OBJECTIVE:To determine the efficacy of ginger (either stand-alone or as an adjunct treatment) for the treatment and management of migraine headaches. METHODS:We searched PubMed, Embase, CINAHL, PsycINFO, Epistemonikos and Cochrane CENTRAL from inception to 26 March 2025 which was updated on 16 April 2026 and conducted a backwards and forwards citation search of included studies. We included randomised controlled trials (RCTs) that compared the effect of ginger (either stand-alone or as an adjunct) to placebo or usual active control (such as Depakine (valproic acid), amitriptyline or sumatriptan). Two authors independently screened articles, extracted data, assessed risk of bias using the Cochrane Risk of Bias 2 Tool (ROB-2) tool. Primary outcomes included headache severity or pain scores post-treatment, proportion of patients pain free or with pain relief post-treatment, frequency and duration of migraine attacks and migraine-associated symptoms. Random-effects meta-analyses were done and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS:Eight RCTs involving 594 patients were included. For acute treatments, ginger with ketoprofen compared with placebo with ketoprofen may have little to no difference on headache severity at 2 hours post (mean difference (MD) 1.27 lower, 95% CI 1.46 lower to 1.08 lower; 1 study, 60 participants; low certainty evidence). It was very uncertain if ginger combined with feverfew versus placebo or ginger alone compared with sumatriptan improved proportions of those with pain relief, pain free or the mean headache severity at 2 hours post. For preventative treatment, ginger in addition to an active drug compared with the same active drug with or without placebo, may result in an important reduction in headache pain severity at 3 months (pooled MD -3.18, 95% CI -3.94 to -2.42; 2 studies, 183 participants; low certainty evidence). However, it was very uncertain if ginger combined with herbs compared with active drugs of both Depakine and amitriptyline lowered headache frequency, duration or headache severity at 3 months. The overall certainty of evidence for all outcome measures ranged from low to very low. CONCLUSIONS:The volume of the existing evidence is limited and combined with either a low or very low certainty of evidence, it is currently too uncertain if ginger is effective either as an acute or preventative treatment. Therefore, additional acute and preventative trials are required to help raise the certainty of evidence. TRIAL REGISTRATION NUMBER:https://www.crd.york.ac.uk/PROSPERO/view/CRD420251025768.
Understanding the risks associated with healthcare interventions is essential for clinical decision-making and for the regulatory evaluation of new drugs. Yet, safety analyses in randomised controlled trials are often conducted without clearly specifying (a) the estimand of interest in the presence of intercurrent events (IEs) (ie, events such as treatment discontinuation or use of rescue medication that occur after randomisation and complicate outcome interpretation) or (b) the estimand implicitly targeted by the statistical estimator used in the analysis. This lack of clarity produces ambiguous results and complicates their interpretation.This paper provides practical guidance on applying the estimand framework from the ICH E9(R1) addendum to safety outcomes in phase III randomised trials conducted for regulatory submissions. We describe how IEs influence the interpretation of treatment effects in safety assessment and how commonly used safety estimators align with different estimands, making explicit both the clinical question and the assumptions required to estimate it.Although the primary emphasis is on regulatory trials, where these decisions are especially consequential, the principles outlined are equally applicable to other randomised interventions and non-interventional studies. As safety results from pivotal regulatory trials are increasingly published using estimand terminology, these concepts are essential not only for researchers such as statisticians, clinicians and regulators involved in clinical development but also for clinicians who prescribe newly approved drugs and need to interpret safety results communicated using estimand terminology to inform their clinical decision-making. This paper aims to make these concepts accessible to a broader medical audience.
In clinical research, statistically significant effects do not necessarily indicate that an intervention provides benefits that are meaningful to patients. This is particularly important for patient-reported outcomes, where thresholds used to interpret clinical relevance are often derived from within-person changes, such as the minimal clinically important difference, and then inappropriately applied to between-group effects in randomised trials and meta-analyses. This article clarifies the conceptual distinction between within-group change and between-group effects, and argues that the latter should be the focus when judging the comparative value of healthcare interventions. We introduce the smallest worthwhile effect (SWE) as a patient-centred, intervention-specific construct representing the smallest between-group effect of an intervention over a comparator that patients consider worthwhile when weighed against harms, costs and other inconveniences. We describe the main methods used to estimate the SWE, including benefit-harm trade-off studies and discrete choice experiments, and illustrate its application by reinterpreting a randomised trial of physiotherapy for low back pain and a meta-analysis of discectomy versus non-surgical care for sciatica. We also show how the SWE can inform judgements of imprecision within the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, offering a patient-derived threshold for distinguishing trivial from worthwhile effects. By focusing on patient-derived thresholds rather than arbitrary statistical or within-group approaches, the SWE construct can help researchers, clinicians and other stakeholders make more transparent and meaningful judgements about the worthwhileness of compared healthcare interventions from a patient perspective.
