Effectiveness of non-pharmacological interventions for fibromyalgia and quality of review methods: an overview of Cochrane Reviews.

BACKGROUND: Fibromyalgia syndrome (FMS) is defined as chronic widespread pain associated with sleep disorders, cognitive dysfunction, and somatic symptoms present for at least three months and cannot be better explained by another diagnosis. OBJECTIVES: To examine efficacy and safety of non-pharmacological interventions for FMS in adults reported in Cochrane Reviews, and reporting quality of reviews. METHODS: Systematic reviews of randomised controlled trials (RCTs) of non-pharmacological interventions for FMS were identified from the Cochrane Database of Systematic Reviews (CDSR 2022, Issue 3 and CDSR 2023 Issue 6). Methodological quality was assessed using the AMSTAR-2 tool and a set of methodological criteria critical for analgesic effects. The primary efficacy outcomes of interest were clinically relevant pain relief, improvement in health-related quality of life (HRQoL), acceptability, safety, and reduction of mobility difficulties as reported by study participants. No pooled analyses were planned. We assumed a clinically relevant improvement was a minimal clinically important difference (MCID) between interventions and controls of 15%, or a SMD of more than 0.2, or a MD of more than 0.5, on a 0 to 10 scale. RESULTS: Ten Cochrane reviews were eligible, reporting 181 randomized or quasi- randomized trials (11,917 participants, average trial size 66 participants). The reviews examined exercise training, acupuncture, transcutaneous electrical nerve stimulation, and psychological therapies. One review was rated moderate according to AMSTAR 2, seven were rated low and two were rated critically low. All reviews met most of the additional methodological quality criteria. All reviews included studies with patient-reported outcomes for pain. We found low certainty evidence of clinically relevant positive effects of aerobic and mixed exercise training and for cognitive behavioural therapies (CBTs) at reducing mobility difficulties and for mixed exercise training and CBTs for improving HRQoL at the end of the intervention. Number needed to treat for an additional beneficial outcome (NNTB) values for a MCID of 15% ranged between 4 and 9. We found low certainty evidence that was clinically relevant for mixed exercise and CBTs for reducing mobility difficulties at an average follow up of 24 weeks. We found low certainty evidence of clinically relevant positive effects of mixed exercise on HRQoL at an average follow up of 24 weeks. NNTB values for a MCID of 15% ranged from 5 to 11. The certainty of evidence of the acceptability (measured by dropouts) of the different non-pharmacological interventions ranged from very low to moderate and the dropout rate for any reason did not differ across the interventions or the controls, except for biofeedback and movement therapies. All the systematic reviews stated that the reporting of adverse events was inconsistent in the studies analysed (very low certainty evidence). AUTHORS' CONCLUSIONS: There is low certainty evidence of clinically relevant reduction of mobility difficulties and of improvement of HRQoL among individuals with FMS by aerobic and mixed exercise training and by CBTs at the end of the intervention. There is low certainty evidence that CBTs and mixed exercise training reduces mobility difficulties post-treatment and that mixed exercise training improves HRQoL at follow-up by clinically meaningful scores.

Trials We Cannot Trust: Investigating Their Impact on Systematic Reviews and Clinical Guidelines in Spinal Pain.

We previously conducted an exploration of the trustworthiness of a group of clinical trials of cognitive-behavioral therapy and exercise in spinal pain. We identified multiple concerns in 8 trials, judging them untrustworthy. In this study, we systematically explored the impact of these trials ("index trials") on results, conclusions, and recommendations of systematic reviews and clinical practice guidelines (CPGs). We conducted forward citation tracking using Google Scholar and the citationchaser tool, searched the Guidelines International Network library and National Institute of Health and Care Excellence archive to June 2022 to identify systematic reviews and CPGs. We explored how index trials impacted their findings. Where reviews presented meta-analyses, we extracted or conducted sensitivity analyses for the outcomes of pain and disability, to explore how the exclusion of index trials affected effect estimates. We developed and applied an 'Impact Index' to categorize the extent to which index studies impacted their results. We included 32 unique reviews and 10 CPGs. None directly raised concerns regarding the veracity of the trials. Across meta-analyses (55 comparisons), the removal of index trials reduced effect sizes by a median of 58% (Inter Quartlie Range (IQR) 40-74). 85% of comparisons were classified as highly, 3% as moderately, and 11% as minimally impacted. Nine out of 10 reviews conducting narrative synthesis drew positive conclusions regarding the intervention tested. Nine out of 10 CPGs made positive recommendations for the intervention(s) evaluated. This cohort of trials, with concerns regarding trustworthiness, has substantially impacted the results of systematic reviews and guideline recommendations. PERSPECTIVE: We found that a group of trials of CBT for spinal pain with concerns relating to their trustworthiness has had substantial impacts on the analyses and conclusions of systematic reviews and clinical practice guidelines. This highlights the need for a greater focus on the trustworthiness of studies in evidence appraisal. PRE-REGISTRATION: Our protocol was preregistered on the Open Science Framework: https://osf.io/m92ax/.

Characteristics of retracted publications related to pain research: a systematic review.

ABSTRACT: Retraction is a mechanism for correcting the scientific record and alerts readers when a study contains unreliable or flawed data. Such data may arise from error or research misconduct. Studies examining the landscape of retracted publications provide insight into the extent of unreliable data and its effect on a medical discipline. We aimed to explore the extent and characteristics of retracted publications in pain research. We searched the EMBASE, PubMed, CINAHL, PsycINFO, and Retraction Watch databases to December 31, 2022. We included retracted articles that (1) investigated mechanisms of painful conditions, (2) tested treatments that aimed to reduce pain, or (3) measured pain as an outcome. Descriptive statistics were used to summarise the included data. We included 389 pain articles published between 1993 and 2022 and retracted between 1996 and 2022. There was a significant upward trend in the number of retracted pain articles over time. Sixty-six percent of articles were retracted for reasons relating to misconduct. The median (interquartile range) time from article publication to retraction was 2 years (0.7-4.3). The time to retraction differed by reason for retraction, with data problems, comprising data falsification, duplication, and plagiarism, resulting in the longest interval (3 [1.2-5.2] years). Further investigations of retracted pain articles, including exploration of their fate postretraction, are necessary to determine the impact of unreliable data on pain research.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

BACKGROUND: Pain is a common symptom in people with cancer; 30% to 50% of people with cancer will experience moderate-to-severe pain. This can have a major negative impact on their quality of life. Opioid (morphine-like) medications are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. Pain is not sufficiently relieved by opioid medications in 10% to 15% of people with cancer. In people with insufficient relief of cancer pain, new analgesics are needed to effectively and safely supplement or replace opioids. OBJECTIVES: To evaluate the benefits and harms of cannabis-based medicines, including medical cannabis, for treating pain and other symptoms in adults with cancer compared to placebo or any other established analgesic for cancer pain. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 26 January 2023. SELECTION CRITERIA: We selected double-blind randomised, controlled trials (RCT) of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment for cancer pain in adults, with any treatment duration and at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The primary outcomes were 1. proportions of participants reporting no worse than mild pain; 2. Patient Global Impression of Change (PGIC) of much improved or very much improved and 3. withdrawals due to adverse events. Secondary outcomes were 4. number of participants who reported pain relief of 30% or greater and overall opioid use reduced or stable; 5. number of participants who reported pain relief of 30% or greater, or 50% or greater; 6. pain intensity; 7. sleep problems; 8. depression and anxiety; 9. daily maintenance and breakthrough opioid dosage; 10. dropouts due to lack of efficacy; 11. all central nervous system adverse events. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified 14 studies involving 1823 participants. No study assessed the proportions of participants reporting no worse than mild pain on treatment by 14 days after start of treatment. We found five RCTs assessing oromucosal nabiximols (tetrahydrocannabinol (THC) and cannabidiol (CBD)) or THC alone involving 1539 participants with moderate or severe pain despite opioid therapy. The double-blind periods of the RCTs ranged between two and five weeks. Four studies with a parallel design and 1333 participants were available for meta-analysis. There was moderate-certainty evidence that there was no clinically relevant benefit for proportions of PGIC much or very much improved (risk difference (RD) 0.06, 95% confidence interval (CI) 0.01 to 0.12; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 8 to 100). There was moderate-certainty evidence for no clinically relevant difference in the proportion of withdrawals due to adverse events (RD 0.04, 95% CI 0 to 0.08; number needed to treat for an additional harmful outcome (NNTH) 25, 95% CI 16 to endless). There was moderate-certainty evidence for no difference between nabiximols or THC and placebo in the frequency of serious adverse events (RD 0.02, 95% CI -0.03 to 0.07). There was moderate-certainty evidence that nabiximols and THC used as add-on treatment for opioid-refractory cancer pain did not differ from placebo in reducing mean pain intensity (standardised mean difference (SMD) -0.19, 95% CI -0.40 to 0.02). There was low-certainty evidence that a synthetic THC analogue (nabilone) delivered over eight weeks was not superior to placebo in reducing pain associated with chemotherapy or radiochemotherapy in people with head and neck cancer and non-small cell lung cancer (2 studies, 89 participants, qualitative analysis). Analyses of tolerability and safety were not possible for these studies. There was low-certainty evidence that synthetic THC analogues were superior to placebo (SMD -0.98, 95% CI -1.36 to -0.60), but not superior to low-dose codeine (SMD 0.03, 95% CI -0.25 to 0.32; 5 single-dose trials; 126 participants) in reducing moderate-to-severe cancer pain after cessation of previous analgesic treatment for three to four and a half hours (2 single-dose trials; 66 participants). Analyses of tolerability and safety were not possible for these studies. There was low-certainty evidence that CBD oil did not add value to specialist palliative care alone in the reduction of pain intensity in people with advanced cancer. There was no difference in the number of dropouts due to adverse events and serious adverse events (1 study, 144 participants, qualitative analysis). We found no studies using herbal cannabis. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that oromucosal nabiximols and THC are ineffective in relieving moderate-to-severe opioid-refractory cancer pain. There is low-certainty evidence that nabilone is ineffective in reducing pain associated with (radio-) chemotherapy in people with head and neck cancer and non-small cell lung cancer. There is low-certainty evidence that a single dose of synthetic THC analogues is not superior to a single low-dose morphine equivalent in reducing moderate-to-severe cancer pain. There is low-certainty evidence that CBD does not add value to specialist palliative care alone in the reduction of pain in people with advanced cancer.

ANTECEDENTES: El dolor es un síntoma común en las personas con cáncer; entre el 30% y el 50% de las personas con cáncer experimentarán dolor de moderado a intenso. Esto puede tener un gran impacto negativo en su calidad de vida. Los fármacos opiáceos (similares a la morfina) se utilizan habitualmente para tratar el dolor por cáncer moderado o intenso, y se recomiendan para este propósito en la escala de tratamiento del dolor de la Organización Mundial de la Salud (OMS). El dolor no se alivia lo suficiente con los medicamentos opiáceos en el 10% al 15% de las personas con cáncer. En las personas con un alivio insuficiente del dolor por cáncer, se necesitan nuevos analgésicos que complementen o sustituyan de forma eficaz y segura a los opiáceos. OBJETIVOS: Evaluar los efectos beneficiosos y perjudiciales de los medicamentos con cannabis, incluido el cannabis medicinal, para tratar el dolor y otros síntomas en adultos con cáncer en comparación con placebo o cualquier otro analgésico establecido para el dolor por cáncer. MÉTODOS DE BÚSQUEDA: Se utilizaron los métodos exhaustivos estándar de búsqueda de Cochrane. La última fecha de búsqueda fue el 26 de enero de 2023. CRITERIOS DE SELECCIÓN: Se seleccionaron los ensayos controlados aleatorizados (ECA) doble ciego de cannabis medicinal, medicamentos derivados de plantas y sintéticos con cannabis versus placebo o cualquier otro tratamiento activo para el dolor por cáncer en adultos, con cualquier duración del tratamiento y al menos 10 participantes por grupo de tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se utilizaron los métodos estándar de Cochrane. Los desenlaces principales fueron los siguientes: 1. proporción de participantes que declararon dolor leve; 2. Patient Global Impression of Change (PGIC) de mucha o muchísima mejoría y 3. retiros debido a eventos adversos. Los desenlaces secundarios fueron 4. número de participantes que declararon un alivio del dolor del 30% o superior y un consumo general de opiáceos reducido o estable; 5. número de participantes que declararon un alivio del dolor del 30% o superior, o del 50% o superior; 6. intensidad del dolor; 7. problemas de sueño; 8. depresión y ansiedad; 9. dosis diaria de opiáceos de mantenimiento y de inicio; 10. abandonos por falta de eficacia; 11. todos los eventos adversos del sistema nervioso central. Se utilizó el método GRADE para evaluar la calidad de la evidencia de cada desenlace. RESULTADOS PRINCIPALES: Se identificaron 14 estudios con 1823 participantes. Ningún estudio evaluó las proporciones de participantes que declararon un dolor no peor que leve a los 14 días de inicio del tratamiento. Se encontraron cinco ECA que evaluaron nabiximoles oromucosos (tetrahidrocannabinol [THC] y cannabidiol [CBD]) o THC solo, con 1539 participantes con dolor moderado o intenso a pesar del tratamiento con opiáceos. Los periodos doble ciego de los ECA variaron entre dos y cinco semanas. Para el metanálisis se dispuso de cuatro estudios con un diseño paralelo y 1333 participantes. Hubo evidencia de certeza moderada de que no hubo efectos beneficiosos clínicamente relevantes en las proporciones de PGIC de mucha o muchísima mejoría (diferencia de riesgos [DR] 0,06; intervalo de confianza [IC] del 95%: 0,01 a 0,12; número necesario a tratar para lograr un resultado beneficioso adicional [NNTB] 16; IC del 95%: 8 a 100). Hubo evidencia de certeza moderada de que no hubo diferencias clínicamente relevantes en la proporción de retiros debido a eventos adversos (DR 0,04; IC del 95%: 0 a 0,08; número necesario a tratar para lograr un desenlace perjudicial adicional [NNTD] 25; IC del 95%: 16 a infinito). Hubo evidencia de certeza moderada de que no hubo diferencias entre nabiximols o THC y placebo en la frecuencia de eventos adversos graves (DR 0,02; IC del 95%: ­0,03 a 0,07). Hubo evidencia de certeza moderada de que los nabiximoles y el THC utilizados como tratamiento complementario para el dolor por cáncer refractario a los opiáceos no difirieron del placebo en cuanto a la reducción de la intensidad media del dolor (diferencia de medias estandarizada [DME] ­0,19; IC del 95%: ­0,40 a 0,02). Hubo evidencia de certeza baja de que un análogo sintético del THC (nabilona) administrado durante ocho semanas no fue superior a placebo para reducir el dolor asociado con la quimioterapia o la radioquimioterapia en personas con cáncer de cabeza y cuello y cáncer de pulmón de células no pequeñas (dos estudios, 89 participantes, análisis cualitativo). En estos estudios no fue posible realizar análisis de tolerabilidad y seguridad. Hubo evidencia de certeza baja de que los análogos sintéticos del THC fueron superiores a placebo (DME ­0,98; IC del 95%: ­1,36 a ­0,60), pero no superiores a la codeína en dosis bajas (DME 0,03; IC del 95%: ­0,25 a 0,32; cinco ensayos de dosis única; 126 participantes) en cuanto a la reducción del dolor moderado a intenso por cáncer después de la interrupción del tratamiento analgésico previo durante tres a cuatro horas y media (dos ensayos de dosis única; 66 participantes). En estos estudios no fue posible realizar análisis de tolerabilidad y seguridad. Hubo evidencia de certeza baja de que el aceite de CBD no agregó valor a los cuidados paliativos especializados solos en la reducción de la intensidad del dolor en personas con cáncer avanzado. No hubo diferencias en el número de abandonos debido a eventos adversos ni eventos adversos graves (un estudio, 144 participantes, análisis cualitativo). No se encontraron estudios que utilizaran la planta de cannabis. CONCLUSIONES DE LOS AUTORES: Existe evidencia de certeza moderada de que los nabiximoles y el THC por vía oromucosa no son efectivos para aliviar el dolor de moderado a intenso por cáncer refractario a los opiáceos. Hay evidencia de certeza baja de que la nabilona no es efectiva para reducir el dolor asociado con la radio­quimioterapia en personas con cáncer de cabeza y cuello y cáncer de pulmón de células no pequeñas. Hay evidencia de certeza baja de que una dosis única de análogos sintéticos del THC no es superior a una dosis única baja equivalente de morfina para reducir el dolor moderado a intenso por cáncer. Hay evidencia de certeza baja de que el CBD no aporta valor a los cuidados paliativos especializados solos en la reducción del dolor en personas con cáncer avanzado.

Antidepressants for pain management in adults with chronic pain: a network meta-analysis.

BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions. OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022. SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm.  DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal. MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain.  Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes. AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.

Combination pharmacotherapy for the treatment of neuropathic pain in adults: systematic review and meta-analysis.

ABSTRACT: Neuropathic pain causes substantial morbidity and healthcare utilization. Monotherapy with antidepressants or anticonvulsants often fails to provide relief. Combining different drugs sometimes provides improved analgesia and/or tolerability. More than half of patients receive 2 or more analgesics, and combination trials continue to emerge. This review comprehensively searched CENTRAL, MEDLINE, and EMBASE for relevant trials. Included studies are double-blind randomized controlled trials evaluating combinations of 2 or more drugs vs placebo or at least one monotherapy in adults with neuropathic pain. Outcomes included measures of efficacy and adverse effects. Risk of bias was assessed. Meta-analyses compared combination to monotherapy wherever 2 or more similar studies were available. Forty studies (4741 participants) were included. Studies were heterogenous with respect to various characteristics, including dose titration methods and administration (ie, simultaneous vs sequential) of the combination. Few combinations involved a nonsedating drug, and several methodological problems were identified. For opioid-antidepressant, opioid-gabapentinoid, and gabapentinoid-antidepressant combinations, meta-analyses failed to demonstrate superiority over both monotherapies. In general, adverse event profiles were not substantially different for combination therapy compared with monotherapy. Despite widespread use and a growing number of trials, convincing evidence has not yet emerged to suggest superiority of any combination over its respective monotherapies. Therefore, implementing combination therapy-as second- or third-line treatment-in situations where monotherapy is insufficient, should involve closely monitored individual dosing trials to confirm safety and overall added benefit. Further research is needed, including trials of combinations involving nonsedating agents, and to identify clinical settings and specific combinations that safely provide added benefit.

Investigating the veracity of a sample of divergent published trial data in spinal pain.

ABSTRACT: Evidence-based medicine is replete with studies assessing quality and bias, but few evaluating research integrity or trustworthiness. A recent Cochrane review of psychological interventions for chronic pain identified trials with a shared lead author with highly divergent results. We sought to systematically identify all similar trials from this author to explore their risk of bias, governance procedures, and trustworthiness. We searched OVID MEDLINE, EMBASE, CENTRAL, and PEDro from 2010 to December 22, 2021 for trials. We contacted the authors requesting details of trial registration, ethical approval, protocol, and access to the trial data for verification. We used the Cochrane risk-of-bias tool and the Cochrane Pregnancy and Childbirth group's Trustworthiness Screening Tool to guide systematic exploration of trustworthiness. Ten trials were included: 9 compared cognitive behavioural therapy and physical exercise to usual care, exercise alone, or physiotherapy and 1 compared 2 brief cognitive behavioural therapy programmes. Eight trials reported results divergent from the evidence base. Assessment of risk of bias and participant characteristics identified no substantial concerns. Responses from the lead author did not satisfactorily explain this divergence. Trustworthiness screening identified concerns about research governance, data plausibility at baseline, the results, and apparent data duplication. We discuss the findings within the context of methods for establishing the trustworthiness of research findings generally. Important concerns regarding the trustworthiness of these trials reduce our confidence in them. They should probably not be used to inform the results and conclusions of systematic reviews, in clinical training, policy documents, or any relevant instruction regarding adult chronic pain management.

Glial-modulating agents for the treatment of pain: protocol for a systematic review.

INTRODUCTION: Evidence suggests a role for Central nervous system glia in pain transmission and in augmenting maladaptive opioid effects. Identification of drugs that modulate glia has guided the evaluation of glial suppression as a pain management strategy. This planned systematic review will describe evidence of the efficacy and adverse effects of glial-modulating drugs in pain management. METHODS AND ANALYSIS: A detailed search will be conducted on the Cochrane Central Register of Controlled Trials, Medline, and Embase from their inception until the date the final searches are run to identify relevant randomised controlled trials. The reference lists of retrieved studies, as well as online trial registries, will also be searched. English language, randomised, double-blind trials comparing various glial-modulating drugs with placebo and/or other comparators, with participant-reported pain assessment, will be included. Two reviewers will independently evaluate studies for eligibility, extract data and assess trial quality and potential bias. Risk of bias will be assessed using criteria outlined in the Cochrane Handbook for Systematic Review of Interventions. Primary outcomes for this review will include any validated measure of pain intensity and/or pain relief. Dichotomous data will be used to calculate risk ratio and number needed to treat or harm. The quality of evidence will be assessed using Grading of Recommendations Assessment, Development and Evaluation. ETHICS AND DISSEMINATION: This systematic review does not require formal ethics approval. The findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42021262074.

Pharmacotherapy for the Prevention of Chronic Pain after Surgery in Adults: An Updated Systematic Review and Meta-analysis.

BACKGROUND: Chronic postsurgical pain can severely impair patient health and quality of life. This systematic review update evaluated the effectiveness of systemic drugs to prevent chronic postsurgical pain. METHODS: The authors included double-blind, placebo-controlled, randomized controlled trials including adults that evaluated perioperative systemic drugs. Studies that evaluated same drug(s) administered similarly were pooled. The primary outcome was the proportion reporting any pain at 3 or more months postsurgery. RESULTS: The authors identified 70 new studies and 40 from 2013. Most evaluated ketamine, pregabalin, gabapentin, IV lidocaine, nonsteroidal anti-inflammatory drugs, and corticosteroids. Some meta-analyses showed statistically significant-but of unclear clinical relevance-reductions in chronic postsurgical pain prevalence after treatment with pregabalin, IV lidocaine, and nonsteroidal anti-inflammatory drugs. Meta-analyses with more than three studies and more than 500 participants showed no effect of ketamine on prevalence of any pain at 6 months when administered for 24 h or less (risk ratio, 0.62 [95% CI, 0.36 to 1.07]; prevalence, 0 to 88% ketamine; 0 to 94% placebo) or more than 24 h (risk ratio, 0.91 [95% CI, 0.74 to 1.12]; 6 to 71% ketamine; 5 to 78% placebo), no effect of pregabalin on prevalence of any pain at 3 months (risk ratio, 0.88 [95% CI, 0.70 to 1.10]; 4 to 88% pregabalin; 3 to 80% placebo) or 6 months (risk ratio, 0.78 [95% CI, 0.47 to 1.28]; 6 to 68% pregabalin; 4 to 69% placebo) when administered more than 24 h, and an effect of pregabalin on prevalence of moderate/severe pain at 3 months when administered more than 24 h (risk ratio, 0.47 [95% CI, 0.33 to 0.68]; 0 to 20% pregabalin; 4 to 34% placebo). However, the results should be interpreted with caution given small study sizes, variable surgical types, dosages, timing and method of outcome measurements in relation to the acute pain trajectory in question, and preoperative pain status. CONCLUSIONS: Despite agreement that chronic postsurgical pain is an important topic, extremely little progress has been made since 2013, likely due to study designs being insufficient to address the complexities of this multifactorial problem.

International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management.

ABSTRACT: The President of the International Association for the Study of Pain established a task force on cannabis and cannabinoid analgesia to systematically examine the evidence on (1) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain; (2) the clinical efficacy of cannabis, cannabinoids, and cannabis-based medicines for pain; (3) harms related to long-term use of cannabinoids; as well as (4) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the task force outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high-quality clinical trials with cannabinoids are needed. Remaining important questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal, and policy challenges associated with medicinal and nonmedicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management.

Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews.

ABSTRACT: Cannabinoids, cannabis, and cannabis-based medicines (CBM) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We assessed methodological quality, scope, and results of systematic reviews of randomised controlled trials of these treatments. Several search strategies sought self-declared systematic reviews. Methodological quality was assessed using both AMSTAR-2 and techniques important for bias reduction in pain studies. Of the 106 articles read, 57 were self-declared systematic reviews, most published since 2010. They included any type of cannabinoid, cannabis, or CBM, at any dose, however administered, in a broad range of pain conditions. No review examined the effects of a particular cannabinoid, at a particular dose, using a particular route of administration, for a particular pain condition, reporting a particular analgesic outcome. Confidence in the results in the systematic reviews using AMSTAR-2 definitions was critically low (41), low (8), moderate (6), or high (2). Few used criteria important for bias reduction in pain. Cochrane reviews typically provided higher confidence; all industry-conflicted reviews provided critically low confidence. Meta-analyses typically pooled widely disparate studies, and, where assessable, were subject to potential publication bias. Systematic reviews with positive or negative recommendation for use of cannabinoids, cannabis, or CBM in pain typically rated critically low or low (24/25 [96%] positive; 10/12 [83%] negative). Current reviews are mostly lacking in quality and cannot provide a basis for decision-making. A new high-quality systematic review of randomised controlled trials is needed to critically assess the clinical evidence for cannabinoids, cannabis, or CBM in pain.

Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials.

ABSTRACT: Cannabinoids, cannabis, and cannabis-based medicines (CBMs) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We summarised efficacy and adverse events (AEs) of these types of drugs for treating pain using randomised controlled trials: in people of any age, with any type of pain, and for any treatment duration. Primary outcomes were 30% and 50% reduction in pain intensity, and AEs. We assessed risk of bias of included studies, and the overall quality of evidence using GRADE. Studies of <7 and >7 days treatment duration were analysed separately. We included 36 studies (7217 participants) delivering cannabinoids (8 studies), cannabis (6 studies), and CBM (22 studies); all had high and/or uncertain risk of bias. Evidence of benefit was found for cannabis <7 days (risk difference 0.33, 95% confidence interval 0.20-0.46; 2 trials, 231 patients, very low-quality evidence) and nabiximols >7 days (risk difference 0.06, 95% confidence interval 0.01-0.12; 6 trials, 1484 patients, very low-quality evidence). No other beneficial effects were found for other types of cannabinoids, cannabis, or CBM in our primary analyses; 81% of subgroup analyses were negative. Cannabis, nabiximols, and delta-9-tetrahydrocannabinol had more AEs than control. Studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. We have little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain.

Cannabinoids, cannabis, and cannabis-based medicine for pain management: a protocol for an overview of systematic reviews and a systematic review of randomised controlled trials.

Pain is an experience that affects many people worldwide and is associated with higher mortality and lower quality of life. Cannabinoid, cannabis, and cannabis-based medicines (CBMs) are thought to reduce pain, but a proliferation of different products has led to variability in trials, creating a challenge when determining the assessment of efficacy in systematic reviews. We will conduct 2 systematic reviews commissioned by the International Association for the Study of Pain Task Force on the use of cannabinoids, cannabis, and CBMs for pain management: first, an overview review of systematic reviews to summarise the evidence base and second, a systematic review of randomised controlled trials of cannabinoids, cannabis, and CBMs. In these reviews we will determine the harm and benefit of CBM from the current literature and will interpret the findings in light of the quality of evidence and reviews included. We will search online databases and registries in any language for systematic reviews and randomised controlled trials. We will include studies that evaluate any cannabinoid or CBM vs any control for people with acute and chronic pain. Our primary outcomes for both reviews are the number of participants achieving (1) a 30% and (2) 50% reduction in pain intensity, (3) moderate improvement, and (4) substantial improvement. A number of secondary outcome measures will also be included. We will assess risk of bias and quality of evidence. We will analyse data using fixed and random effect models, with separate comparators for cannabis and CBMs. Prospero ID (CRD42019124710; CRD42019124714).

Pharmacological interventions for chronic pain in children: an overview of systematic reviews.

We know little about the safety or efficacy of pharmacological medicines for children and adolescents with chronic pain, despite their common use. Our aim was to conduct an overview review of systematic reviews of pharmacological interventions that purport to reduce pain in children with chronic noncancer pain (CNCP) or chronic cancer-related pain (CCRP). We searched the Cochrane Database of Systematic Reviews, Medline, EMBASE, and DARE for systematic reviews from inception to March 2018. We conducted reference and citation searches of included reviews. We included children (0-18 years of age) with CNCP or CCRP. We extracted the review characteristics and primary outcomes of ≥30% participant-reported pain relief and patient global impression of change. We sifted 704 abstracts and included 23 systematic reviews investigating children with CNCP or CCRP. Seven of those 23 reviews included 6 trials that involved children with CNCP. There were no randomised controlled trials in reviews relating to reducing pain in CCRP. We were unable to combine data in a meta-analysis. Overall, the quality of evidence was very low, and we have very little confidence in the effect estimates. The state of evidence of randomized controlled trials in this field is poor; we have no evidence from randomised controlled trials for pharmacological interventions in children with cancer-related pain, yet cannot deny individual children access to potential pain relief. Prospero ID: CRD42018086900.

Pregabalin for neuropathic pain in adults.

BACKGROUND: This review updates part of an earlier Cochrane Review titled "Pregabalin for acute and chronic pain in adults", and considers only neuropathic pain (pain from damage to nervous tissue). Antiepileptic drugs have long been used in pain management. Pregabalin is an antiepileptic drug used in management of chronic pain conditions. OBJECTIVES: To assess the analgesic efficacy and adverse effects of pregabalin for chronic neuropathic pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase for randomised controlled trials from January 2009 to April 2018, online clinical trials registries, and reference lists. SELECTION CRITERIA: We included randomised, double-blind trials of two weeks' duration or longer, comparing pregabalin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality and biases. Primary outcomes were: at least 30% pain intensity reduction over baseline; much or very much improved on the Patient Global Impression of Change (PGIC) Scale (moderate benefit); at least 50% pain intensity reduction; or very much improved on PGIC (substantial benefit). We calculated risk ratio (RR) and number needed to treat for an additional beneficial (NNTB) or harmful outcome (NNTH). We assessed the quality of the evidence using GRADE. MAIN RESULTS: We included 45 studies lasting 2 to 16 weeks, with 11,906 participants - 68% from 31 new studies. Oral pregabalin doses of 150 mg, 300 mg, and 600 mg daily were compared with placebo. Postherpetic neuralgia, painful diabetic neuropathy, and mixed neuropathic pain predominated (85% of participants). High risk of bias was due mainly to small study size (nine studies), but many studies had unclear risk of bias, mainly due to incomplete outcome data, size, and allocation concealment.Postherpetic neuralgia: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (50% vs 25%; RR 2.1 (95% confidence interval (CI) 1.6 to 2.6); NNTB 3.9 (3.0 to 5.6); 3 studies, 589 participants, moderate-quality evidence), and more had at least 50% pain intensity reduction (32% vs 13%; RR 2.5 (95% CI 1.9 to 3.4); NNTB 5.3 (3.9 to 8.1); 4 studies, 713 participants, moderate-quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (62% vs 24%; RR 2.5 (95% CI 2.0 to 3.2); NNTB 2.7 (2.2 to 3.7); 3 studies, 537 participants, moderate-quality evidence), and more had at least 50% pain intensity reduction (41% vs 15%; RR 2.7 (95% CI 2.0 to 3.5); NNTB 3.9 (3.1 to 5.5); 4 studies, 732 participants, moderate-quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate-quality evidence): somnolence 300 mg 16% versus 5.5%, 600 mg 25% versus 5.8%; dizziness 300 mg 29% versus 8.1%, 600 mg 35% versus 8.8%.Painful diabetic neuropathy: More participants had at least 30% pain intensity reduction with pregabalin 300 mg than with placebo (47% vs 42%; RR 1.1 (95% CI 1.01 to 1.2); NNTB 22 (12 to 200); 8 studies, 2320 participants, moderate-quality evidence), more had at least 50% pain intensity reduction (31% vs 24%; RR 1.3 (95% CI 1.2 to 1.5); NNTB 22 (12 to 200); 11 studies, 2931 participants, moderate-quality evidence), and more had PGIC much or very much improved (51% vs 30%; RR 1.8 (95% CI 1.5 to 2.0); NNTB 4.9 (3.8 to 6.9); 5 studies, 1050 participants, moderate-quality evidence). More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (63% vs 52%; RR 1.2 (95% CI 1.04 to 1.4); NNTB 9.6 (5.5 to 41); 2 studies, 611 participants, low-quality evidence), and more had at least 50% pain intensity reduction (41% vs 28%; RR 1.4 (95% CI 1.2 to 1.7); NNTB 7.8 (5.4 to 14); 5 studies, 1015 participants, low-quality evidence). Somnolence and dizziness were more common with pregabalin than with placebo (moderate-quality evidence): somnolence 300 mg 11% versus 3.1%, 600 mg 15% versus 4.5%; dizziness 300 mg 13% versus 3.8%, 600 mg 22% versus 4.4%.Mixed or unclassified post-traumatic neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (48% vs 36%; RR 1.2 (1.1 to 1.4); NNTB 8.2 (5.7 to 15); 4 studies, 1367 participants, low-quality evidence), and more had at least 50% pain intensity reduction (34% vs 20%; RR 1.5 (1.2 to 1.9); NNTB 7.2 (5.4 to 11); 4 studies, 1367 participants, moderate-quality evidence). Somnolence (12% vs 3.9%) and dizziness (23% vs 6.2%) were more common with pregabalin.Central neuropathic pain: More participants had at least 30% pain intensity reduction with pregabalin 600 mg than with placebo (44% vs 28%; RR 1.6 (1.3 to 2.0); NNTB 5.9 (4.1 to 11); 3 studies, 562 participants, low-quality evidence) and at least 50% pain intensity reduction (26% vs 15%; RR 1.7 (1.2 to 2.3); NNTB 9.8 (6.0 to 28); 3 studies, 562 participants, low-quality evidence). Somnolence (32% vs 11%) and dizziness (23% vs 8.6%) were more common with pregabalin.Other neuropathic pain conditions: Studies show no evidence of benefit for 600 mg pregabalin in HIV neuropathy (2 studies, 674 participants, moderate-quality evidence) and limited evidence of benefit in neuropathic back pain or sciatica, neuropathic cancer pain, or polyneuropathy.Serious adverse events, all conditions: Serious adverse events were no more common with placebo than with pregabalin 300 mg (3.1% vs 2.6%; RR 1.2 (95% CI 0.8 to 1.7); 17 studies, 4112 participants, high-quality evidence) or pregabalin 600 mg (3.4% vs 3.4%; RR 1.1 (95% CI 0.8 to 1.5); 16 studies, 3995 participants, high-quality evidence). AUTHORS' CONCLUSIONS: Evidence shows efficacy of pregabalin in postherpetic neuralgia, painful diabetic neuralgia, and mixed or unclassified post-traumatic neuropathic pain, and absence of efficacy in HIV neuropathy; evidence of efficacy in central neuropathic pain is inadequate. Some people will derive substantial benefit with pregabalin; more will have moderate benefit, but many will have no benefit or will discontinue treatment. There were no substantial changes since the 2009 review.

Amitriptyline for fibromyalgia in adults.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 12, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of amitriptyline for neuropathic pain is now dealt with in a separate review. Amitriptyline is a tricyclic antidepressant that is widely used to treat fibromyalgia, and is recommended in many guidelines. It is usually used at doses below those at which the drugs act as antidepressants. OBJECTIVES: To assess the analgesic efficacy of amitriptyline for relief of fibromyalgia, and the adverse events associated with its use in clinical trials. SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE to March 2015, together with reference lists of retrieved papers, previous systematic reviews and other reviews, and two clinical trial registries. We also used our own hand searched database for older studies. SELECTION CRITERIA: We included randomised, double-blind studies of at least four weeks' duration comparing amitriptyline with placebo or another active treatment in fibromyalgia. DATA COLLECTION AND ANALYSIS: We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both. For efficacy, we calculated the number needed to treat to benefit (NNT), and for harm we calculated the number needed to treat to harm (NNH) for adverse events and withdrawals. We used a fixed-effect model for meta-analysis. MAIN RESULTS: We included seven studies from the earlier review and two new studies (nine studies, 649 participants) of 6 to 24 weeks' duration, enrolling between 22 and 208 participants; none had 50 or more participants in each treatment arm. Two studies used a cross-over design. The daily dose of amitriptyline was 25 mg to 50 mg, and some studies had an initial titration period. There was no first or second tier evidence for amitriptyline in the treatment of fibromyalgia. Using third tier evidence the risk ratio (RR) for at least 50% pain relief, or equivalent, with amitriptyline compared with placebo was 3.0 (95% confidence interval (CI) 1.7 to 4.9), with an NNT) of 4.1 (2.9 to 6.7) (very low quality evidence). There were no consistent differences between amitriptyline and placebo or other active comparators for relief of symptoms such as fatigue, poor sleep, quality of life, or tender points. More participants experienced at least one adverse event with amitriptyline (78%) than with placebo (47%). The RR was 1.5 (1.3 to 1.8) and the NNH was 3.3 (2.5 to 4.9). Adverse event and all-cause withdrawals were not different, but lack of efficacy withdrawals were more common with placebo (12% versus 5%; RR 0.42 (0.19 to 0.95)) (very low quality evidence). AUTHORS' CONCLUSIONS: Amitriptyline has been a first-line treatment for fibromyalgia for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against years of successful treatment in many patients with fibromyalgia. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline will be one option in the treatment of fibromyalgia, while recognising that only a minority of patients will achieve satisfactory pain relief. It is unlikely that any large randomised trials of amitriptyline will be conducted in fibromyalgia to establish efficacy statistically, or measure the size of the effect.