogeneity (see below). We did not use continuous data in analyses.

We have used the following terms to describe adverse outcomes in terms of harm or prevention of harm.

  • When significantly fewer adverse outcomes occurred with treatment than with control (placebo or active), we used the term 'number needed to treat to prevent' one event (NNTp).

  • When significantly more adverse outcomes occurred with treatment compared with control (placebo or active), we used the term 'number needed to harm' (NNH).

Unit of analysis issues

We accepted randomisation to individual participant only. In the event of a study having more than one active treatment arm in which data were not combined for analysis, we planned to split the control treatment arm between active treatment arms.

Dealing with missing data

We have used intention-to-treat (ITT) analysis where the ITT population consists of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one post-baseline assessment. We assigned missing participants zero improvement wherever possible.

Assessment of heterogeneity

We dealt with clinical heterogeneity by combining studies that examined similar conditions. We assessed statistical heterogeneity visually (L'Abbé 1987), and by using the I² statistic. When the I² value was greater than 50%, we considered possible reasons for this for in studies of classic design.

Assessment of reporting biases

The aim of this review was to use dichotomous outcomes of known utility and of value to patients (Hoffman 2010; Moore 2010b; Moore 2010c; Moore 2010d; Moore 2013a). The review did not depend on what the authors of the original studies chose to report or not, though clearly difficulties would arise if studies failed to report relevant dichotomous results. We extracted and used continuous data, which probably reflect efficacy and utility poorly, where useful for illustrative purposes only.

We planned to assess publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean a NNT of 10 or higher) (Moore 2008), but this was not possible with low effect sizes.

Data synthesis

We planned to use a fixed-effect model for meta-analysis. We would have used a random-effects model if we had found significant clinical heterogeneity and considered it appropriate to combine studies.

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

  • The first tier used data meeting current best standards, where studies report the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method for dropouts, report an ITT analysis, last eight or more weeks, have a parallel-group design, and have at least 200 participants (preferably at least 400) in the comparison (Moore 1998; Moore 2010a; Moore 2012a; Moore 2012b). We have reported these top-tier results first.

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

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

Quality of the evidence

We have used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) system to assess the quality of the evidence related to the key outcomes listed in Types of outcome measures, as appropriate (Appendix 5; Section 12.2, Higgins 2011). Two review authors independently rated the quality of evidence for each outcome.

We paid particular attention to:

  1. inconsistency, where point estimates vary widely across studies, or confidence intervals of studies show minimal or no overlap (Guyatt 2011);

  2. potential for publication bias, based on the amount of unpublished data required to make the result clinically irrelevant (Moore 2008).

In addition, there may be circumstances where the overall rating for a particular outcome needs to be adjusted as recommended by GRADE guidelines (Guyatt 2013a). For example, if there are so few data that the results are highly susceptible to the random play of chance, or if a studies use LOCF imputation in circumstances where there are substantial differences in adverse event withdrawals, one would have no confidence in the result, and would need to downgrade the quality of the evidence by three levels, to very low quality. In circumstances where no data were reported for an outcome, we would report the level of evidence as very low quality (Guyatt 2013b).

'Summary of findings' table

We have included 'Summary of findings' tables as set out in the Cochrane Pain, Palliative and Supportive Care Group author guide (PaPaS 2012), and recommended in the Cochrane Handbook (Chapter 11, Higgins 2011). The tables include, where possible, outcomes of at least 50% (substantial benefit) and at least 30% pain intensity reduction or maintenance of therapeutic response (MTR) (moderate benefit), PGIC (possibly at least substantial improvement and at least moderate improvement), withdrawals due to lack of efficacy, withdrawals due to adverse events, serious adverse events, and death (a particular serious adverse event).

Subgroup analysis and investigation of heterogeneity

We did not plan subgroup analyses since our experience based on previous reviews indicates that there would be inadequate information for meaningful subgroup analysis beyond dose, for example information on age or severity of pain is not usually recorded separately.

Sensitivity analysis

We did not plan any sensitivity analysis.

Results

Description of studies

The original review included five studies on fibromyalgia. Four were full publications (Arnold 2008; Crofford 2005; Crofford 2008; Mease 2008), and one was a PhRMA Web Synopsis (A0081100 2008). This trial was registered as NCT00333866 and was subsequently published (Pauer 2011).

Results of the search

The flow diagram of the search results is shown in Figure 1. We examined 19 articles for possible inclusion, which included the five identified in the original review.

We also identified three ongoing studies in ClinicalTrials.gov (NCT01387607; NCT02146430; NCT02187159).

Included studies

We included eight studies in this review.

  • We included five studies (3283 participants) in the main analysis using a 'classical' clinical trial design where participants were randomised at the start of the trial to pregabalin or placebo using fixed-dose titration strategies (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011). One other study compared a single nightly dose of pregabalin (morning dose placebo) with twice-daily dosing in 177 participants (Nasser 2014), and did not contribute to any analyses.

  • We have also reported on two studies using an enriched enrolment randomised withdrawal (EERW) design, in which participants underwent titration to effect and tolerance with pregabalin, and those successfully reaching those targets were then randomised to continued pregabalin or phased withdrawal to placebo (Arnold 2014; Crofford 2008). In these studies 687 participants entered the randomised withdrawal phase.

The majority of participants were women (89% to 95%) and white (76% to 96%), and the mean age was 47 to 50 years. All participants had fibromyalgia diagnosed according to the American College of Rheumatology (ACR) 1990 criteria (Wolfe 1990). Full details are in the Characteristics of included studies table. Where mentioned, the duration of fibromyalgia symptoms averaged about four years; baseline pain intensity averaged between 6.5 and 7.8/10, equivalent to severe pain (Collins 1997).

Studies were generally carried out over a duration of two to three months. Of the six classic studies, two lasted eight weeks (Crofford 2005; Nasser 2014), and the others lasted a total of 13 or 14 weeks, generally with 12 weeks on stable doses. The two EERW studies had double-blind treatment periods after randomisation lasting 13 weeks, in Arnold 2014, or 26 weeks, in Crofford 2008.

All of the studies of classic design used LOCF imputation for missing data, including when participants withdrew from treatment. The two EERW studies reported an outcome of loss of therapeutic effect, which was without imputation.

Excluded studies

We excluded 11 studies (12 reports) from the search (Arnold 2012; Arnold 2015; Byon 2010; Emir 2010; NCT00760474; NCT01268631; NCT01904097; Ohta 2013; Ramzy 2016; Roth 2012; Russell 2009). Reasons for exclusion are in the Characteristics of excluded studies table. The earlier review identified one study, Arnold 2013, in ClinicalTrials.gov, which has since been published as Arnold 2015.

Risk of bias in included studies

Figure 2 shows the overall 'Risk of bias' assessment of included studies. 'Risk of bias' assessments for each criterion for each study are given in the Characteristics of included studies table and Figure 3. All included studies had Oxford Quality Scores of 3/5 to 5/5.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

All of the studies were randomised, but only five adequately described the method used to generate the random sequence (Arnold 2008; Crofford 2005; Crofford 2008; Nasser 2014; Ohta 2012). Arnold 2008, Arnold 2014, Crofford 2008, and Ohta 2012 adequately described the methods used to ensure that allocation of participants to treatment groups was concealed. The remaining four studies did not report the method used (Crofford 2005; Mease 2008; Nasser 2014; Pauer 2011).

Blinding

All studies were described as double blind, but Crofford 2005, Mease 2008, and Pauer 2011 did not describe the methods used to ensure that participants and interacting investigators were unable to differentiate between the treatment and control tablets. The other five studies provided adequate information.

Incomplete outcome data

Five studies used LOCF to impute data for participants who withdrew for any reason in analyses of individual pain outcomes (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011). Nasser 2014 did not provide any information on the imputation method for missing data. Two studies did not use imputation (Arnold 2014; Crofford 2008).

Selective reporting

All studies reported the outcomes specified in the methods.

Other potential sources of bias

Only two studies had more than 200 participants in individual trial arms (Crofford 2008; Ohta 2012), and none had fewer than 50 participants in a trial arm.

Effects of interventions

See: Summary of findings for the main comparison Pregabalin compared with placebo for fibromyalgia in studies of classic design; Summary of findings 2 Pregabalin compared with placebo for fibromyalgia in enriched enrolment randomised withdrawal (EERW) studies

Details of results in individual studies are in Appendix 6. The analyses are necessarily different for classic study designs and EERW designs, so the format of the analyses is for efficacy and harm to be analysed for the classic study design and EERW design separately.

1. Classic study design

Efficacy in studies of classic design

All studies of classic design used LOCF imputation, so despite good trial design and large numbers, we classified them as second-tier evidence. We assessed the evidence as high quality because studies were randomised and double blind, had large numbers of participants, and were consistent; this was downgraded because of the use of LOCF imputation, but upgraded because the LOCF NNT estimations were similar to non-imputed analyses from individual patient data analyses from the same studies (see Summary of findings for the main comparison) (Straube 2010a).

One small study showed no benefit of nightly over twice-daily pregabalin dosing (Nasser 2014).

Various doses of pregabalin were compared with placebo in classic studies (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011. In this analysis we have chosen to include a single study in which 150 mg pregabalin was used, because it had more than 200 participants in the comparison and examined a general dose-response relationship. Efficacy outcomes are provided in the table Summary of results A below.

Pregabalin 150 mg daily versus placebo
At least 30% pain intensity reduction over baseline (moderate benefit)

One study (263 participants) reported at least 30% improvement from baseline pain intensity (Crofford 2005).

  • The proportion of participants with ≥ 30% pain relief with pregabalin 150 mg was 31% (41/132).

  • The proportion of participants with ≥ 30% pain relief with placebo was 27% (36/131).

  • The risk ratio (RR) for pregabalin compared with placebo was 1.1 (95% confidence interval (CI) 0.78 to 1.7) (Analysis 1.1). NNT was not calculated.

At least 50% pain intensity reduction over baseline (substantial benefit)

One study (263 participants) reported at least 50% improvement from baseline pain intensity (Crofford 2005).

  • The proportion of participants with ≥ 50% pain relief with pregabalin 150 mg was 13% (17/132).

  • The proportion of participants with ≥ 50% pain relief with placebo was 13% (17/131).

  • The RR for pregabalin compared with placebo was 0.99 (95% CI 0.53 to 1.9) (Analysis 1.2; Figure 4). NNT was not calculated.

    Figure 4.

    Forest plot of comparison: 1 Pregabalin versus placebo, outcome: 1.2 At least 50% pain relief.

PGIC 'much or very much improved' (moderate benefit)

One study (263 participants) reported PGIC of much or very much improved (Crofford 2005).

  • The proportion of participants with PGIC of much or very much improved with pregabalin 150 mg was 32% (42/132).

  • The proportion of participants with PGIC of much or very much improved with placebo was 26% (34/131).

  • The RR for pregabalin compared with placebo was 1.2 (95% CI 0.84 to 1.8) (Analysis 1.3; Figure 5). NNT was not calculated.

    Figure 5.

    Forest plot of comparison: 1 Pregabalin versus placebo, outcome: 1.3 Much or very much improved.

PGIC 'very much improved' (substantial benefit)

There were no data for this outcome.

Pregabalin 300 mg daily versus placebo
At least 30% pain intensity reduction over baseline (moderate benefit)

Four studies (1375 participants) reported at least 30% pain relief (Arnold 2008; Crofford 2005; Mease 2008; Pauer 2011).

  • The proportion of participants with ≥ 30% pain relief with pregabalin 300 mg was 39% (268/686).

  • The proportion of participants with ≥ 30% pain relief with placebo was 28% (194/689)

  • The RR for pregabalin compared with placebo was 1.4 (95% CI 1.2 to 1.6) (Analysis 1.1), and the NNT was 9.2 (6.3 to 17) for at least moderate pain relief.

At least 50% pain intensity reduction over baseline (substantial benefit)

Four studies (1375 participants) reported at least 50% pain relief (Arnold 2008; Crofford 2005; Mease 2008; Pauer 2011).

  • The proportion of participants with ≥ 50% pain relief with pregabalin 300 mg was 22% (148/686).

  • The proportion of participants with ≥ 50% pain relief with placebo was 14% (99/689).

  • The RR for pregabalin compared with placebo was 1.5 (95% CI 1.2 to 1.9) (Analysis 1.2; Figure 4), and the NNT was 14 (8.9 to 32) for at least substantial pain relief.

PGIC 'much or very much improved' (moderate benefit)

Four studies (1375 participants) reported PGIC of much or very much improved (Arnold 2008; Crofford 2005; Mease 2008; Pauer 2011).

  • The proportion of participants with PGIC of much or very much improved with pregabalin 300 mg was 36% (245/686).

  • The proportion of participants with PGIC of much or very much improved with placebo was 27% (185/689).

  • The RR for pregabalin compared with placebo was 1.3 (95% CI 1.1 to 1.6) (Analysis 1.3; Figure 5), and the NNT was 11 (7.3 to 25) for moderate benefit.

PGIC 'very much improved' (substantial benefit)

Four studies (1375 participants) reported PGIC of very much improved (Arnold 2008; Crofford 2005; Mease 2008; Pauer 2011).

  • The proportion of participants with PGIC of very much improved with pregabalin 300 mg was 17% (115/686).

  • The proportion of participants with PGIC of very much improved with placebo was 10% (72/689).

  • The RR for pregabalin compared with placebo was 1.6 (95% CI 1.2 to 2.1) (Analysis 1.4), and the NNT was 16 (10 to 37) for substantial benefit.

Pregabalin 450 mg daily versus placebo

Ohta 2012 reported combined results for 300 mg and 450 mg daily. The results are analysed as 450 mg daily because the majority of participants received that dose (59/250 received 300 mg daily and 178/250 received 450 mg daily).

At least 30% pain intensity reduction over baseline (moderate benefit)

Five studies (1874 participants) reported at least 30% pain relief (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011).

  • The proportion of participants with ≥ 30% pain relief with pregabalin 450 mg was 43% (400/937).

  • The proportion of participants with ≥ 30% pain relief with placebo was 29% (270/937)

  • The RR for pregabalin compared with placebo was 1.5 (95% CI 1.3 to 1.7) (Analysis 1.1), and the NNT was 7.2 (5.5 to 10) for at least moderate pain relief.

At least 50% pain intensity reduction over baseline (substantial benefit)

Five studies (1874 participants) reported at least 50% pain relief (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011).

  • The proportion of participants with ≥ 50% pain relief with pregabalin 450 mg was 24% (226/937).

  • The proportion of participants with ≥ 50% pain relief with placebo was 14% (129/937).

  • The RR for pregabalin compared with placebo was 1.8 (95% CI 1.4 to 2.1) (Analysis 1.2; Figure 4), and the NNT was 9.7 (7.2 to 15) for at least substantial pain relief.

PGIC 'much or very much improved' (moderate benefit)

Five studies (1869 participants) reported PGIC of much or very much improved (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011).

  • The proportion of participants with PGIC of much or very much improved with pregabalin 450 mg was 36% (331/932).

  • The proportion of participants with PGIC of much or very much improved with placebo was 27% (251/937).

  • The RR for pregabalin compared with placebo was 1.3 (95% CI 1.2 to 1.5) (Analysis 1.3; Figure 5), and the NNT was 11 (7.8 to 22) for moderate benefit.

PGIC 'very much improved' (substantial benefit)

Five studies (1869 participants) reported PGIC of very much improved (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011).

  • The proportion of participants with PGIC of very much improved with pregabalin 450 mg was 17% (163/932).

  • The proportion of participants with PGIC of very much improved with placebo was 9% (88/937).

  • The RR for pregabalin compared with placebo was 1.9 (95% CI 1.5 to 2.4) (Analysis 1.4), and the NNT was 12 (9.0 to 20) for substantial benefit.

Pregabalin 600 mg daily versus placebo
At least 30% pain intensity reduction over baseline (moderate benefit)

Three studies (1122 participants) reported at least 30% pain relief (Arnold 2008; Mease 2008; Pauer 2011).

  • The proportion of participants with ≥ 30% pain relief with pregabalin 600 mg was 39% (220/564).

  • The proportion of participants with ≥ 30% pain relief with placebo was 28% (158/558)

  • The RR for pregabalin compared with placebo was 1.4 (95% CI 1.2 to 1.6) (Analysis 1.1), and the NNT was 9.4 (6.2 to 19) for at least moderate pain relief.

At least 50% pain intensity reduction over baseline (substantial benefit)

Three studies (1122 participants) reported at least 50% pain relief (Arnold 2008; Mease 2008; Pauer 2011).

  • The proportion of participants with ≥ 50% pain relief with pregabalin 600 mg was 24% (136/564).

  • The proportion of participants with ≥ 50% pain relief with placebo was 15% (82/558).

  • The RR for pregabalin compared with placebo was 1.6 (95% CI 1.3 to 2.1) (Analysis 1.2; Figure 4), and the NNT was 11 (7.1 to 21) for at least substantial pain relief.

PGIC 'much or very much improved' (moderate benefit)

Three studies (1122 participants) reported PGIC of much or very much improved (Arnold 2008; Mease 2008; Pauer 2011).

  • The proportion of participants with PGIC of much or very much improved with pregabalin 600 mg was 40% (225/564).

  • The proportion of participants with PGIC of much or very much improved with placebo was 27% (151/558).

  • The RR for pregabalin compared with placebo was 1.5 (95% CI 1.3 to 1.8) (Analysis 1.3; Figure 5), and the NNT was 7.8 (5.5 to 14) for moderate benefit.

PGIC 'very much improved' (substantial benefit)

Three studies (1122 participants) reported PGIC of very much improved (Arnold 2008; Mease 2008; Pauer 2011).

  • The proportion of participants with PGIC of very much improved with pregabalin 600 mg was 12% (66/564).

  • The proportion of participants with PGIC of very much improved with placebo was 7% (40/558).

  • The RR for pregabalin compared with placebo was 1.6 (95% CI 1.1 to 2.4) (Analysis 1.4), and the NNT was 22 (13 to 89) for substantial benefit.

Summary of results A: Efficacy outcomes with different doses of pregabalin in fibromyalgia
Outcome
- daily dose
Number ofPer cent with outcomeRelative benefit
(95% CI)
NNT
(95% CI)
StudiesParticipantsPregabalinPlacebo
At least 30% pain intensity reduction over baseline (moderate benefit)
150 mg*126331271.1 (0.8 to 1.7)Not calculated
300 mg4137539281.4 (1.2 to 1.6)9.2 (6.3 to 17)
450 mg5187443291.5 (1.3 to 1.7)7.2 (5.5 to 10)
600 mg3112239281.4 (1.2 to 1.6)9.4 (6.2 to 19)
At least 50% pain intensity reduction over baseline (substantial benefit)
150 mg*126313130.99 (0.5 to 1.9)Not calculated
300 mg4137522141.5 (1.2 to 1.9)14 (8.9 to 32)
450 mg5187424141.8 (1.4 to 2.1)9.7 (7.2 to 15)
600 mg3112224151.6 (1.3 to 2.1)11 (7.1 to 21)
PGIC much or very much improved (moderate benefit)
150 mg*126332261.2 (0.8 to 1.8)Not calculated
300 mg4137536271.3 (1.1 to 1.6)11 (7.3 to 25)
450 mg5186936271.3 (1.2 to 1.5)11 (7.8 to 22)
600 mg3112240271.5 (1.3 to 1.8)7.8 (5.5 to 14)
PGIC very much improved (substantial benefit)
300 mg4137517101.6 (1.2 to 2.1)16 (10 to 37)
450 mg518691791.9 (1.5 to 2.4)12 (9.0 to 20)
600 mg311221271.6 (1.1 to 2.4)22 (13 to 89)

*Information from a single study, included to examine a general dose-response relationship and should be interpreted with caution.

CI: confidence interval; NNT: number needed to treat; PGIC: Patient Global Impression of Change

All of these analyses demonstrated a high degree of consistency between studies (Figure 4, Figure 5), with generally low I² values.

As we had good reporting of these efficacy outcomes of substantial and moderate benefit, we did not need to perform an analysis for any pain-related improvement.

Withdrawals

All studies in the main analysis provided data on withdrawals over the study period for all causes, due to lack of efficacy, and due to adverse events (Arnold 2008; Crofford 2005; Mease 2008; Nasser 2014; Ohta 2012; Pauer 2011). We assessed the evidence as high quality because studies were randomised and double blind, and had large numbers of participants.

Nasser 2014 reported no significant difference in withdrawal rates between once-nightly administration and twice-daily administration of pregabalin.

Withdrawal outcomes are provided in the table Summary of results B below.

All-cause withdrawals

The analysis for all-cause withdrawals is shown in Analysis 1.5.

  • Pregabalin 150 mg: 22% (29/132); placebo 26% (34/131). The RR was 0.85 (95% CI 0.55 to 1.3).

  • Pregabalin 300 mg: 30% (206/686); placebo 28% (196/689). The RR was 1.1 (95% CI 0.90 to 1.3).

  • Pregabalin 450 mg: 27% (252/937); placebo 30% (236/937). The RR was 1.1 (95% CI 0.92 to 1.2).

  • Pregabalin 600 mg: 39% (219/564); placebo 29% (162/558). The RR was 1.3 (95% CI 1.1 to 1.6), and the NNH was 10 (6.5 to 23).

Adverse event withdrawals

The analysis for adverse event withdrawals is shown in Analysis 1.6.

  • Pregabalin 150 mg: 8% (11/132); placebo 8% (10/131). The RR was 1.1 (95% CI 0.48 to 2.5).

  • Pregabalin 300 mg: 16% (113/686); placebo 10% (72/689). The RR was 1.6 (95% CI 1.2 to 2.1), and the NNH was 17 (10 to 41).

  • Pregabalin 450 mg: 17% (163/937); placebo 9% (80/937). The RR was 2.0 (95% CI 1.6 to 2.6), and the NNH was 11 (8.4 to 17).

  • Pregabalin 600 mg: 28% (159/564); placebo 11% (62/568). The RR was 2.5 (95% CI 1.9 to 3.3), and the NNH was 5.9 (4.6 to 8).

Lack of efficacy withdrawals

The analysis for lack of efficacy withdrawals is shown in Analysis 1.7.

  • Pregabalin 150 mg: 9% (12/132); placebo 14% (13/131). The RR was 0.66 (95% CI 0.33 to 1.3).

  • Pregabalin 300 mg: 4% (29/686); placebo 10% (68/689). The RR was 0.43 (95% CI 0.28 to 0.65), and the NNTp was 18 (12 to 34).

  • Pregabalin 450 mg: 4% (33/937); placebo 10% (94/937). The RR was 0.35 (95% CI 0.24 to 0.52), and the NNTp was 15 (11 to 24).

  • Pregabalin 600 mg: 2% (14/564); placebo 9% (50/568). The RR was 0.28 (95% CI 0.15 to 0.50), and the NNTp was 15 (11 to 26).

Summary of results B: Withdrawal with different doses of pregabalin in fibromyalgia
Outcome
- daily dose
Number ofPer cent with outcomeRelative risk
(95% CI)
NNH
(95% CI)
StudiesParticipantsPregabalinPlacebo
All-cause withdrawals
150 mg126322260.85 (0.55 to 1.3)Not calculated
300 mg4137530281.1 (0.90 to 1.3)Not calculated
450 mg5187427301.1 (0.92 to 1.2)Not calculated
600 mg3112239291.3 (1.1 to 1.6)10 (6.5 to 23)
Adverse event withdrawals
150 mg1263881.1 (0.48 to 2.5)Not calculated
300 mg4137516101.6 (1.2 to 2.1)17 (10 to 41)
450 mg518741792.0 (1.6 to 2.6)11 (8.4 to 17)
600 mg3112228112.5 (1.9 to 3.3)5.9 (4.6 to 8)
Lack of efficacy withdrawalsNNTp (95% CI)
150 mg12639140.66 (0.33 to 1.3)Not calculated
300 mg413754100.43 (0.28 to 0.65)18 (12 to 34)
450 mg518744100.35 (0.24 to 0.52)15 (11 to 24)
600 mg31122290.28 (0.15 to 0.50)15 (11 to 26)
CI: confidence interval; NNH: number needed to harm; NNTp: number needed to treat to prevent

Adverse events in studies of classic design

All the randomised studies of classic design provided some information on participants experiencing adverse events over the study period, which was collected from spontaneous reports and clinical observation and evaluation. Ohta 2012 reported combined results for 300 mg and 450 mg daily. The results are analysed as 450 mg daily because the majority of participants received that dose.

Nasser 2014 did not provide data suitable for pooled analysis. It reported no significant difference in adverse events with different dosing regimens.

Adverse event outcomes are provided in the table Summary of results C below.

Participants with at least one adverse event

Five studies provided data on the number of participants reporting one or more adverse events with different dose regimens over the period of the study (8 to 14 weeks) (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011). We assessed the evidence as high quality because studies were randomised and double blind, and had large numbers of participants.

The majority of participants reported at least one adverse event over the period, including 77% to 73% of those participants receiving placebo, and the adverse event frequency increased with dose escalation (Analysis 1.8).

  • One study provided data for 150 mg pregabalin versus placebo (Crofford 2005); 78% with active treatment experienced at least one adverse event, compared to 77% on placebo. The RR was 1.01 (95% CI 0.89 to 1.2).

  • Four studies provided data for 300 mg pregabalin versus placebo (Arnold 2008; Crofford 2005; Mease 2008; Pauer 2011); 85% with active treatment experienced at least one adverse event, compared to 74% on placebo. The RR was 1.2 (95% CI 1.1 to 1.2), and the NNH was 9.0 (6.5 to 15).

  • Five studies provided data for 450 mg pregabalin versus placebo (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011); 90% with active treatment experienced at least one adverse event, compared to 73% on placebo. The RR was 1.2 (95% CI 1.18 to 1.3), and the NNH was 5.9 (4.9 to 7.4).

  • Three studies provided data for 600 mg pregabalin versus placebo (Arnold 2008; Mease 2008; Pauer 2011); 91% with active treatment experienced at least one adverse event, compared to 73% on placebo. The RR was 1.2 (95% CI 1.17 to 1.3), and the NNH was 5.7 (4.6 to 7.5).

Serious adverse events

Three studies provided data on participants experiencing a serious adverse event (Arnold 2008; Ohta 2012; Pauer 2011). We assessed the evidence as very low quality because while studies were randomised and double blind, the incidence of serious adverse events was low, and so the number of events for analysis was small, meaning that random play of chance might have affected the result.

The incidence rate for pregabalin at various doses with corresponding placebo follows.

  • Pregabalin 300 mg: 1.1% (4/367); placebo: 1.6% (6/368).

  • Pregabalin 450 mg: 2.1% (13/622); placebo: 1.1% (7/616).

  • Pregabalin 600 mg: 1.6% (6/374); placebo: 1.6% (6/368).

There were no significant differences between either dose of pregabalin and corresponding placebo or between the three doses of pregabalin (Analysis 1.9).

Death

No deaths were reported in the six studies with a classic design comparing pregabalin with placebo, or comparing two different pregabalin dosing regimens.

Specific adverse events

Five RCTs provided data for numbers of participants experiencing specific adverse events (Arnold 2008; Crofford 2005; Mease 2008; Ohta 2012; Pauer 2011). Rates for each event are presented below for individual doses and all doses combined.

The combined results for somnolence, dizziness, weight gain, and peripheral oedema showed a significant difference from placebo (Analysis 1.10; Analysis 1.11; Analysis 1.12; Analysis 1.13).

The results for somnolence, dizziness, weight gain, and peripheral oedema for different doses showed that higher doses of pregabalin produced higher adverse event rates, with consequent lower (worse) NNH values (Analysis 1.10; Analysis 1.11; Analysis 1.12; Analysis 1.13).

Summary of results C: Adverse events with different doses of pregabalin in fibromyalgia
Outcome
- daily dose
Number ofPer cent with outcomeRelative risk
(95% CI)
NNH
(95% CI)
StudiesParticipantsPregabalinPlacebo
Any adverse event
150 mg*126378771.01 (0.89 to 1.2)Not calculated
300 mg4127585741.2 (1.1 to 1.2)9.0 (6.5 to 15)
450 mg5187490731.2 (1.18 to 1.3)5.9 (4.9 to 7.4)
600 mg3112291741.2 (1.17 to 1.3)5.7 (4.6 to 7.5)
Serious adverse event
300 mg2735120.7 (0.2 to 2.4)Not calculated
450 mg31238211.9 (0.8 to 4.6)Not calculated
600 mg2742221.0 (0.3 to 3.0)Not calculated
Specific adverse events - 150 mg
Somnolence*12631653.5 (1.5 to 8.3)Not calculated
Dizziness*126323112.1 (1.2 to 3.8)Not calculated
Weight gain*1263825.0 (1.1 to 22)Not calculated
Peripheral oedema*1263517.0 (0.9 to 56)Not calculated
Specific adverse events - 300 mg
Somnolence413752054.0 (2.8 to 5.8)6.7 (5.5 to 8.7)
Dizziness4137532103.1 (2.4 to 3.9)4.6 (3.9 to 5.7)
Weight gain413751124.6 (2.7 to 7.9)12 (9.1 to 17)
Peripheral oedema41375723.0 (1.7 to 5.3)23 (15 to 45)
Specific adverse events - 450 mg
Somnolence518742883.3 (2.6 to 4.1)5.2 (4.5 to 6.4)
Dizziness518743994.2 (3.4 to 5.2)3.4 (3 to 3.8)
Weight gain518741234.5 (2.9 to 6.8)11 (8.6 to 14)
Peripheral oedema51874723.5 (2.1 to 5.8)21 (15 to 34)
Specific adverse events - 600 mg
Somnolence311222354.5 (3.1 to 6.7)5.7 (4.6 to 7.3)
Dizziness3112246104.4 (3.4 to 5.8)2.8 (2.5 to 3.2)
Weight gain311221335.4 (3.1 to 9.4)9.1 (7.1 to 13)
Peripheral oedema311221134.2 (2.4 to 7.5)12 (9.1 to 19)
Specific adverse events - all doses combined
Somnolence5325623102.4 (1.9 to 3)7.4 (6.1 to 9.2)
Dizziness5325638113.5 (2.3 to 4.3)3.7 (3.3 to 4.2)
Weight gain53256932.8 (1.8 to 4.1)18 (14 to 26)
Peripheral oedema53256823.4 (2.1 to 5.5)19 (14 to 26)

*Information from a single study, included to examine a general dose-response relationship and should be interpreted with caution.

CI: confidence interval; NNH: number needed to harm

2. Enriched enrolment randomised withdrawal study designs

Both EERW studies had a similar overall design. Both screened participants for eligibility, as would occur with a classical design. Participants were then given single (participant)-blind pregabalin at increasing doses over three weeks, to determine the dose giving maximum benefit with tolerable adverse events, and then maintained on that dose for a further three weeks. Those who met criteria for an adequate response were at that point randomised to double-blind treatment with continued pregabalin at the maintenance dose, or a phased dose reduction to placebo over a week, with treatment continuing for up to 13 weeks, in Arnold 2014, or 26 weeks, in Crofford 2008 (see Summary of findings 2).

Dosing was different between the studies. Arnold 2014 used pregabalin controlled release (CR) at doses of 330 to 495 mg per day. Crofford 2008 used fixed doses of 300, 450, and 600 mg per day.

In both studies a high-level response was required to enter the double-blind randomised phase. To continue in the study, both required at least 50% reduction in pain relative to baseline as measured using the daily pain diary. Crofford 2008 also required participants to have overall improvement on the PGIC scale of "much improved" or "very much improved", with the criteria met at weeks four, five, and six.

The primary outcome in both studies was the loss of therapeutic response, which was defined differently. Arnold 2014 used a definition of less than 30% pain reduction relative to the single-blind baseline (based on daily pain diary), or patient discontinuation because of lack of efficacy or adverse events in the double-blind phase. Crofford 2008 used less than 30% reduction in pain visual analogue scale score relative to open-label baseline value at two consecutive visits in the double-blind phase or worsening of fibromyalgia symptoms necessitating alternate treatment; this definition did not include withdrawals due to lack of efficacy or adverse events.

We have therefore chosen to extract an outcome similar to Arnold 2014 from both studies, but to make the outcome positive: the maintenance of therapeutic response (MTR). Participants fulfilling this outcome would have at least 30% pain intensity reduction over baseline AND continue treatment, with any adverse events being of at least tolerable intensity (withdrawal for any cause being a treatment failure). This allowed efficacy results from both EERW studies to be combined, and to be compared with the similar outcome of moderate benefit used in classical design studies.

EERW study participant flows

In order to understand the results of EERW studies it is necessary to understand the participant flows. We have therefore combined the patient flow data from Arnold 2014 and Crofford 2008 and simplified it to provide a background.

  • Number of participants screened and entered into the dose titration phase: 1492 (100% of original).

  • Number discontinued in dose titration phase: 509; number completing dose titration: 983 (66%).

  • Number with inadequate therapeutic response to proceed: 295; number entering randomised double-blind phase: 688 (46%).

  • Number completing randomised double-blind phase (pregabalin and placebo) with MTR: 208 (14%).

One difference between a randomised withdrawal study and a classic design is the complete enrichment of the double-blind phase, which is limited only to responders (Straube 2008). In this case, only 46% of the participants who would have entered a classically designed study have been randomised.

Efficacy in EERW studies

Maintenance of therapeutic effect

Because no imputation was used, we regarded this evidence as first-tier evidence. We assessed the evidence as high quality because studies were randomised and double blind, had large numbers of participants, and were consistent.

Two studies with 687 participants reported results equivalent to 'moderate benefit': MTR of at least 30% pain intensity reduction over baseline and continued treatment at 13 or 26 weeks (Arnold 2014; Crofford 2008).

  • The proportion of participants with MTR with pregabalin was 40% (136/342).

  • The proportion of participants with MTR with placebo was 20% (72/345).

  • The RR for pregabalin compared with placebo was 1.9 (95% CI 1.5 to 2.4) (Analysis 2.1), and the NNT was 5.3 (3.9 to 8.2) for MTR.

Other pain outcomes were not relevant to the EERW trial design, or were not reported.

Withdrawals during the randomised double-blind phase of EERW studies

Two studies with 687 participants reported the number of participants withdrawing for any reason during the double-blind period over 13 or 26 weeks (Arnold 2014; Crofford 2008). We assessed the evidence as high quality because studies were randomised and double blind, had large numbers of participants, and were consistent.

  • The proportion of participants withdrawing with pregabalin was 55% (189/342).

  • The proportion of participants withdrawing with placebo was 70% (243/345).

  • The RR for pregabalin compared with placebo was 0.79 (95% CI 0.71 to 0.89) (Analysis 2.2), and the NNTp was 6.6 (4.5 to 12).

The I² value for this analysis was 71%, likely because one of the studies was small (121 participants in comparison) and highly susceptible to random chance. The point estimate for this study had very wide confidence intervals.

Adverse events in the randomised double-blind phase of EERW studies
Participants with at least one adverse event

Two studies with 687 participants reported the number of participants experiencing adverse events during the double-blind period over 13 or 26 weeks (Arnold 2014; Crofford 2008). We assessed the evidence as high quality because studies were randomised and double blind, had large numbers of participants, and were consistent.

  • The proportion of participants experiencing an adverse event with pregabalin was 65% (222/342).

  • The proportion of participants experiencing an adverse event with placebo was 49% (168/345).

  • The RR for pregabalin compared with placebo was 1.3 (95% CI 1.2 to 1.5) (Analysis 2.3), and the NNH was 6.2 (4.3 to 11).

Serious adverse events

Serious adverse events were uncommon in the double-blind phase. In the two studies combined, 8/342 (2.3%) experienced a serious adverse event with pregabalin, compared with 2/345 (0.6%) with placebo. We assessed the evidence as very low quality because of the small number of events.

Death

Crofford 2008 reported that two participants died during the trial, one while taking placebo and the other after pregabalin use had ended. Neither was considered associated with the study drug. We assessed the evidence as very low quality because of the small number of events.

Adverse events in the titration phase of EERW studies

At least one adverse event was experienced by 82% (1216/1492) participants during the initial titration with pregabalin, and 250 participants withdrew because of adverse events. Thirteen serious adverse events were reported, a rate of 0.9%.

Discussion

Summary of main results

Participants in these studies all had moderate or severe pain of fibromyalgia, often long-lasting with an initial average pain score of about 7/10, and an average duration of symptoms of four years. The primary outcomes were 'substantial' pain relief, ideally a reduction in pain intensity by 50% or more, and 'moderate' pain relief, a reduction by 30% or more, and sustained over the duration of the trial, typically three months. These outcomes are judged as desirable by people with pain (Moore 2013a).

Classical trial designs

Five large studies involving 3283 participants compared pregabalin with placebo.

The ideal would have been for this pain reduction outcome to be combined with that of tolerability, where withdrawal for any reason would be regarded as treatment failure; most withdrawals were due to adverse events or lack of efficacy. Results in all of the trials of classic design used a LOCF imputation, where pain measures at withdrawal were counted as if they had been scored at the end of the trial. This form of imputation has the potential to overestimate the treatment effect by a large amount (Moore 2012b). Overestimation is more likely when adverse event withdrawals are greater with active than placebo. As this was the case for pregabalin, we could not judge the evidence as first tier, and so classified efficacy results from studies of classic design as second-tier evidence.

There was little evidence for pregabalin 150 mg, coming from a single study indicating that this dose was no better than placebo. For pregabalin doses of 300 to 600 mg daily, the NNT for substantial benefit outcomes were different: at least 50% pain intensity reduction was about 10, and for PGIC very much improved was about 20. There was more agreement for moderate-benefit outcomes: at least 30% pain intensity reduction was about 9, and for PGIC much or very much improved was about 11. There was no pronounced dose response for efficacy, though the better results tended to come from 450 mg daily. The results showed that a very significant degree of pain benefit was achieved by about 10% more people with pregabalin 300 to 600 mg daily than with placebo. The importance of the benefit is discussed below.

Participants tended to report more adverse events with higher doses of pregabalin, giving lower (worse) NNH values with the higher doses. It was common for participants to report an adverse event in these long-duration studies. Around three-quarters of participants taking placebo reported an adverse event, though this was higher at up to 90% with pregabalin. Somnolence, dizziness, weight gain, and peripheral oedema were amongst the most common adverse events, with around a quarter of participants affected by dizziness, for example. Serious adverse events were no more common with pregabalin than placebo, and were in the range of 1% to 2%.

Withdrawals because of adverse events were more common with higher doses of pregabalin, by 6% to 17% more than with placebo over the range 300 to 600 mg daily. By contrast, lack of efficacy withdrawals were around 6% lower with pregabalin.

EERW trial designs

Two large studies involving 1492 participants compared pregabalin with placebo. Of these participants, 687 achieved adequate pain intensity reduction with an initial pregabalin titration and were able to tolerate any adverse events; they were then randomised to continuing the effective dose of pregabalin, or tapered withdrawal to placebo in a double-blind manner.

In order to combine the two studies and make a comparison with studies of classic design, we used the outcome of maintenance of therapeutic response of at least 30% pain intensity reduction over baseline and continued treatment at 13 or 26 weeks without withdrawal. As there was no imputation, we regarded this evidence as first tier.

The outcome of maintenance of therapeutic response is equivalent to a 'moderate benefit' and was achieved by 20% more participants taking pregabalin than taking placebo, giving a NNT of about 5. This was 20% of the randomised population, which was only half of the initial population for the studies, so the NNT of 5 would be comparable to a NNT of 10 in a trial of classic design, close to what was found.

About 15% more participants experienced an adverse event in the double-blind phase with pregabalin than with placebo. Serious adverse events were rare, and two deaths were not likely to have been connected with the drugs tested.

Importance of outcomes in fibromyalgia

Four of the five studies of classic design included in this review have previously been the subject of individual patient level analyses, and for pregabalin we are in the unique situation of having individual patient level analyses for both pain response and the link between pain and other important outcomes in fibromyalgia. These analyses have shown that with greater degrees of pain relief there is a graded response for other symptoms, such as sleep, depression, impact of fibromyalgia, quality of life, functional ability, ability to work, and interference with work (Moore 2010b; Straube 2011).

Achieving a pain outcome of at least 30% or at least 50% pain intensity reduction with ongoing therapy (no withdrawal) comes with major improvements in all these other outcomes, so that for many of these patients substantial pain benefit (at least 50% pain intensity reduction) was associated with normalisation of these other symptoms.

This finding is possibly unique for fibromyalgia, and comes from an analysis of these four studies that is without imputation, and provides efficacy results for responders with both pain relief and ability to keep taking the medication (Straube 2010a).

As yet unpublished analysis of the pregabalin trials indicates that if pain relief is not achieved by about six weeks, then it is highly unlikely good pain relief will be achieved with continued treatment.

Overall completeness and applicability of evidence

The included studies were of insufficient duration to determine long-term use, but at least one of the EERW studies had a 26-week (six-month) duration, demonstrating largely unchanged responses over the longer term (Crofford 2008). In addition, extension studies have demonstrated tolerability and efficacy for up to one year (Arnold 2012; Ohta 2013).

Study participants were typical of people with fibromyalgia, being mainly women in their 50s, with a reliable diagnosis of fibromyalgia, with moderate or severe pain and functional disability. There is no reason to suspect that results of these studies would not be applicable to the majority of people with fibromyalgia, although more comorbidities are likely in the general population. We excluded one study because it had a duration of less than eight weeks (Arnold 2015). In this cross-over study conducted in 197 people with fibromyalgia and comorbid depression taking concurrent antidepressant medicines, addition of pregabalin at 300 mg or 450 mg daily significantly improved fibromyalgia pain and other symptoms.

Data from many of the studies of classic design in this review have been the subject of independent individual patient level analyses that linked pain benefit to benefits in a wide range of other concomitant symptoms, including quality of life and work (Moore 2010b; Straube 2011). Good pain relief was associated with major improvements in all of these, in common with other findings in acute and chronic pain conditions (Conaghan 2015; Moore 2013a).

However, it is worth noting that the studies often excluded people with depression, which is commonly associated with fibromyalgia. For example, the longest-duration study excluded people "with severe depression or other severe psychiatric or severe medical conditions that made entry into a clinical trial inappropriate in the judgment of the investigator" (Crofford 2008). Others excluded people with "clinically significant or unstable medical or psychological conditions" (Mease 2008). Trials were exclusively of pregabalin monotherapy where other therapies were discontinued, which may well be rather different from what occurs in everyday clinical practice. While it could be argued that exclusions were sensible in the context of a clinical trial, it also means that results may not be unthinkingly extrapolated to all people presenting with fibromyalgia.

Objections to the clinical trial evidence include the populations studied. The trials generally exclude people with mental illness, concomitant medical/rheumatic conditions, men, and people without the ability to participate in clinical trials. In clinical practice, long-term use of medications is unusual, with only about 20% using medicines (including pregabalin) for longer than a year (Kim 2013). Benefits are not apparent in longitudinal studies, but that might reflect treatment continuing in the absence of benefit (Wolfe 2012).

Quality of the evidence

All of the studies in the review were described as randomised and double blind, had Oxford Quality Scores of 3/5 or above, and not at high risk of bias for any item. Studies lasted for eight weeks or longer, and reported clinically useful outcomes, making them valid. Diagnostic criteria for inclusion were reasonable, using appropriate definitions and duration of pain. Participants had to have had initial pain of at least moderate intensity, meaning that studies would be sensitive enough to measure any analgesic effect. Sample sizes were moderate or large, minimising the effects of random chance and small study bias.

The one major problem was the use of LOCF imputation for missing data in a situation where around 10% more participants withdrew because of adverse events with pregabalin compared with placebo. This is known to give rise to overestimation of treatment effects (Moore 2012b). The potential effects of imputation method for pregabalin in fibromyalgia can be seen in Summary of results D below, which compares meta-analyses on essentially the same data sets carried out where LOCF data were available, or where non-imputed responder analyses were possible where withdrawal was considered to be treatment failure.

Summary of results D: Comparison of pregabalin efficacy in different meta-analyses, using different imputation methods
ReviewDoseParticipants in comparisonsNNT for ≥ 30% PIRNNT for ≥ 50% PIRNNT for PGIC
much or very much improved
NNT for PGIC
very much improved
Trials of classic design with LOCF imputation
This review300 mg13759.2 (6.3 to 17)14 (8.9 to 32)11 (7.3 to 25)16 (10 to 37)
450 mg18747.2 (5.5 to 10)9.7 (7.2 to 15)11 (7.8 to 22)12 (9.0 to 20)
600 mg11229.4 (6.2 to 19)11 (7.1 to 21)7.8 (5.5 to 14)22 (13 to 89)
2009 review300 mg13749.2 (6.3 to 17)14 (9.0 to 33)11 (7.3 to 26)16 (9.9 to 37)
450 mg13766.6 (5.0 to 9.8)9.8 (7.0 to 16)6.8 (5.1 to 10)11 (7.9 to 20)
600 mg11229.1 (6.1 to 18)11 (7.1 to 21)7.7 (5.4 to 13)21 (12 to 83)

Straube 2010b

Review of clinical trial reports

300 mg13749.2 (6.1 to 19)14 (9.0 to 33)12 (7.4 to 27)Not available
450 mg13767.1 (5.1 to 12)9.9 (7.0 to 17)6.9 (5.2 to 10)Not available
600 mg11228.8 (5.9 to 17)11 (7.1 to 21)7.8 (5.5 to 14)Not available
Studies or analyses with no imputation

This review

EERW study design

300 to 600 mg68711.5 (8.5 to 18)*––––––

Straube 2010a

Responder analysis

300 mg1374Not calculated22 (11 to 870)14 (8.5 to 44)26 (15 to > 100)
450 mg137611 (6.9 to 29)16 (9.3 to 59)8.9 (6.2 to 16)24 (14 to 80)
600 mg1122Not calculated13 (8.1 to 31)13 (7.7 to 41)Not calculated

*The NNT for the EERW design study is normalised to the starting population by multiplying NNT values obtained in the randomised double-blind phase by 1/0.46 to correct for the fact that only 46% of the initial population were able to enter the randomised phase, and withdrew beforehand or had insufficient pain response.

EERW: enriched enrolment randomised withdrawal; LOCF: last observation carried forward; NNT: number needed to treat; PGIC: Patient Global Impression of Change; PIR: pain intensity reduction

At least three meta-analyses, this review, a previous version of this review (Moore 2009), and a meta-analysis based on company clinical trial reports, Straube 2010b, have used substantially similar sources of data from four or five of the studies of classic design that compare pregabalin with placebo in fibromyalgia. The results in Summary of results D above show that they have come to essentially the same magnitude of effect size, with virtually identical NNT values for particular outcomes.

By contrast, a responder analysis based on individual patient level data, where a responder was defined as both having the response and NOT withdrawing, produced numerically higher (worse) values for NNT for each of the outcomes. Moreover, if the results of the EERW meta-analysis in this review are normalised to the starting population for the studies, then the calculated NNT for comparison with classical study designs is, at 11, the same as that for the same outcome in the responder analysis (Straube 2010b), but also numerically higher than equivalent NNTs in studies of classic design.

However, there is also substantial agreement between all of these different analyses. None claims exceptional efficacy. All demonstrate modest efficacy, with perhaps 10% more people having a moderate or substantial benefit with pregabalin who would not have done so with placebo. Moreover, this result occurred at three months after treatment began, and where we know that good pain response is associated with substantial improvements with a range of other important outcomes such as sleep, depression, quality of life, and work.

In view of the overall quality and size of studies, consistency of effect between imputation methods, and consistency between studies, we considered the overall GRADE rating for efficacy to be high quality, meaning that further research is very unlikely to change our confidence in the estimate of effect. For serious adverse events and deaths, where there were few events, results could be radically changed by additional data, so we gave these lower GRADE ratings.

Potential biases in the review process

We know of no potential biases in the review process. We had planned to calculate the number of participants who would need to be in trials with zero effect (risk ratio of 1.0) needed for the point estimate of the NNT to increase beyond a clinically useful level (Moore 2008), but this method is not applicable with low effect sizes.

Agreements and disagreements with other studies or reviews

The results in this review are in substantial agreement with the previous version (Moore 2009), and two other reviews that also examined four of the five classical studies (Straube 2010a; Straube 2010b), though none of these reviews were able to perform a pooled analysis of the EERW studies. A review using three published studies with LOCF imputation reported very similar NNT values to the LOCF analyses in other reviews (Tzellos 2010). Another review used the same four studies, but pooled doses, and also concluded that pregabalin was better than placebo for reducing pain (Häuser 2010). The evidence base for pregabalin in fibromyalgia was regarded as strong in a guideline for fibromyalgia treatment developed by a group of German associations (Häuser 2008). Pregabalin is also recommended by the European League Against Rheumatism (Macfarlane 2016).

It is also worth noting that the magnitude of response to pregabalin in fibromyalgia for long-term outcomes of moderate or substantial improvement is similar to that seen for both milnacipran (NNTs 6 to 10; Cording 2015) and duloxetine, whether a LOCF imputation was used (NNT 8; Lunn 2014), or true responder definition (NNT 9; Moore 2014c).

Authors' conclusions

Implications for practice

For people with fibromyalgia

Pregabalin offers good pain relief to only a minority of people with fibromyalgia; it will not work for most people. This is also the case for other treatments for fibromyalgia, such as duloxetine and milnacipran. These treatments provide moderate or substantial pain benefit to about 10% more people than does placebo. The good news is that pain relief comes together with improved sleep, relief of any depression, less impact on life, and improved quality of life and ability to work.

People who take pregabalin are likely to experience adverse events, which may be troublesome. Pregabalin is not licensed to treat fibromyalgia in many countries, but has been licensed by the US Food and Drug Administration and a number of other countries worldwide.

For clinicians

Pregabalin offers good pain relief to only a minority of people with fibromyalgia; it will not work for most people. This is also the case for other treatments for fibromyalgia, such as duloxetine and milnacipran, which are the only other drug treatments with good evidence of efficacy in fibromyalgia. Pregabalin is not licensed to treat fibromyalgia in many countries.

Since relatively few participants achieve a worthwhile response with pregabalin, it is important to establish switching rules, so that when someone does not respond within a specified time, they can be switched to an alternative treatment. Emerging evidence indicates that the lack of any worthwhile pain relief within four to six weeks means that no pain relief is likely in the longer term. Stopping or switching rules will reduce the number of participants exposed to adverse events in the absence of benefit.

The available evidence shows that there is no difference between nighttime dosing and divided, twice-daily dosing.

Because adverse events are common, dosing in clinical practice often follows the following general principles to generate maximum likelihood of benefit and minimal likelihood of early withdrawal.

  • Start with low doses. For those patients who work, changes might be made over the weekend, with five to seven days on the new dose before any further increase.

  • Giving the drug at bedtime may increase the benefit and decrease side effects.

  • Adverse effects are common, so carefully balance these to analgesia.

  • Do not expect any major pain relief until 150 mg is reached.

  • While some patients may achieve good relief with lower doses, it is likely that 450 mg daily will provide the most effective balance between benefit and adverse events for most patients.

For policymakers

Since no single treatment is effective in a majority of individuals with fibromyalgia, this relatively small number who benefit may be considered worthwhile, particularly if switching rules are in place.

For funders

Since no single treatment is effective in a majority of individuals with fibromyalgia, this relatively small number who benefit may be considered worthwhile, particularly if switching rules are in place. The magnitude of benefit in those people who do respond is worthwhile, and it extends to major improvement in quality of life, function, and ability to work. This probably makes successful treatment of fibromyalgia cost-effective, as people with moderate or severe chronic pain consume much greater health service and non-health service resources than those with well-treated pain.

Implications for research

General

Because the trials of classic design in this review used the last-observation-carried-forward (LOCF) imputation method for study withdrawals, post-hoc individual participant level analyses using baseline observation carried forward (BOCF) would be regarded as appropriate to strengthen the findings, especially if the pain reduction was linked to improved quality of life and function. For pregabalin we are in the unique situation of having individual patient level analyses for both pain response and the link between pain and other important outcomes in fibromyalgia.

However, there is a gap between the dosing regimens used in the clinical trials, where fairly rapid dose elevations are made over a few weeks, and clinical practice, where dosing increases can be quite slow. Practical research about the most effective use of medicines known to be effective in only a small proportion of patients could be very important. Indeed, situations could be envisaged where the degree of recruitment to successful treatment might have a major impact on treating a very difficult, debilitating, and costly condition.

Design

The design of trials was adequate, but reporting of clinically relevant outcomes using appropriate imputation for withdrawal would improve the relevance of the findings for clinical practice. The use of EERW designs for comparison with classic trial designs indicates that good-quality EERW designs of long duration may be appropriate for fibromyalgia.

No immediate design for testing initial dosing regimens presents itself.

Measurement (endpoints)

Assessment of fibromyalgia symptoms should be based on dichotomous participant-reported outcomes of proven clinical utility. The endpoint used in this review, of maintenance of therapeutic response without withdrawal, might be more clearly stated in trial reports, and used as a primary outcome in future trials, including pragmatic trials of dosing regimens.

Comparison between active treatments

Studies involving other treatments, including non-pharmacological interventions, may be valuable in this context. A multicomponent approach reflects current practice.

Acknowledgements

The protocol was developed in collaboration with the Cochrane Musculoskeletal Group, the Cochrane Neuromuscular Diseases Group, and the Cochrane Pain, Palliative and Supportive Care Group, and followed an agreed template for fibromyalgia. The editorial process was managed by the Cochrane Pain, Palliative and Supportive Care Group.

Institutional support is provided by the Oxford Pain Relief Trust.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pain, Palliative and Supportive Care Review Group.

Disclaimer: The views and opinions expressed herein are those of the review authors and do not necessarily reflect those of the NIHR, National Health Service (NHS), or the Department of Health.

Data and analyses

Download statistical data

Comparison 1. Pregabalin versus placebo (studies of classic design)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 At least 30% pain relief5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)1.13 [0.78, 1.65]
1.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)1.39 [1.20, 1.62]
1.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)1.48 [1.31, 1.68]
1.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)1.38 [1.17, 1.63]
2 At least 50% pain relief5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.53, 1.86]
2.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)1.51 [1.20, 1.90]
2.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.44, 2.13]
2.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.28, 2.10]
3 Much or very much improved5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)1.23 [0.84, 1.80]
3.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)1.33 [1.14, 1.56]
3.3 Pregabalin 450 mg daily51869Risk Ratio (M-H, Fixed, 95% CI)1.33 [1.16, 1.52]
3.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)1.48 [1.25, 1.75]
4 Very much improved5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)1.59 [1.22, 2.08]
4.2 Pregabalin 450 mg daily51869Risk Ratio (M-H, Fixed, 95% CI)1.86 [1.47, 2.35]
4.3 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.13, 2.38]
5 All-cause withdrawal5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.55, 1.30]
5.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.90, 1.25]
5.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.92, 1.24]
5.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)1.34 [1.13, 1.58]
6 Adverse event withdrawal5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.48, 2.48]
6.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)1.58 [1.20, 2.08]
6.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)2.04 [1.59, 2.62]
6.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)2.54 [1.94, 3.32]
7 Lack of efficacy withdrawal5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.33, 1.32]
7.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.28, 0.65]
7.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.24, 0.52]
7.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)0.28 [0.15, 0.50]
8 Participants with at least one adverse event5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.89, 1.15]
8.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)1.15 [1.09, 1.21]
8.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)1.23 [1.18, 1.29]
8.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)1.24 [1.17, 1.31]
9 Participants with at least one serious adverse event3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 Pregabalin 300 mg daily2735Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.19, 2.35]
9.2 Pregabalin 450 mg daily31238Risk Ratio (M-H, Fixed, 95% CI)1.85 [0.75, 4.60]
9.3 Pregabalin 600 mg daily2742Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.32, 3.03]
10 Participants experiencing somnolence5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
10.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)3.47 [1.45, 8.33]
10.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)4.01 [2.80, 5.76]
10.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)3.26 [2.59, 4.10]
10.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)4.53 [3.06, 6.70]
11 Participants experiencing dizziness5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
11.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)2.13 [1.18, 3.82]
11.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)3.08 [2.41, 3.93]
11.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)4.22 [3.40, 5.23]
11.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)4.44 [3.42, 5.75]
12 Participants experiencing weight gain5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
12.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)4.96 [1.11, 22.21]
12.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)4.64 [2.73, 7.89]
12.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)4.47 [2.93, 6.83]
12.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)5.37 [3.07, 9.38]
13 Participants experiencing peripheral oedema5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
13.1 Pregabalin 150 mg daily1263Risk Ratio (M-H, Fixed, 95% CI)6.95 [0.87, 55.68]
13.2 Pregabalin 300 mg daily41375Risk Ratio (M-H, Fixed, 95% CI)3.01 [1.69, 5.33]
13.3 Pregabalin 450 mg daily51874Risk Ratio (M-H, Fixed, 95% CI)3.49 [2.08, 5.84]
13.4 Pregabalin 600 mg daily31122Risk Ratio (M-H, Fixed, 95% CI)4.23 [2.40, 7.46]
Analysis 1.1.

Analysis 1.1.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 1 At least 30% pain relief.

Analysis 1.2.

Analysis 1.2.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 2 At least 50% pain relief.

Analysis 1.3.

Analysis 1.3.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 3 Much or very much improved.

Analysis 1.4.

Analysis 1.4.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 4 Very much improved.

Analysis 1.5.

Analysis 1.5.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 5 All-cause withdrawal.

Analysis 1.6.

Analysis 1.6.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 6 Adverse event withdrawal.

Analysis 1.7.

Analysis 1.7.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 7 Lack of efficacy withdrawal.

Analysis 1.8.

Analysis 1.8.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 8 Participants with at least one adverse event.

Analysis 1.9.

Analysis 1.9.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 9 Participants with at least one serious adverse event.

Analysis 1.10.

Analysis 1.10.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 10 Participants experiencing somnolence.

Analysis 1.11.

Analysis 1.11.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 11 Participants experiencing dizziness.

Analysis 1.12.

Analysis 1.12.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 12 Participants experiencing weight gain.

Analysis 1.13.

Analysis 1.13.

Comparison 1 Pregabalin versus placebo (studies of classic design), Outcome 13 Participants experiencing peripheral oedema.

Comparison 2. Pregabalin versus placebo (EERW studies)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Maintenance of therapeutic response2687Risk Ratio (M-H, Fixed, 95% CI)1.90 [1.49, 2.42]
2 All-cause withdrawal2687Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.71, 0.89]
3 Participants with at least one adverse event2687Risk Ratio (M-H, Fixed, 95% CI)1.33 [1.16, 1.51]
Analysis 2.1.

Analysis 2.1.

Comparison 2 Pregabalin versus placebo (EERW studies), Outcome 1 Maintenance of therapeutic response.

Analysis 2.2.

Analysis 2.2.

Comparison 2 Pregabalin versus placebo (EERW studies), Outcome 2 All-cause withdrawal.

Analysis 2.3.

Analysis 2.3.

Comparison 2 Pregabalin versus placebo (EERW studies), Outcome 3 Participants with at least one adverse event.

Appendices

Appendix 1. Methodological considerations for chronic pain

There have been several recent changes in how the efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now better defined, particularly with new criteria for what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with 'any improvement'. Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be of longer duration, up to 12 weeks, and provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, and we are now applying stricter criteria for the inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment. A summary of some of the recent insights that must be considered in this new review follows.

  1. Pain results tend to have a U-shaped distribution rather than a bell-shaped distribution. This is true in acute pain (Moore 2011a; Moore 2011b), back pain (Moore 2010d), and arthritis (Moore 2010c), as well as in fibromyalgia (Straube 2010a); in all cases average results usually describe the experience of almost no one in the trial. Data expressed as averages are potentially misleading, unless they can be proven to be suitable.

  2. As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from pain changes or patient global assessments. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials of less than 12 weeks' duration, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2010c); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic-type pain.

  3. The proportion of patients with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective medicine in arthritis to 30% in fibromyalgia (Moore 2009; Moore 2010c; Moore 2013b; Moore 2014c; Straube 2008; Sultan 2008). A Cochrane review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore 2009). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should not be done unless there are good grounds for doing so.

  4. Individual patient analyses indicate that patients who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way (Moore 2010b; Moore 2014a).

  5. Imputation methods such as last observation carried forward (LOCF), used when participants withdraw from clinical trials, can overstate drug efficacy, especially when adverse event withdrawals with drug are greater than those with placebo (Moore 2012b).

Appendix 2. Search strategy for CENTRAL (via CRSO)

  1. MESH DESCRIPTOR Pain EXPLODE ALL TREES (32202)

  2. MESH DESCRIPTOR Somatosensory Disorders EXPLODE ALL TREES (778)

  3. MESH DESCRIPTOR Fibromyalgia (614)

  4. MESH DESCRIPTOR Myofascial Pain Syndromes EXPLODE ALL TREES (373)

  5. MESH DESCRIPTOR Polymyalgia Rheumatica EXPLODE ALL TREES (44)

  6. ((pain* or discomfort*) and (central or complex or rheumat* or muscl* or muscul* or myofasci* or nerv* or neuralg* or neuropath*)):TI,AB,KY (21303)

  7. (fibromyalgi* or fibrosti* or FM or FMS):TI,AB,KY (2139)

  8. ((neur* or nerv*) and (compress* or damag*)):TI,AB,KY (2286)

  9. 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 (49957)

  10. MESH DESCRIPTOR pregabalin EXPLODE ALL TREES (258)

  11. lyrica:TI,AB,KY (13)

  12. 10 or 11 (267)

  13. 9 and 12 (182)

Appendix 3. Search strategy for MEDLINE (via Ovid)

  1. exp PAIN/ (325527)

  2. exp SOMATOSENSORY DISORDERS/ (17815)

  3. FIBROMYALGIA/ (6858)

  4. exp MYOFASCIAL PAIN SYNDROMES/ (6007)

  5. POLYMYALGIA RHEUMATICA/ (2246)

  6. ((pain* or discomfort*) adj10 (central or complex or rheumat* or muscl* or muscul* or myofasci* or nerv* or neuralg* or neuropath*)).mp. (68934)

  7. (fibromyalgi* or fibrosti* or FM or FMS).mp. (21973)

  8. 1 or 2 or 3 or 4 or 5 or 6 or 7 (382871)

  9. pregabalin.mp. (1266)

  10. Lyrica.mp. (65)

  11. 9 or 10 (1273)

  12. randomized controlled trial.pt. (409198)

  13. controlled clinical trial.pt. (90242)

  14. randomized.ab. (306265)

  15. placebo.ab. (156066)

  16. drug therapy.fs. (1829870)

  17. randomly.ab. (216534)

  18. trial.ab. (315943)

  19. groups.ab. (1370026)

  20. 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 (3471873)

  21. 8 and 11 and 20 (688)

Appendix 4. Search strategy for EMBASE (via Ovid)

  1. exp PAIN/ (964426)

  2. exp SOMATOSENSORY DISORDERS/ (73535)

  3. FIBROMYALGIA/ (15344)

  4. exp MYOFASCIAL PAIN SYNDROMES/ (6916)

  5. POLYMYALGIA RHEUMATICA/ (3408)

  6. ((pain* or discomfort*) adj10 (central or complex or rheumat* or muscl* or muscul* or myofasci* or nerv* or neuralg* or neuropath*)).mp. (133427)

  7. (fibromyalgi* or fibrosti* or FM or FMS).mp. (35108)

  8. 1 or 2 or 3 or 4 or 5 or 6 or 7 (1039981)

  9. exp Pregabalin/ (9173)

  10. Lyrica.mp. (883)

  11. 9 or 10 (9179)

  12. crossover-procedure/ (46381)

  13. double-blind procedure/ (129344)

  14. randomized controlled trial/ (397653)

  15. (random* or factorial* or crossover* or cross over* or cross-over* or placebo* or (doubl* adj blind*) or assign* or allocat*).tw. (1426945)

  16. 12 or 13 or 14 or 15 (1511078)

  17. 8 and 11 and 16 (1241)

Appendix 5. GRADE: criteria for assigning grade of evidence

The GRADE system uses the following criteria for assigning a quality level to a body of evidence (Chapter 12, Higgins 2011).

  • High: randomised trials; or double-upgraded observational studies.

  • Moderate: downgraded randomised trials; or upgraded observational studies.

  • Low: double-downgraded randomised trials; or observational studies.

  • Very low: triple-downgraded randomised trials; or downgraded observational studies; or case series/case reports.

Factors that may decrease the quality level of a body of evidence are:

  • limitations in the design and implementation of available studies suggesting high likelihood of bias;

  • indirectness of evidence (indirect population, intervention, control, outcomes);

  • unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);

  • imprecision of results (wide confidence intervals);

  • high probability of publication bias.

Factors that may increase the quality level of a body of evidence are:

  • large magnitude of effect;

  • all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results show no effect;

  • dose-response gradient.

Appendix 6. Outcome results from individual studies

StudyEfficacyWithdrawalsAt least one AE or a serious AESpecific AE
Classic study design
Arnold 2008

NCT00230776
PGIC much improved:
Pla = 27/184, P300 = 33/183, P450 = 55/190, P600 = 59/188

PGIC very much improved:
Pla = 12/184, P300 = 18/183, P450 = 25/190, P600 = 19/188

PGIC much worse:
Pla = 11/184, P300 = 13/183, P450 = 9/190, P600 = 14/188

PGIC very much worse:
Pla = 11/184, P300 = 3/183, P450 = 2/190, P600 = 3/188

≥ 30% pain improvement:
Pla = 56/184, P300 = 76/183, P450 = 94/190, P600 = 88/188

≥ 50% pain improvement:
Pla = 28/184, P300 = 44/183, P450 = 52/190, P600 = 57/188
Pla:
AC = 59/184
AE = 20/184
LOE = 20/184

P300:
AC = 60/183
AE = 31/183
LOE = 6/183

P450:
AC = 65/190
AE = 43/190
LOE = 6/190

P600:
AC = 75/188
AE = 50/188
LOE = 8/188

≥ 1 AE:
Pla = 132/184
P300 = 148/183

P450 = 167/190
P600 = 165/188


SAE:
Pla = 2/184
P300 = 2/183

P450 = 2/190
P600 = 2/188

Not clear if participant numbers or event numbers (assumed participant numbers)
Top 6 AE by frequency:
Dizziness
Pla = 14/184, P300 = 51/183, P450 = 71/190, P600 = 79/188
Somnolence
Pla = 7/184, P300 = 23/183, P450 = 37/190, P600 = 41/188
Weight gain
Pla = 4/184, P300 = 22/183, P450 = 24/190, P600 = 26/188
Headache
Pla = 19/184, P300 = 14/183, P450 = 24/190, P600 = 14/188
Peripheral oedema
Pla = 5/184, P300 = 12/183, P450 = 12/190, P600 = 23/188
Fatigue
Pla = 8/184, P300 = 151/183, P450 = 11/190, P600 = 17/188
Crofford 2005PGIC much or very much improved:
Pla = 34/131, P150 = 42/132, P300 = 60/134, P450 = 69/132

PGIC very much improved:
Pla = 32/131, P150 = 42/132, P300 = 58/134, P450 = 65/132

≥ 30% pain improvement:
Pla = 36/131, P150 = 41/132, P300 = 51/134, P450 = 64/132

≥ 50% pain improvement:
Pla = 17/131, P150 = 17/132, P300 = 25/134, P450 = 38/132
Pla:
AC = 34/131
AE = 10/131
LOE = 18/131

P150:
AC = 29/132
AE = 11/132
LOE = 12/132

P300:
AC = 23/134
AE = 10/134
LOE = 6/134

P450:
AC = 33/132
AE = 17/132
LOE = 8/132
≥ 1 AE:
Pla = 101/131
P150 = 103/132
P300 = 118/134
P450 = 121/132
Top 6 AE by frequency:
Dizziness
Pla = 14/131, P150 = 30/132,
P300 = 42/134, P450 = 65/132
Somnolence
Pla = 6/131, P150 = 21/132,
P300 = 37/134, P450 = 37/132
Weight gain
Pla = 2/131, P150 = 10/132,
P300 = 13/134, P450 = 9/132
Headache
Pla = 25/131, P150 = 16/132,
P300 = 20/134, P450 = 17/132
Dry mouth
Pla = 2/131, P150 = 9/132,
P300 = 8/134, P450 = 17/132
Peripheral oedema
Pla = 1/131, P150 = 7/132,
P300 = 9/134, P450 = 14/132
Infection
Pla = 22/131, P150 = 11/132,
P300 = 13/134, P450 = 13/132
Mease 2008

NCT00645398
PGIC much improved:
Pla = 41/190, P300 = 48/185, P450 = 45/183, P600 = 54/190

PGIC very much improved:
Pla = 21/190, P300 = 28/185, P450 = 26/183, P600 = 27/190

PGIC much worse:
Pla = 19/190, P300 = 11/185, P450 = 12/183, P600 = 8/190

PGIC very much worse:
Pla = 6/190, P300 = 4/185, P450 = 7/183, P600 = 1/190
Pla:
AC = 60/190
AE = 19/190
LOE = 22/190

P300:
AC = 62/185
AE = 35/185
LOE = 9/185

P450:
AC = 62/183
AE = 41/183
LOE = 6/183

P600:
AC = 79/190
AE = 62/190
LOE = 3/190

≥ 1 AE:
Pla = 144/190
P300 = 165/185

P450 = 168/183

P600 = 179/190

Top 6 AE by frequency:
Dizziness
Pla = 16/190, P300 = 60/185, P450 = 80/183, P600 = 88/190
Somnolence
Pla = 10/190, P300 = 39/185, P450 = 44/183, P600 = 53/190
Weight gain
Pla = 4/190, P300 = 15/185, P450 = 16/183, P600 = 26/190
Headache
Pla = 12/190, P300 = 15/185, P450 = 17/183, P600 = 15/190
Dry mouth
Pla = 4/190, P300 = 14/185, P450 = 19/183, P600 = 20/190
Peripheral oedema
Pla = 2/190, P300 = 5/185, P450 = 4/183, P600 = 10/190
Nausea
Pla = 11/190, P300 = 9/185, P450 = 8/183, P600 = 20/190
Amblyopia (blurred vision)
Pla = 3/190, P300 = 12/185, P450 = 12/183, P600 = 17/190
Nasser 2014

NCT01226667
≥ 30% pain improvement:
ON = 41/89
TD = 35/88

≥ 50% pain improvement:
ON = 27/89
TD = 25/88

Moderately better + better + great deal better:
ON = 48/89
TD = 45/88

Better + great deal better:
ON = 26/89
TD = 24/88
ON:
AC = 29/89
AE = 21/89
LOE = 1/89


TD:
AC = 24/88
AE = 20/88
LOE = 1/88
≥ 1 AE:
ON = 62/89
TD = 74/88
No significant difference in AE
Dizziness
TD = 18/88, ON = 18/89
Somnolence
TD = 8/88, ON = 4/89
Headache
TD = 6/88, ON = 7/89
Blurred vision
TD = 7/88, ON = 8/89
Fatigue
TD = 10/88, ON = 14/89
Oedema
TD = 11/88, ON = 7/89
Cognitive
TD = 14/88, ON = 13/89
Nausea
TD = 3/88, ON = 7/89
Euphoria
TD = 5/88, ON = 1/89
Vertigo
TD = 8/88, ON = 3/89
Ohta 2012

NCT00830167
PGIC much improved:
Pla = 50/248, P300/450 = 65/250

PGIC very much improved:
Pla = 16/248, P300/450 = 31/250

PGIC much worse:
Pla = 13/248, P300/450 = 13/250

PGIC very much worse:
P = 6/287, P300/450 = 4/250

≥ 30% pain improvement:
P = 76/248, P300/450 = 101/250

≥ 50% pain improvement:
P = 30/248, P300/450 = 57/250
Pla:
AC = 40/248
AE = 6/248
LOE = 26/250

P300/450:
AC = 43/250
AE = 19/248
LOE = 10/248
≥ 1 AE:
Pla = 175/248, P300/450 = 225/250


SAE:
Pla = 1/248, P300/450 = 3/250
Somnolence
Pla = 45/248, P300/450 = 116/250
Dizziness
Pla = 15/248, P300/450 = 74/250
Nasopharyngitis
Pla = 45/248, P300/450 = 45/250
Increased weight
Pla = 9/248, P300/450 = 39/250
Constipation
Pla = 17/248, P300/450 = 36/250
Feeling abnormal
Pla = 3/248, P300/450 = 20/250
Peripheral oedema
Pla = 3/248, P300/450 = 18/250
Headache
Pla = 15/248, P300/450 = 15/250
Blurred vision
Pla = 3/248, P300/450 = 13/250
Pauer 2011

NCT00333866
PGIC much improved:
Pla = 43/184, P300 = 45/184, P450 = 50/182, P600 = 46/186

PGIC very much improved:
Pla = 7/184, P300 = 13/184, P450 = 16/182, P600 = 20/186

PGIC much worse:
Pla = 17/184, P300 = 14/184, P450 = 8/182, P600 = 10/186

PGIC very much worse:
Pla = 3/184, P300 = 5/184, P450 = 2/182, P600 = 3/186

≥ 30% pain improvement:
Pla = 35/184, P300 = 61/184, P450 = 62/182, P600 = 48/186

≥ 50% pain improvement:
Pla = 17/184, P300 = 33/184, P450 = 33/182, P600 = 28/186
Pla:
AC = 43/184
AE = 23/184
LOE = 8/184

P300:
AC = 61/184
AE = 37/184
LOE = 6/184

P450:
AC = 65/182
AE = 38/182
LOE = 3/182

P600:
AC = 43/186
AE = 47/186
LOE = 5/186
≥ 1 AE:
Pla = 135/184, P300 = 155/184, P450 = 164/182, P600 = 171/186


SAE:
Pla = 4/184, P300 = 2/184, P450 = 8/182, P600 = 4/186
Top 6 AE by frequency:
Dizziness
Pla = 28/184, P300 = 68/184, P450 = 76/182, P600 = 93/186
Somnolence
Pla = 11/184, P300 = 37/184, P450 = 24/182, P600 = 34/186
Weight increase
Pla = 6/184, P300 = 24/184, P450 = 24/182, P600 = 24/186
Peripheral oedema
Pla = 7/184, P300 = 19/184, P450 = 15/182, P600 = 27/186
Dry mouth
Pla = 4/184, P300 = 16/184, P450 = 20/182, P600 = 20/186
Fatigue
Pla = 15/184, P300 = 14/184, P450 = 26/182, P600 = 17/186
Enriched enrolment randomised withdrawal (EERW) study design
Arnold 2014

NCT01271933
Pla:
AC = 11/58
AE = 0/58


P330-495 CR:
AC = 17/63
AE = 3/63
––≥ 1 AE:
Pla = 39/58
P330-495 CR = 50/63


SAE:
Pla = 0/58
P330-495 CR = 2/63
Dizziness
Pla = 13/58, P330-495 CR = 12/63
Somnolence
Pla = 6/58, P330-495 CR = 6/63
Weight gain
Pla = 6/58, P330-495 CR = 4/63
Headache
Pla = 3/58, P330-495 CR = 2/63
Fatigue
Pla = 5/58, P330-495 CR = 1/63
Nausea
Pla = 5/58, P330-495 CR = 1/63
Peripheral oedema
Pla = 11/58, P330-495 CR = 5/63
Vision blurred
Pla = 4/58, P330-495 CR = 0/63
Dry mouth
Pla = 3/58, P330-495 CR = 6/63
Insomnia
Pla = 7/58, P330-495 CR = 1/63
Disturbance in attention
Pla = 1/58, P330-495 CR = 1/63
Nasopharyngitis
Pla = 1/58, P330-495 CR = 3/63
Crofford 2008Pla:
AC = 232/287
AE = 20/287

P300:
AC = 30/63
AE = 12/63

P450:
AC = 24/73
AE = 13/73

P600:
AC = 53/143
AE = 22/143
––≥ 1 AE:
Pla = 129/287
P300 = 37/63
P450 = 46/73
P600 = 89/143

SAE:
Pla = 3/287
P300 = 1/63
P450 = 0/73
P600 = 7/143

Deaths: 2
Participant no.:
Top 6 AE by frequency:
Insomnia
Pla = 18/287, P300 = 5/63,
P450 = 2/73, P600 = 9/143
Nausea
Pla = 13/287, P300 = 4/63,
P450 = 5/73, P600 = 5/143
Anxiety
Pla = 5/287, P300 = 3/63,
P450 = 3/73, P600 = 8/143
Arthralgia
Pla = 5/287, P300 = 3/63,
P450 = 5/73, P600 = 6/143
Sinusitis
Pla = 8/287, P300 = 1/63,
P450 = 4/73, P600 = 9/143
Influenza
Pla = 3/287, P300 = 3/63,
P450 = 3/73, P600 = 7/143
Weight gain
Pla = 1/287, P300 = 1/63,
P450 = 3/73, P600 = 6/143
Peripheral oedema:
Pla = 2/287, P300 = 2/63,
P450 = 3/73, P600 = 3/143

No information on dizziness and somnolence because patients with these AE at the end of open label treatment were censored.
AC: all cause; AE: adverse event; CR: controlled release; LOE: lack of efficacy; ON: once nightly; P[number]: pregabalin[dose in mg]; PGIC: Patient Global Impression of Change; Pla: placebo; SAE: serious adverse event; TD: twice daily

What's new

DateEventDescription
12 January 2017AmendedMinor typo corrected: 'x pathology' changed to 'pathology' in Description of the condition.

History

Protocol first published: Issue 7, 2015
Review first published: Issue 9, 2016

DateEventDescription
30 September 2016Review declared as stableSee Published notes.

Contributions of authors

MC and PW carried out searches and selected studies for inclusion. RAM and SD carried out data extraction, assessed risk of bias, and carried out analyses. All authors were involved in writing the final review. All authors will be involved in any future updates.

Declarations of interest

SD: none known.

MC: none known.

PW: none known.

SL: none known; SL is a specialist pain physician and manages patients with fibromyalgia.

TP: none known; TP is a specialist pain physician and manages patients with fibromyalgia.

RAM has received grant support from RB relating to individual patient level analyses of trial data on ibuprofen in acute pain and the effects of food on drug absorption of analgesics (2013), and from Grünenthal relating to individual patient level analyses of trial data regarding tapentadol in osteoarthritis and back pain (2015). He has received honoraria for attending boards with Menarini concerning methods of analgesic trial design (2014), with Novartis (2014) about the design of network meta-analyses, and RB on understanding pharmacokinetics of drug uptake (2015).

Sources of support

Internal sources

  • Oxford Pain Relief Trust, UK.

    General institutional support

External sources

  • The National Institute for Health Research (NIHR), UK.

    NIHR Cochrane Programme Grant: 13/89/29 - Addressing the unmet need of chronic pain: providing the evidence for treatments of pain

Differences between protocol and review

Minor differences exist between protocol and review, mainly relating to the improvements in knowledge that have occurred, for example studies had to have at least 20 participants per treatment arm to be included, and we used GRADE to assess the quality of the evidence and included 'Summary of findings' tables.

For the EERW trials, we used the outcome 'maintenance of therapeutic response' (MTR), which was not in the protocol, but is equivalent to 'moderate benefit'.

Notes

A new search within two years is not likely to identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors. If appropriate, we will update the review if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arnold 2008

Methods14-week randomised, placebo-controlled, double-blind, parallel-group trial
Participants

Fibromyalgia according to ACR classification and pain of at least 40/100 mm and pain score ≥ 4 on 11-point numerical rating scale in week before randomisation

N = 750 (745 analysed)

Mean age 50 years, 95% female, 91% white

Baseline pain: 6.7/10

Interventions

1-week single-blinded placebo run-in phase, 2-week double-blinded dose escalation phase, 12-week fixed dose

Pregabalin 300 mg daily, n = 183

Pregabalin 450 mg daily, n = 190

Pregabalin 600 mg daily, n = 188

Placebo daily, n = 184

Outcomes

Proportion of participants with ≥ 30% or ≥ 50% decrease in mean pain score between endpoint and baseline

PGIC (7-point scale from very much improved to very much worse)

Adverse events

Withdrawals

Notes

Pfizer Global Research and Development sponsored. LOCF used to account for missing data and withdrawals

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Random assignment to treatment regimens used a 1:1:1:1 ratio according to a computer generated pseudo-random code using the method of random permuted blocks"
Allocation concealment (selection bias)Low risk"Random assignment was managed by a tele-randomisation system"
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"To maintain the blinding, all doses of pregabalin and placebo were packaged using identical encapsulation" "were identical in appearance and taste from which they took 1 capsule twice a day"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"To maintain the blinding, all doses of pregabalin and placebo were packaged using identical encapsulation"; "were identical in appearance and taste from which they took 1 capsule twice a day"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF imputation
Selective reporting (reporting bias)Low riskAll relevant outcomes reported
SizeUnclear risk50 to 199 participants per treatment arm (183 to 190)

Arnold 2014

Methods13-week multicentre, controlled-release, double-blind, placebo-controlled, EERW trial
Participants

Fibromyalgia according to ACR classification and pain diary score ≥ 4 on 11-point numerical rating scale

N = 441 entered titration phase, 121 randomised to double-blind phase

Mean age 50 years, 91% female, 90% white

Baseline mean pain score: 6.8/10

Interventions

4 phases: 1) baseline (1 week), 2) single-blind (participants were blinded) treatment (6 weeks), 3) double-blind treatment (13 weeks), and 4) a double-blind taper period (1 week)

Pregabalin controlled release 330 to 495 mg daily, n = 63

Placebo, n = 58

Outcomes

PI on an 11-point numerical rating scale, using daily pain diary

Adverse events

Withdrawals

Notes

Pfizer sponsored

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described, "randomly assigned"
Allocation concealment (selection bias)Low risk"telephone using the Interactive Voice Recognition System (IVRS)"
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated to be double blind. Used a matching placebo
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated to be double blind. Used a matching placebo
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants included in analysis
Selective reporting (reporting bias)Low riskAll relevant outcomes reported
SizeUnclear risk50 to 199 participants per treatment arm (58, 63)

Crofford 2005

Methods8-week multicentre, randomised, double-blind, placebo-controlled, parallel-group trial
Participants

Fibromyalgia according to ACR classification. Pain of at least 40/100 mm and pain diary score ≥ 4 on 11-point numerical rating scale in week before randomisation

N = 529

Mean age 49 years, 92% female, 93% white

Baseline mean pain score: 7/10

Interventions

8-week fixed dose (except for pregabalin 450 mg/day who received 300 mg/day for the first 3 days, and then 450 mg/day)

Pregabalin 150 mg daily, n = 132

Pregabalin 300 mg daily, n = 134

Pregabalin 450 mg daily, n = 132

Placebo daily, n = 131

Outcomes

Proportion of participants with ≥ 30% or ≥ 50% decrease in mean pain score between endpoint and baseline

PGIC (7-point scale from very much improved to very much worse)

Adverse events

Withdrawals

Notes

Pfizer Global Research and Development sponsored. LOCF used to account for missing data and participant withdrawn

Oxford Quality Score: R2, DB1, W1. Total = 4/5

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomisation was by computer-generated code using a block size of 8"
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDescribed as double blind, no details of method used
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskDescribed as double blind, no details of method used
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF imputation
Selective reporting (reporting bias)Low riskAll relevant outcomes reported
SizeUnclear risk50 to 199 participants per treatment arm (131 to 134)

Crofford 2008

Methods26-week randomised, double-blind, placebo-controlled, parallel-group, EERW trial. Participants initially screened for response (≥ 50% decrease in pain and PGIC of much or very much improved). Responders to initial titration selected for randomisation to placebo or continued use of tolerated effective dose
Participants

Fibromyalgia according to ACR classification and pain of at least 40/100 mm in week before randomisation, with 6 months of follow-up

N = 1051 entered open-label phase (6 weeks); 566 randomised to double-blind phase (26 weeks)

Mean age 49 years, 93.5% female, 90% white

Baseline mean pain: 78/100

Interventions

Pregabalin titrated to a maximum of 600 mg daily, n = 279 (300 mg = 63; 450 mg = 73; 600 mg = 143)

Placebo daily, n = 287

Outcomes

Loss of therapeutic response (worsening of pain or other symptoms, pain reduction less than 30% of baseline on several occasions, withdrawal) measured in days, converted to maintenance of therapeutic response for analysis

Adverse events

Withdrawals

Notes

Pfizer Global Research and Development sponsored

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

"A tele-randomisation system randomised responders to either matching placebo or optimal open label dosage of pregabalin (1:1)"

Review authors judged this low risk, assuming computer generation

Allocation concealment (selection bias)Low riskTele-randomisation system
Blinding of participants and personnel (performance bias)
All outcomes
Low risk"matching placebo or optimal open-label dosage of pregabalin"
Blinding of outcome assessment (detection bias)
All outcomes
Low risk"matching placebo or optimal open-label dosage of pregabalin"
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants included in analysis
Selective reporting (reporting bias)Low riskAll relevant outcomes reported
SizeLow risk> 200 participants per treatment arm

Mease 2008

Methods12-week multicentre, randomised, double-blind, placebo-controlled, parallel-group trial
Participants

Fibromyalgia according to ACR classification and pain of at least 40/100 mm in week before randomisation

N = 748

Mean age 49 years, 94% female, 90% white

Baseline mean pain: 7.1/10

Interventions

1-week dose escalation (all participants started at 150 mg), 12 weeks with fixed dose

Pregabalin 300 mg daily, n = 185

Pregabalin 450 mg daily, n = 183

Pregabalin 600 mg daily, n = 190

Placebo daily, n = 190

Outcomes

Proportion of participants with ≥ 50% decrease in mean pain score

PGIC (7-point scale from very much improved to very much worse) between endpoint and baseline

Adverse events

Withdrawals

Notes

Pfizer sponsored. LOCF used to account for missing data and participant withdrawn

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated to be randomised. Method of sequence generation not described
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated to be double blind, method not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStated to be double blind, method not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF imputation
Selective reporting (reporting bias)Low riskAll relevant outcomes reported
SizeUnclear risk50 to 199 participants per treatment arm (183 to 190)

Nasser 2014

Methods8-week multicentre, randomised, double-blind comparison of 2 dosing schedules
Participants

Females with fibromyalgia according to ACR classification and pain diary score ≥ 4 on 11-point numerical rating scale

N = 177

Mean age 50 years, 96% white

Baseline mean pain: 7.1/10

Interventions300 mg dose taken once nightly (placebo in the morning) or as a divided dose, twice daily
Once nightly (week 1: 75 mg; week 2: 150 mg; week 3: 225 mg; weeks 4 to 8: 300 mg; week 9: taper dose, n = 89)
Twice daily (week 1: 75 mg x 2; week 2 to 8: 150 mg x 2; week 9: taper dose, n = 88)
Outcomes

Proportion of participants with ≥ 30% or ≥ 50% decrease in mean pain score between endpoint and baseline

PGIC (7-point scale from very much improved to very much worse)

Adverse events

Withdrawals

Notes

Pfizer sponsored

Oxford Quality Score: R2, DB2, W1. Total = 4/5

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomised using a random number generator to assign patients to either group"
Allocation concealment (selection bias)Unclear riskMethod not described
Blinding of participants and personnel (performance bias)
All outcomes
Low riskStated to be double blind, placebo replaced morning dose for nightly dosing (judged as low risk)
Blinding of outcome assessment (detection bias)
All outcomes
Low riskStated to be double blind, placebo replaced morning dose for nightly dosing (judged as low risk)
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF imputation
Selective reporting (reporting bias)Low riskAll relevant outcomes reported
SizeUnclear risk50 to 199 participants per treatment arm (88 and 89)

Ohta 2012

Methods12-week multicentre, randomised, double-blind, placebo-controlled trial
Participants

Japanese participants with fibromyalgia according to ACR classification. Pain of ≥ 40/100 mm and pain diary score ≥ 4 on 11-point numerical rating scale before randomisation

N = 498

Mean age 48 years, 89% female

Baseline mean pain: 6.5/10

Interventions

4 phases: 1-week single-blind run-in period, 3-week dose escalation, 12-week fixed dose at 300 or 450 mg, 1-week taper phase

Pregabalin all doses, n = 250

Placebo, n = 248

Outcomes

Proportion of participants with ≥ 30% or ≥ 50% decrease in mean pain score

PGIC (7-point scale from very much improved to very much worse) between endpoint and baseline

Adverse events

Withdrawals

Notes

Pfizer sponsored

Oxford Quality Score: R2, DB2, W1. Total = 5/5

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomisation control system (IMPALA), which provided subject randomisation numbers"
Allocation concealment (selection bias)Low risk"Randomisation control system (IMPALA), which provided subject randomisation numbers". Review authors judged this as low risk, assuming remote allocation
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

"Pregabalin and placebo capsules were prescribed by the investigator using blinded drug numbers issued by IMPALA"

"identical placebo"

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

"Pregabalin and placebo capsules were prescribed by the investigator using blinded drug numbers issued by IMPALA"

"identical placebo"

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF imputation
Selective reporting (reporting bias)Low riskAll relevant outcomes reported
SizeLow risk> 200 participants per treatment arm (248 and 250)

Pauer 2011

  1. a

    ACR: American College of Rheumatology; DB: double-blind; EERW: enriched enrolment randomised withdrawal; LOCF: last observation carried forward; N: number of participants in study; n: number of participants in treatment arm; PGIC: Patient Global Impression of Change; PI: pain intensity; R: randomised; W: withdrawals

Methods14-week multicentre, randomised, double-blind, placebo-controlled trial
Participants

Fibromyalgia according to ACR classification. Pain ≥ 40/100 mm and pain diary score ≥ 4 on 11-point numerical rating scale in week before randomisation

N = 747

Mean age 49 years, 91% female, 76% white

Baseline mean pain score: 6.7/10

Interventions

1-week placebo run-in phase, 2-week randomised dose escalation phase, 12-week fixed-dose phase

Placebo, n = 184

Pregabalin 300 mg, n = 184

Pregabalin 450 mg, n = 182

Pregabalin 600 mg, n = 186

Outcomes

Proportion of participants with ≥ 30% or ≥ 50% decrease in mean pain score between endpoint and baseline

PGIC (7-point scale from very much improved to very much worse)

Adverse events

Withdrawals

Notes

Pfizer Global Research and Development sponsored. LOCF used to account for missing data and participant withdrawn

Oxford Quality Score: R1, DB1, W1. Total = 3/5

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStated to be randomised. Method of sequence generation not described
Allocation concealment (selection bias)Unclear riskMethod not described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStated to be double blind. Method not described
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskStated to be double blind. Method not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLOCF imputation
Selective reporting (reporting bias)Low riskAll relevant outcomes reported
SizeUnclear risk50 to 199 participants per treatment arm (182 to 186)

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomised controlled trial

Arnold 2012Pooled analysis
Arnold 2015Cross-over: 3-week escalation, 3-week fixed dose, 2-week taper/placebo washout period
Byon 2010Summary
Emir 2010Summary of 4 RCTs
NCT007604744-week study only
NCT01268631Cross-over 2 x 2 weeks
NCT01904097Single blind
Ohta 2013Non-randomised, open-label extension trial
Ramzy 2016Participants already taking pregabalin randomised to 1 of 3 antidepressants
Roth 20124-week study on sleep maintenance in people with fibromyalgia
Russell 2009Summary of 2 RCTs

Characteristics of ongoing studies [ordered by study ID]

NCT01387607

Trial name or titleA 14-week, randomized, double-blind placebo-controlled study for pregabalin in subjects with fibromyalgia
Methods14-week randomised, parallel, double-blind, placebo-controlled study
Participants

Estimated: 324

Fibromylagia (ACR), pain intensity ≥ 40/100

Men and women over 18 years

Interventions

Pregabalin capsule, 300 to 450 mg/day, twice daily

Placebo, twice daily

Outcomes

Relief of pain associated with fibromyalgia by comparing with the baseline, the difference for endpoint mean pain score (the mean of the last 7 pain diary entries) in the double-blind treatment period between pregabalin and placebo groups

Fibromyalgia symptoms

Adverse events

Withdrawals

Starting dateFebruary 2012
Contact informationPfizer
Notes

Recruiting, estimated completion date: November 2016

Record verified February 2016

NCT02146430

Trial name or titleA randomized, double-blind, placebo- and active-controlled study of DS-5565 for treatment of pain associated with fibromyalgia
Methods13-week randomised, parallel, double-blind, placebo- and active-controlled study
Participants

N = 1294

Fibromylagia (ACR), pain intensity ≥ 40/100

Men and women over 18 years

Interventions

DS-5565 (mirogabalin) 15 mg tablet, once daily

DS-5565 (mirogabalin) 15 mg tablet, twice daily

Pregabalin 150 mg capsule, twice daily

Placebo tablet matching DS-5565 tablet

Placebo capsule matching pregabalin capsule

Participants take half daily dose in first week

Outcomes

≥ 30% and ≥ 50% responders at 13 weeks

PGIC

Fibromyalgia symptoms

Adverse events

Withdrawals

Starting dateMay 2014
Contact informationDaiichi Sankyo Inc, Domenico Merante, MD
Notes

Estimated completion date: February 2017

Record verified March 2016

NCT02187159

  1. a

    ACR: American College of Rheumatology; PGIC: Patient Global Impression of Change

Trial name or titleA randomized, double-blind, placebo- and active-controlled study of DS-5565 for treatment of pain associated with fibromyalgia
Methods13-week randomised, parallel, double-blind, placebo- and active-controlled study
Participants

Estimated 1270

Fibromylagia (ACR), pain intensity ≥ 40/100

Men and women over 18 years

Interventions

DS-5565 15 mg tablet

150 mg pregabalin capsule

Placebo tablet matching DS-5565 tablet

Placebo capsule matching pregabalin capsule

75 mg pregabalin capsule

OutcomesChange in weekly average daily pain score, DS-5565 versus placebo
Starting dateOctober 2014
Contact informationDaiichi Sankyo Inc, Domenico Merante, MD
NotesEstimated completion date: March 2017