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.

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.

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.

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.

Mirtazapine for fibromyalgia in adults.

BACKGROUND: Fibromyalgia is a clinically defined chronic condition of unknown etiology characterised by chronic widespread pain, sleep disturbance, cognitive dysfunction, and fatigue. Many patients report high disability levels and poor quality of life. Drug therapy aims to reduce key symptoms, especially pain, and improve quality of life. The tetracyclic antidepressant, mirtazapine, may help by increasing serotonin and noradrenaline in the central nervous system (CNS). OBJECTIVES: To assess the efficacy, tolerability and safety of the tetracyclic antidepressant, mirtazapine, compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, SCOPUS, the US National Institutes of Health, and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials, and examined reference lists of reviewed articles, to 9 July 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any formulation of mirtazapine against placebo, or any other active treatment of fibromyalgia, in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study characteristics, outcomes of efficacy, tolerability and safety, examined issues of study quality, and assessed risk of bias, resolving discrepancies by discussion. Primary outcomes were participant-reported pain relief (at least 50% or 30% pain reduction), Patient Global Impression of Change (PGIC; much or very much improved), safety (serious adverse events), and tolerability (adverse event withdrawal). Other outcomes were health-related quality of life (HRQoL) improved by 20% or more, fatigue, sleep problems, mean pain intensity, negative mood and particular adverse events. We used a random-effects model to calculate risk difference (RD), standardised mean difference (SMD), and numbers needed to treat. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Three studies with 606 participants compared mirtazapine with placebo (but not other drugs) over seven to 13 weeks. Two studies were at unclear or high risk of bias in six or seven of eight domains. We judged the evidence for all outcomes to be low- or very low-quality because of poor study quality, indirectness, imprecision, risk of publication bias, and sometimes low numbers of events.There was no difference between mirtazapine and placebo for any primary outcome: participant-reported pain relief of 50% or greater (22% versus 16%; RD 0.05, 95% confidence interval (CI) -0.01 to 0.12; three studies with 591 participants; low-quality evidence); no data available for PGIC; only a single serious adverse event for evaluation of safety (RD -0.00, 95% CI -0.01 to 0.02; three studies with 606 participants; very low-quality evidence); and tolerability as frequency of dropouts due to adverse events (3% versus 2%; RD 0.00, 95% CI -0.02 to 0.03; three studies with 606 participants; low-quality evidence).Mirtazapine showed a clinically-relevant benefit compared to placebo for some secondary outcomes: participant-reported pain relief of 30% or greater (47% versus 34%; RD 0.13, 95% CI 0.05 to 0.21; number needed to treat for an additional beneficial outcome (NNTB) 8, 95% CI 5 to 20; three studies with 591 participants; low-quality evidence); participant-reported mean pain intensity (SMD -0.29, 95% CI -0.46 to -0.13; three studies with 591 participants; low-quality evidence); and participant-reported sleep problems (SMD -0.23, 95% CI -0.39 to -0.06; three studies with 573 participants; low-quality evidence). There was no benefit for improvement of participant-reported improvement of HRQoL of 20% or greater (58% versus 50%; RD 0.08, 95% CI -0.01 to 0.16; three studies with 586 participants; low-quality evidence); participant-reported fatigue (SMD -0.02, 95% CI -0.19 to 0.16; two studies with 533 participants; low-quality evidence); participant-reported negative mood (SMD -0.67, 95% CI -1.44 to 0.10; three studies with 588 participants; low-quality evidence); or withdrawals due to lack of efficacy (1.5% versus 0.1%; RD 0.01, 95% CI -0.01 to 0.02; three studies with 605 participants; very low-quality evidence).There was no difference between mirtazapine and placebo for participants reporting any adverse event (76% versus 59%; RD 0.12, 95 CI -0.01 to 0.26; three studies with 606 participants; low-quality evidence). There was a clinically-relevant harm with mirtazapine compared to placebo: in the number of participants with somnolence (42% versus 14%; RD 0.24, 95% CI 0.18 to 0.30; number needed to treat for an additional harmful outcome (NNTH) 5, 95% CI 3 to 6; three studies with 606 participants; low-quality evidence); weight gain (19% versus 1%; RD 0.17, 95% CI 0.11 to 0.23; NNTH 6, 95% CI 5 to 10; three studies with 606 participants; low-quality evidence); and elevated alanine aminotransferase (13% versus 2%; RD 0.13, 95% CI 0.04 to 0.22; NNTH 8, 95% CI 5 to 25; two studies with 566 participants; low-quality evidence). AUTHORS' CONCLUSIONS: Studies demonstrated no benefit of mirtazapine over placebo for pain relief of 50% or greater, PGIC, improvement of HRQoL of 20% or greater, or reduction of fatigue or negative mood. Clinically-relevant benefits were shown for pain relief of 30% or greater, reduction of mean pain intensity, and sleep problems. Somnolence, weight gain, and elevated alanine aminotransferase were more frequent with mirtazapine than placebo. The quality of evidence was low or very low, with two of three studies of questionable quality and issues over indirectness and risk of publication bias. On balance, any potential benefits of mirtazapine in fibromyalgia were outweighed by its potential harms, though, a small minority of people with fibromyalgia might experience substantial symptom relief without clinically-relevant adverse events.

Combination pharmacotherapy for the treatment of fibromyalgia in adults.

BACKGROUND: Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects. OBJECTIVES: To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries. SELECTION CRITERIA: Double-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain. DATA COLLECTION AND ANALYSIS: From all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5-hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta-analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient-reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain-related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache. AUTHORS' CONCLUSIONS: There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.

Perioperative intravenous ketamine for acute postoperative pain in adults.

BACKGROUND: Inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. Perioperative ketamine may enhance conventional analgesics in the acute postoperative setting. OBJECTIVES: To evaluate the efficacy and safety of perioperative intravenous ketamine in adult patients when used for the treatment or prevention of acute pain following general anaesthesia. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to July 2018 and three trials registers (metaRegister of controlled trials, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)) together with reference checking, citation searching and contact with study authors to identify additional studies. SELECTION CRITERIA: We sought randomised, double-blind, controlled trials of adults undergoing surgery under general anaesthesia and being treated with perioperative intravenous ketamine. Studies compared ketamine with placebo, or compared ketamine plus a basic analgesic, such as morphine or non-steroidal anti-inflammatory drug (NSAID), with a basic analgesic alone. DATA COLLECTION AND ANALYSIS: Two review authors searched for studies, extracted efficacy and adverse event data, examined issues of study quality and potential bias, and performed analyses. Primary outcomes were opioid consumption and pain intensity at rest and during movement at 24 and 48 hours postoperatively. Secondary outcomes were time to first analgesic request, assessment of postoperative hyperalgesia, central nervous system (CNS) adverse effects, and postoperative nausea and vomiting. We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We included 130 studies with 8341 participants. Ketamine was given to 4588 participants and 3753 participants served as controls. Types of surgery included ear, nose or throat surgery, wisdom tooth extraction, thoracotomy, lumbar fusion surgery, microdiscectomy, hip joint replacement surgery, knee joint replacement surgery, anterior cruciate ligament repair, knee arthroscopy, mastectomy, haemorrhoidectomy, abdominal surgery, radical prostatectomy, thyroid surgery, elective caesarean section, and laparoscopic surgery. Racemic ketamine bolus doses were predominantly 0.25 mg to 1 mg, and infusions 2 to 5 µg/kg/minute; 10 studies used only S-ketamine and one only R-ketamine. Risk of bias was generally low or uncertain, except for study size; most had fewer than 50 participants per treatment arm, resulting in high heterogeneity, as expected, for most analyses. We did not stratify the main analysis by type of surgery or any other factor, such as dose or timing of ketamine administration, and used a non-stratified analysis.Perioperative intravenous ketamine reduced postoperative opioid consumption over 24 hours by 8 mg morphine equivalents (95% CI 6 to 9; 19% from 42 mg consumed by participants given placebo, moderate-quality evidence; 65 studies, 4004 participants). Over 48 hours, opioid consumption was 13 mg lower (95% CI 10 to 15; 19% from 67 mg with placebo, moderate-quality evidence; 37 studies, 2449 participants).Perioperative intravenous ketamine reduced pain at rest at 24 hours by 5/100 mm on a visual analogue scale (95% CI 4 to 7; 19% lower from 26/100 mm with placebo, high-quality evidence; 82 studies, 5004 participants), and at 48 hours by 5/100 mm (95% CI 3 to 7; 22% lower from 23/100 mm, high-quality evidence; 49 studies, 2962 participants). Pain during movement was reduced at 24 hours (6/100 mm, 14% lower from 42/100 mm, moderate-quality evidence; 29 studies, 1806 participants), and 48 hours (6/100 mm, 16% lower from 37 mm, low-quality evidence; 23 studies, 1353 participants).Results for primary outcomes were consistent when analysed by pain at rest or on movement, operation type, and timing of administration, or sensitivity to study size and pain intensity. No analysis by dose was possible. There was no difference when nitrous oxide was used. We downgraded the quality of the evidence once if numbers of participants were large but small-study effects were present, or twice if numbers were small and small-study effects likely but testing not possible.Ketamine increased the time for the first postoperative analgesic request by 54 minutes (95% CI 37 to 71 minutes), from a mean of 39 minutes with placebo (moderate-quality evidence; 31 studies, 1678 participants). Ketamine reduced the area of postoperative hyperalgesia by 7 cm² (95% CI -11.9 to -2.2), compared with placebo (very low-quality evidence; 7 studies 333 participants). We downgraded the quality of evidence because of small-study effects or because the number of participants was below 400.CNS adverse events occurred in 52 studies, while 53 studies reported of absence of CNS adverse events. Overall, 187/3614 (5%) participants receiving ketamine and 122/2924 (4%) receiving control treatment experienced an adverse event (RR 1.2, 95% CI 0.95 to 1.4; high-quality evidence; 105 studies, 6538 participants). Ketamine reduced postoperative nausea and vomiting from 27% with placebo to 23% with ketamine (RR 0.88, 95% CI 0.81 to 0.96; the number needed to treat to prevent one episode of postoperative nausea and vomiting with perioperative intravenous ketamine administration was 24 (95% CI 16 to 54; high-quality evidence; 95 studies, 5965 participants). AUTHORS' CONCLUSIONS: Perioperative intravenous ketamine probably reduces postoperative analgesic consumption and pain intensity. Results were consistent in different operation types or timing of ketamine administration, with larger and smaller studies, and by higher and lower pain intensity. CNS adverse events were little different with ketamine or control. Perioperative intravenous ketamine probably reduces postoperative nausea and vomiting by a small extent, of arguable clinical relevance.

Single dose oral ketoprofen or dexketoprofen for acute postoperative pain in adults.

BACKGROUND: This review is an update of "Single dose oral ketoprofen and dexketoprofen for acute postoperative pain in adults" last updated in Issue 4, 2009. Ketoprofen is a non-selective nonsteroidal anti-inflammatory drug (NSAID) used to treat acute and chronic painful conditions. Dexketoprofen is the (S)-enantiomer, which is believed to confer analgesia. Theoretically dexketoprofen is expected to provide equivalent analgesia to ketoprofen at half the dose, with a consequent reduction in gastrointestinal adverse events. This review is one of a series on oral analgesics for acute postoperative pain. Individual reviews have been brought together in two overviews to provide information about the relative efficacy and harm of the different interventions. OBJECTIVES: To assess the efficacy and safety of single dose oral ketoprofen and oral dexketoprofen compared with placebo for acute postoperative pain, using methods that permit comparison with other analgesics evaluated in the same way, and criteria of efficacy recommended by an in-depth study at the individual patient level. SEARCH METHODS: For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from 2009 to 28 March 2017. We also searched the reference lists of retrieved studies and reviews, and two online clinical trial registries. SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials of single dose orally administered ketoprofen or dexketoprofen in adults with moderate to severe acute postoperative pain. DATA COLLECTION AND ANALYSIS: Two review authors independently considered studies for inclusion in the review, examined issues of study quality and potential bias, and extracted data. For dichotomous outcomes, we calculated risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH) with 95% confidence intervals (CI) for ketoprofen and dexketoprofen, compared with placebo, where there were sufficient data. We collected information on the number of participants with at least 50% of the maximum possible pain relief over six hours, the median time to use of rescue medication, and the proportion of participants requiring rescue medication. We also collected information on adverse events and withdrawals. We assessed the quality of the evidence using GRADE, and created 'Summary of findings' tables. MAIN RESULTS: This updated review included 24 studies; six additional studies added 1001 participants involved in comparisons of ketoprofen or dexketoprofen and placebo, with a 12% increase in participants taking ketoprofen and a 65% increase for dexketoprofen. Most participants (70%) were women. Dental studies typically involved young participants (mean age 20 to 30 years); other types of surgery involved older participants (mean age 37 to 68 years). Overall, we judged the studies at high risk of bias only for small size, which can lead to an overestimation of benefit.Ketoprofen doses ranged between 6.5 mg and 150 mg. The proportion of participants achieving at least 50% pain relief over six hours with the usual ketoprofen oral dose of 50 mg was 57%, compared to 23% with placebo, giving an NNT of 2.9 (95% CI 2.4 to 3.7) (RR 2.5, 95% CI 2.0 to 3.1; 594 participants; 8 studies; high quality evidence). Efficacy was significantly better in dental studies (NNT 1.8) than other surgery (NNT 4.2). The proportion of participants using rescue medication within six hours was lower with ketoprofen (32%) than with placebo (75%), giving a number needed to treat to prevent use of rescue medication (NNTp) of 2.3 (95% CI 1.8 to 3.1); 263 participants; 4 studies; high quality evidence). Median time to remedication estimates were poorly reported. Reports of any adverse event were similar with ketoprofen (18%) and placebo (11%) (RR 1.6, 95% CI 0.98 to 2.8; 342 participants; 5 studies; high quality evidence). No study reported any serious adverse events (very low quality evidence).Dexketoprofen doses ranged between 5 mg and 100 mg. The proportion of participants achieving at least 50% pain relief over six hours with the usual dexketoprofen oral dose of 20 mg or 25 mg was 52%, compared to 27% with placebo, giving an NNT of 4.1 (95% CI 3.3 to 5.2) (RR 2.0, 95% CI 1.6 to 2.2; 1177 participants; 8 studies; high quality evidence). Efficacy was significantly better in dental studies (NNT 2.7) than other surgery (NNT 5.7). The proportion of participants using rescue medication within six hours was lower with dexketoprofen (47%) than placebo (69%), giving an NNTp of 4.7 (95% CI 3.3 to 8.0); 445 participants; 5 studies; high quality evidence). Median time to remedication estimates were poorly reported. Reports of any adverse event were similar with dexketoprofen (14%) and placebo (10%) (RR 1.4, 95% CI 0.89 to 2.2; 536 participants, 6 studies; high quality evidence). No study reported any serious adverse events (very low quality evidence). AUTHORS' CONCLUSIONS: Ketoprofen at doses of 25 mg to 100 mg is an effective analgesic in moderate to severe acute postoperative pain with an NNT for at least 50% pain relief of 2.9 with a 50 mg dose. This is similar to that of commonly used NSAIDs such as ibuprofen (NNT 2.5 for 400 mg dose) and diclofenac (NNT 2.7 for 50 mg dose). Dexketoprofen is also effective with an NNT of 4.1 in the dose range 10 mg to 25 mg. Differential efficacy between dental surgery and other types of surgery seen for both drugs is unusual. Both drugs were well tolerated in single doses.

Tramadol with or without paracetamol (acetaminophen) for cancer pain.

BACKGROUND: Tramadol is an opioid analgesic licensed for use in moderate to severe pain. It is considered as a low risk for abuse, so control regulations are not as stringent as for 'strong' opioids such as morphine. It has a potential role as a step 2 option of the World Health Organization (WHO) analgesic ladder. OBJECTIVES: To assess the benefits and adverse effects of tramadol with or without paracetamol (acetaminophen) for cancer-related pain. SEARCH METHODS: We searched the following databases using a wide range of search terms: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched three clinical trials registry databases. The date of the last search was 2 November 2016. SELECTION CRITERIA: We selected studies that were randomised, with placebo or active controls, or both, and included a minimum of 10 participants per treatment arm. We were interested particularly in blinded studies, but also included open studies.We excluded non-randomised studies, studies of experimental pain, case reports, and clinical observations. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standard form and checked for agreement before entry into Review Manager 5. We included information about the number of participants treated and demographic details, type of cancer, drug and dosing regimen, study design (placebo or active control) and methods, study duration and follow-up, analgesic outcome measures and results, withdrawals, and adverse events. We collated multiple reports of the same study, so that each study, rather than each report, was the unit of interest in the review. We assessed the evidence using GRADE and created a 'Summary of findings' table.The main outcomes of interest for benefit were pain reduction of 30% or greater and 50% or greater from baseline, participants with pain no worse than mild, and participants feeling much improved or very much improved. MAIN RESULTS: We included 10 studies (12 reports) with 958 adult participants. All the studies enrolled participants with chronic malignant tumour-related pain who were experiencing pain intensities described as moderate to severe, with most experiencing at least 4/10 with current treatment. The mean ages were 59 to 70 years, with participants aged between 24 and 87 years. Study length ranged from one day to six months. Five studies used a cross-over design. Tramadol doses ranged from 50 mg as single dose to 600 mg per day; doses of 300 mg per day to 400 mg per day were most common.Nine studies were at high risk of bias for one to four criteria (only one high risk of bias for size). We judged all the results to be very low quality evidence because of widespread lack of blinding of outcome assessment, inadequately described sequence generation, allocation concealment, and small numbers of participants and events. Important outcomes were poorly reported. There were eight different active comparators and one comparison with placebo. There was little information available for any comparison and no firm conclusions could be drawn for any outcome.Single comparisons of oral tramadol with codeine plus paracetamol, of dihydrocodeine, and of rectal versus oral tramadol provided no data for key outcomes. One study used tramadol combined with paracetamol; four participants received this intervention. One study compared tramadol with flupirtine - a drug that is no longer available. One study compared tramadol with placebo and a combination of cobrotoxin, tramadol, and ibuprofen, but the dosing schedule poorly explained.Two studies (191 participants) compared tramadol with buprenorphine. One study (131 participants) reported a similar proportion of no or mild pain at 14 days.Three studies (300 participants) compared tramadol with morphine. Only one study, combining tramadol, tramadol plus paracetamol, and paracetamol plus codeine as a single weak-opioid group reported results. Weak opioid produced reduction in pain of at least 30% from baseline in 55/117 (47%) participants, compared with 91/110 (82%) participants with morphine. Weak opioid produced reduction in pain of at least 50% in 49/117 (42%) participants, compared with 83/110 (75%) participants with morphine.There was no useful information for any other outcome of benefit or harm. AUTHORS' CONCLUSIONS: There is limited, very low quality, evidence from randomised controlled trials that tramadol produced pain relief in some adults with pain due to cancer and no evidence at all for children. There is very low quality evidence that it is not as effective as morphine. This review does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high. The place of tramadol in managing cancer pain and its role as step 2 of the WHO analgesic ladder is unclear.