Neuropathic pain clinical trials: factors associated with decreases in estimated drug efficacy

Abstract

Multiple recent pharmacological clinical trials in neuropathic pain have failed to show beneficial effect of drugs with previously demonstrated efficacy, and estimates of drug efficacy seems to have decreased with accumulation of newer trials. However, this has not been systematically assessed. Here, we analyze time-dependent changes in estimated treatment effect size in pharmacological trials together with factors that may contribute to decreases in estimated effect size. This study is a secondary analysis of data from a previous published NeuPSIG systematic review and meta-analysis, updated to include studies published up till March 2017. We included double-blind, randomized, placebo-controlled trials examining the effect of drugs for which we had made strong or weak recommendations for use in neuropathic pain in the previously published review. As the primary outcome, we used an aggregated number needed to treat for 50% pain reduction (alternatively 30% pain reduction or moderate pain relief). Analyses involved 128 trials. Number needed to treat values increased from around 2 to 4 in trials published between 1982 and 1999 to much higher (less effective) values in studies published from 2010 onwards. Several factors that changed over time, such as larger study size, longer study duration, and more studies reporting 50% or 30% pain reduction, correlated with the decrease in estimated drug effect sizes. This suggests that issues related to the design, outcomes, and reporting have contributed to changes in the estimation of treatment effects. These factors are important to consider in design and interpretation of individual study data and in systematic reviews and meta-analyses.

Neuropathic Pain in Low Back-Related Leg Pain Patients: What Is the Evidence of Prevalence, Characteristics, and Prognosis in Primary Care? A Systematic Review of the Literature

“…Identification of mechanisms that underlie the development and persistence of back pain presentations, and the development of and testing of ways to better match treatment to patients, are both internationally agreed research priorities 14 . There are specific medication options for patients with neuropathic pain, based on underlying mechanisms that may M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 7 accompany nerve damage 20 and these are advocated for patients (including those with sciatica) consulting in primary care 43,44 . Recognising neuropathic pain in LBLP patients in primary care is important as this may facilitate timely access to recommended medications, if deemed appropriate, which in turn may contribute to better outcomes for these patient.…”

“…With the addition of appropriate findings from diagnostic tests, a patient can meet the criteria for probable neuropathic pain. When clinical examination is not possible in epidemiological research, (for example, Torrance et al 54 and VanDenKerfhof et al 60 ) neuropathic case ascertainment tools use self-reported neuropathic characteristics (for example, Self-report version of Leeds Assessment of Neuropathic Symptoms and Signs (S-LANSS) 8 to identify, at best, possible cases of neuropathic pain 20,52 .…”

Botulinum toxin and neuropathic pain: New contributions

“…Como sabemos, el dolor neuropático es un trastorno de dolor crónico debilitante y presenta unas necesidades médicas insatisfechas (7). La mayoría de los medicamentos utilizados para el tratamiento del dolor neuropático tienen limitados la dosis efectiva por efectos secundarios, por lo que se necesitan fármacos efectivos sin los efectos secundarios sistémicos (8). Los datos publicados sugieren que la toxina botulínica tipo A tiene efectos analgésicos contra el dolor neuropático periférico (3,8).…”

“…Se identificaron dos ensayos controlados aleatorios adicionales que cumplieron con los criterios de calidad, pero estos estudios se centraron específicamente en la neuralgia del trigémino, que está fuera de los criterios de inclusión de este estudio que acabamos de comentar. La evidencia existente es compatible con el uso de antidepresivos tricíclicos, antidepresivos inhibidores de la recaptación de serotoninanoradrenalina, pregabalina, gabapentina (incluyendo la formulación de liberación prolongada) y enacarbil gabapentina, tramadol, opioides fuertes y los tratamientos tópicos, apósitos de lidocaína 5 % y parches de capsaicina 8 % para el tratamiento de dolor neuropático periférico (8).…”

“…Para la toxina botulínica tipo A, la evidencia disponible, según este metanálisis, de cuatro ensayos controlados aleatorizados (para el dolor neuropático periférico) sugería una eficacia, con un bajo número necesario a tratar de 1•9, mientras que en el estudio no publicado multicéntrico de una mayor escala, este tratamiento fue ineficaz (9). Por tanto, según este metanálisis la toxina botulínica tipo A constituiría una tercera línea de tratamiento en dolor neuropático periférico (8). Sin embargo, los estudios incluidos en esta revisión tenían varias limitaciones y fueron realizados en un solo centro, lo que podría explicar los bajos números reportados necesarios para el tratamiento, ya que los estudios pequeños, en general, tienden a sobrestimar la eficacia.…”