Dipyrone for the acute treatment of migraine attacks in children and adults

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the efficacy and safety of dipyrone for the acute treatment of migraine headache in children and adults.

Background

Description of the condition

Migraine is a disabling, multifactorial neurological disorder affecting approximately 14 per cent of the world's population (GBD 2019; Stovner 2022; Vos 2012). People suffering from migraine experience recurrent attacks of moderate to severe headache, associated with nausea or vomiting (or both), and light‐ or sound‐induced (or both) discomfort lasting from a few hours to a few days (IHS 2018). Although the etymological roots of the word migraine translate to 'half of the cranium', migraine pain distribution can be unilateral, bilateral, or loHansencalised in the occipital region or the neck (Kelman 2005; Loder 2018). Nausea is an associated symptom for 75.7% of people with migraine, photophobia is reported by 92.3%, phonophobia by 92.5%, and all three together by 64.9% (Munjal 2020). In most cases, migraine attacks lead to a cessation of daily activities, negatively affecting the person's quality of life (IHS 2018). The world‐wide prevalence of migraine was estimated as 1.1 billion cases in 2019 (Safiri 2022). More females than males across all age groups suffer from migraine. The highest incidence rate of migraine has been recorded among both males and females aged 10 to 14 years (Safiri 2022), and in the middle‐aged (Steiner 2018). The risk factors for migraine include hormone imbalances; metabolic, genetic, and demographic factors;‐and lower socioeconomic and education levels (Amiri 2022). The high prevalence of migraine, combined with the substantial frequency and duration of its attacks, make it the second most disabling disease worldwide, measured in years lived with disability, and the first among the female population between 19 and 50 years (Steiner 2020). In addition to the significant personal burden it creates, migraine is an important cause of presenteeism and absenteeism, yielding significant direct and indirect costs to society (Linde 2012). Most of the migraine‐associated burden is carried by people living in the developing world (Ashina 2021b).

The exact pathophysiology of migraine is still not completely understood. Preclinical evidence suggests that both cortical spreading depression (the mechanism behind migraine with aura (Hadjikhani 2001)), and metabolic impairment in the cerebral cortex (a plausible mechanism explaining migraine without aura (Gross 2019; Lisicki 2018)), can generate the opening of pannexin channels in neurons (Karatas 2013; Kiliç 2018). These mega channels act as sensors of cortical homeostasis. When activated, they induce a cascade of cellular communication processes that leads to the release of inflammatory mediators into the subarachnoid space, activating the trigeminovascular system, and producing pain (Karatas 2013). Because of these converging mechanisms of pain development, it is uncertain whether migraine pain with an aura or without one should be treated differently; clinical evidence is mixed on this point.

Although migraine with aura and migraine without aura are classified as different subtypes of migraine, most people who suffer migraine with aura also suffer attacks of migraine without aura, supporting a partially common pathophysiological background. Aura may also occur without headache, or may accompany rather than precede it (Hansen 2019). One hypothesis suggests that the pathophysiological mechanism of aura (cortical spreading depression) plays a primary role in all migraine attacks, producing overt symptoms (the aura) in some, but evolving 'silently' or unnoticed in others (Charles 2017).

One complication of migraine is the risk of medication‐overuse headache, which is defined as headache occurring more than 15 days a month in a person with a pre‐existing headache disorder who overuses symptomatic treatment for headache for over three months (IHS 2018; Negro 2011). The definition of overuse depends on the class of the symptomatic drug. For simple analgesics, overuse is using medication for 15 days or more a month, whereas for triptans and opioids, it is using medication 10 days or more a month (IHS 2018). Medication‐overuse headache imposes an additional burden on people with migraine (Vandenbussche 2018).

Description of the intervention

Commonly used to treat postoperative pain, colic pain, cancer pain, and migraine, dipyrone is a simple analgesic that is sold over the counter in many developing countries, but is banned in the USA, Eastern Europe, and recently, in India because of a presumed risk of agranulocytosis (a potentially life‐threatening haematological disorder (Andersohn 2007; Andrade 1998; Bhaumik 2013)).

Dipyrone is an organic sodium salt of antipyrine whose chemical structure is similar to amidopyrine (NCBI 2022). It has anti‐inflammatory, spasmolytic, and antipyretic properties, and is available as a single drug or is combined with other medications (Levy 1995; Sznejder 2022). Dipyrone is mainly administered orally or by intravenous infusion, but it can also be administered intramuscularly or in suppositories. Dipyrone is rapidly hydrolised to its principal active metabolite, 4‐methyl‐amino‐antipyrine (MAA), which reaches maximal systemic concentration in about 1.2 to 2 hours. MAA pharmacokinetics are non‐linear. Excretion of its metabolites is reduced with multiple dosing and in the elderly, and might be increased in children (Levy 1995). A dosage of 500 mg to 1000 mg may be administered up to three times a day in adults, with a daily limit of four grams (Bordini 2016; Peres 2021). Clinical evidence in paediatric populations is sparse, but an expert consensus recommends a dose of up to one gram a day for children younger than six years old, up to two grams a day for six‐ to 12‐year‐olds, and up to three grams a day from age 12 years to adulthood (Ziesenitz 2019).

Where available, dipyrone is commonly used by people with migraine to treat attacks (Peres 2021). If, as suggested by some current evidence, the risk of dipyrone‐induced adverse events has been overestimated in the past, this analgesic may represent a clinically effective and safe alternative for the acute treatment of migraine, worthy of recommendation (Ibáñez 2005; Kötter 2015).

How the intervention might work

First‐line options for acute migraine treatment are simple analgesics (such as paracetamol), non‐steroidal anti‐inflammatory drugs, and triptans (Ashina 2021). Although the mechanism of action of dipyrone is not fully understood, it could improve migraine pain through several pathways. Experiments suggest that dipyrone inhibits central prostaglandin synthesis and cyclooxygenase‐3, and induces activation of the opioidergic system, reducing inflammation and pain perception (Jasiecka 2014; Shimada 1994). Dipyrone also inhibits thalamocortical nociceptive transmission associated with trigeminal activation, a mechanism of major interest in migraine pathophysiology (Coppola 2020; Sokolov 2014). Finally, research has shown that dipyrone induces neuronal ATP‐sensitive potassium channel (K_ATP) opening and cannabinoid receptor 1 (CB₁) activation (dos Santos 2014). These are important observations since the fundamental role of potassium channels (K_ATP) in triggering migraine has recently been demonstrated (Al‐Karagholi 2019; Al‐Karagholi 2021), and evidence suggests that the cannabinoid system can modulate trigeminal nociception linked to migraine pain (Leimuranta 2014).

Why it is important to do this review

Studies have shown that there is room for improvement in migraine management (Ashina 2021b). Both preventive and acute therapeutic options have limited clinical efficacy, and are often associated with undesirable side effects. Ineffective therapies increase the risk of medication‐overuse headache (Charles 2017).

New therapeutic alternatives for migraine attacks are being introduced. Serotonin 1F receptor agonists (ditans, e.g. lasmiditan) and calcitonin gene‐related peptide (CGRP) receptor antagonists (gepants, e.g. ubrogepant, atogepant and rimegepant (Puledda 2023)), are now available, along with common analgesics and triptans (serotonin 1B and 1D receptor agonists (Al‐Hassany 2022; Clemow 2021; Tfelt‐Hansen 2000)). However, the newer drugs are often unavailable or unaffordable for people living in economically‐struggling nations (Ashina 2021), and public health models suggest that self‐management with simple analgesics is probably the most cost‐effective strategy for migraine treatment in low‐ and middle‐income countries. This represents an efficient use of health resources that contributes to reducing disease‐associated direct and indirect costs (Linde 2015). Therefore, existent attack‐treatment options cannot be disregarded, particularly if they show established benefits, and prove to be safe for people with migraine.

The previous review on this topic focused on acute primary headaches (including migraine, tension‐type headache, cluster headache, or unclassified primary headache) in both adults and children. Ramacciotti 2007 only identified a few trials, with a limited number of participants. Three of the four trials evaluated intravenous dipyrone for migraine and episodic tension‐type headache in adults. They found no evidence for children, and concluded the effectiveness of dipyrone for acute treatment of migraine remained unclear.

With the introduction of newer treatments, it is time to update the review. Tension‐type headaches will be reviewed in a separate, future review. This review will focus on the potential risks and benefits of dipyrone for migraine, in both adults and children. We hope to find more evidence on the occurrence of agranulocytosis and other haematologic dyscrasias, which led to its ban in several countries.

We will use up‐to‐date Cochrane methods for a comprehensive report on dipyrone treatment. We will review and present evidence for adults and children separately, as effects are likely to differ between these groups. The evidence identified in this review will also help pinpoint gaps and highlight areas where future research is needed.

Objectives

To assess the efficacy and safety of dipyrone for the acute treatment of migraine headache in children and adults.

Methods

Criteria for considering studies for this review

Types of studies

We will include parallel randomised controlled trials (RCTs), including cross‐over trials.

We will include online clinical trial results, summaries of otherwise unpublished clinical trials, and abstracts; if there are insufficient data for analysis in the abstracts, we will attempt to locate the full study (e.g. by contacting the study authors). If the data from the full study are unavailable, we will add the abstract to studies awaiting classification.

We will include cluster‐RCTs, provided they account for randomisation of groups of individuals, rather than the individuals, to interventions (i.e. unit of analysis).

We will exclude non‐randomised studies, experimental studies using pain induction, case reports, and clinical observations.

Types of participants

We will include studies of children (2 years to 17 years) and adults (18 years to 65 years), in all settings, with a diagnosis of migraine with aura or without aura for at least one year before inclusion into the trial. Migraine with aura can be classified as having one or more fully reversible aura (visual, sensory, speech or language (or both), motor, brainstem, or retinal symptoms) with at least two of the following occurring in succession.

• At least one type of aura spreading gradually for five minutes or longer

• Each aura lasts for 5 minutes to 60 minutes

• At least one unilateral aura (e.g. aphasia)

• Aura accompanied by, or followed by, headache within 60 minutes (IHS 2018)

We will analyse results from both populations (migraine with and without aura) together, with exploratory subgroup analysis performed when possible.

We will include participants who are receiving concomitant therapies to treat non‐migraine conditions.

For studies that involve participants who have migraine with co‐existing headache, we will consider whether migraine is the primary focus of the study.

If we find studies in which only a subset of relevant participants are included, we will contact the study authors to obtain data.

We will exclude studies in which participants are receiving the following.

• Antipsychotics and antidepressants

• Preventative migraine treatment

• Other drugs suspected to cause agranulocytosis, such as carbamazepine, sulfasalazine, methimazole, piperacillin‐tazobactam, vancomycin and meropenem

Types of interventions

We will include studies involving dipyrone, at any dosage, frequency, timing, or route of administration, intended to target migraine as a primary or secondary outcome.

We will compare dipyrone to placebo, or another active comparator.

Types of outcome measures

We selected specific outcomes based on recommendations from the International Headache Society Guidelines for Controlled Trials of Acute Treatment of Migraine Attacks in Adults (Diener 2019).

The ideal time to measure an outcome takes into consideration both the time to effective plasma concentration of a certain drug and the principles of good clinical practice (Diener 2019). To avoid possible undue harm associated with unnecessarily long periods without relief, the two‐hour cut‐off has been established, and several drugs approved for the treatment of a migraine attack have presented efficacy for this time point (Yang 2021).

Reporting one or more of the outcomes listed is not an inclusion criterion for the review. When a published study report does not appear to report one of these outcomes, we will access the trial protocol and contact the trial authors to ascertain whether the outcomes were measured but not reported. We will include any relevant trials that measure these outcomes but do not report the data, or do not report the data in a usable format. We will describe such trials narratively.

Primary outcomes

• Pain relief at two hours after treatment (pain reduced from severe or moderate to none or mild without the use of rescue medication)

• Absence of the most bothersome migraine‐associated symptom at two hours after treatment

• Adverse events (proportion of participants reporting any adverse event during the 24 hours after treatment: agranulocytosis, other serious adverse events, and adverse events leading to withdrawal)

Secondary outcomes

• Pain‐free response (complete resolution of migraine pain) at two hours after treatment (without the use of rescue medication)

• Sustained pain freedom at 24 hours after treatment (pain free within two hours, with no use of rescue medication or a second dose of study medication, i.e. dipyrone for 24 hours)

• Sustained pain relief (pain reduced from severe or moderate to none or mild without the use of rescue medication) during the 24 hours after treatment

• Relief of other symptoms associated with migraine at two hours after treatment (specifically aura, nausea, vomiting, photophobia, and phonophobia);

• Quality of life, measured at conclusion of the intervention (e.g. Migraine Specific Quality of Life Questionnaire (MSQ (Jhingran 1998))

• Functional disability, measured at conclusion of the intervention (e.g. Functional Impairment Scale (FIS))

• Participant satisfaction, measured at conclusion of the intervention

Search methods for identification of studies

Electronic searches

We will search the following databases from inception and without language restrictions, assuming we are able to find relevant translation assistance.

• The Cochrane Central Register of Controlled Trials (CENTRAL; latest issue) in the Cochrane Library

• MEDLINE Ovid (1946 to search date)

• Embase Ovid (1974 to search date)

• SciELO (Scientific Electronic Library Online; 1998 to search date)

• LILACS ((Latin American and Caribbean Health Science Information database; 1982 to search date)

The search strategy for MEDLINE is in Appendix 1. We will tailor searches to individual databases.

Searching other resources

We will search clinicaltrials.gov (www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (ICTRP; apps.who.int/trialsearch/) for ongoing trials. In addition, we will search the grey literature (i.e. conference proceedings, government reports, theses and dissertations, or working papers), check reference lists of identified reviews and included studies for additional studies, and perform citation searches on key articles. We will contact experts in the field for unpublished and ongoing trials. We will contact study authors for additional information where necessary.

Data collection and analysis

Selection of studies

Two review authors (ML, ALR) will independently assess the eligibility of each study identified through the search and remove duplicates with the assistance of Rayyan software (Ouzzani 2016). Independently, review authors will eliminate studies that clearly do not satisfy the inclusion criteria, and will obtain full copies of the remaining studies. Two review authors (ML, ALR) will independently read these reports to select relevant studies. In the event of disagreement, a third review author will adjudicate (SJ). We will not anonymise the studies before assessment. We will include a PRISMA flowchart in the full review (Moher 2009), as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2023). We will include studies in the review regardless of whether they report measured outcome data in a usable way.

Data extraction and management

Two review authors (ML, LL) will independently extract data using a standard piloted form and check for agreement before entering them into Review Manager (RevMan (RevMan 2024)). In the event of disagreement, a third review author will adjudicate (SJ). We will collate multiple reports of the same study, so that each study rather than each report is the unit of interest in the review. We will collect characteristics of the included studies in sufficient detail to populate a characteristics of included studies table in the full review.

We will extract the following information.

• Study design (including study date, publication type, methods, location, funding sources, study author declarations of interest)

• Setting

• Duration (post‐treatment and follow‐up)

• Participants (N, mean age, gender distribution, baseline migraine severity, duration of migraine, comorbidities, concomitant medication, inclusion and exclusion criteria, withdrawals)

• Intervention(s) (number of intervention groups, type, description of intervention, mode of intervention)

• Comparator(s) (type of comparator e.g. placebo or other active comparator, description of comparator)

• Outcomes (including measures and time points)

• Numerical data for outcomes of interest

• Type of analyses presented

Assessment of risk of bias in included studies

Two review authors (ALR, MNS)will independently assess the risk of bias in each included RCT using the RoB 2 tool (Higgins 2023c). RoB 2 is an improved version that accounts for developments in understanding bias and addresses limitations of the original Cochrane risk of bias tool (Sterne 2019). RoB 2 evaluates biases across five domains:

• random sequence generation

• allocation concealment

• blinding of participants and personnel

• incomplete outcome data

• selective outcome reporting

For each domain, we will answer the relevant signalling questions, based on trial information. These assessments will lead to judgements of low risk of bias, some concerns, or high risk of bias. We will transparently report these assessments in our systematic review.

We will synthesise the judgements across domains to determine the overall risk of bias for each trial. Trials with a low overall risk of bias contribute more robust evidence, while those with a high risk of bias may affect the certainty of evidence.

We will incorporate risk of bias assessments into the GRADE process.

By following this approach, we aim to provide a rigorous assessment of bias and enhance the transparency and reliability of our evidence synthesis.

Measures of treatment effect

We will follow guidance provided in the Cochrane Handbook (Schünemann 2023a). We will present dichotomous outcomes (e.g. adverse events) as risk ratios (RRs) with 95% confidence intervals (CIs).

For continuous outcomes, we will report the mean difference (MD) and 95% CIs for studies that have used similar or the same scales, the minimum and maximum of the scales, the direction of the scales, and the minimum clinically important difference (MCID) for the scales, where possible. We will ensure that all scales measure their effect in the same direction, and we will convert any that run counter to others to a uniform scale before we combine them (e.g. a high value for a scale indicates a poorer outcome for the participant and a low value indicates a good outcome). When studies report different scales to measure the same outcome, we will use standardised mean differences (SMD) and 95% CIs to evaluate treatment effects. We will interpret SMDs as small (0.2), moderate (0.5), and large (0.8 (Cohen 1988)).

The most commonly used scales for pain assessment are the visual analogue scale (VAS) and the numeric pain rating scale (NPRS), where reductions of two points or more are considered clinically important.

We will use the number needed to treat for an additional beneficial outcome (NNTB) and pooled percentages as absolute measures of benefit or harm.

When significantly more adverse outcomes occur with dipyrone compared with control (placebo or active treatment), we will use the number needed to treat for an additional harmful outcome (NNTH). When fewer adverse events occur less frequently in the dipyrone arm, we will use the number needed to treat to prevent harm (NNTp).

Unit of analysis issues

We expect that studies will randomise at the individual level. We will follow the Cochrane Handbook if we include studies that used cluster randomisation, and consider the clusters as the unit of analysis, rather than participants (Higgins 2023). Similarly, we will follow the guidance in the Cochrane Handbook on cross‐over trials, such as only including data from the first treatment phase to avoid unit of analysis issues (Higgins 2023). When studies include multiple interventions or control arms, or both, we will categorise them into intervention or control groups, as indicated. We will divide the control group equally across intervention arms to avoid double counting.

Dealing with missing data

We will contact study authors if outcome data are missing from study publications. We will use the available statistical information from the publication to calculate the necessary data (e.g. standard deviations from confidence intervals), where possible, if the data are not available from the study authors (Higgins 2023a; Higgins 2023b).

We will also attempt to assess differences between intervention groups as reasons for missing data (i.e. data not missing at random) and how these differences might bias results.

We will assess data using two primary approaches: available case analysis, and modified intention‐to‐treat (ITT) analysis. In our analyses, we will not impute missing variables when outcome data are not available or calculable. If published studies present both per‐protocol and ITT analyses, we will prioritise and extract ITT data. This approach minimises the impact of unknown information due to study participant attrition.

We will exclude data from outcomes where results from ≥ 10% of participants are missing with no valid justification provided or apparent, and comment on this. Given this case, we will undertake sensitivity analyses to investigate the effect.

Assessment of heterogeneity

We will assess the heterogeneity of response rates using L'Abbé plots, a visual method for assessing differences in results of individual studies. (L'Abbé 1987). Where data can be pooled, we will report the I² statistic.

We will assess heterogeneity by visually inspecting forest plots of pooled studies, and Chi² and I² statistics. We will interpret I² using the following thresholds (Deeks 2023):

• 0% to 40% might not be important;

• 30% to 60% may represent moderate heterogeneity;

• 50% to 90% may represent substantial heterogeneity;

• 75% to 100% – considerable heterogeneity.

Where heterogeneity is substantial or considerable (> 50%), we will investigate, and conduct sensitivity analyses if appropriate. We will also assess the clinical and methodological differences in population, intervention, outcomes, and study characteristics to determine whether meta‐analysis is appropriate.

Assessment of reporting biases

In evaluating publication bias, we will analyse the number of participants in trials where no effect is observed (relative risk of 1.0). We will assess the point estimate of the NNTB to determine if it surpasses a clinically significant threshold, following the approach outlined by Moore (Moore 2008). For this review, a clinically meaningful level will be defined as NNTB ≥ 8 for achieving pain‐free status at two hours, and NNTB ≥ 6 for headache relief at two hours.

We will investigate publication bias using funnel plots when there are at least 10 studies included in an analysis (Higgins 2023).

Data synthesis

We will analyse data using RevMan (RevMan 2024). We will calculate effect sizes and combine data for analysis when there are at least two studies and 200 participants for an outcome (Moore 1998). We will calculate the relative risk of benefit or harm with 95% CIs using a fixed‐effect model (Morris 1995). If there is substantial or considerable heterogeneity, we will compare this to a random‐effects model. We will calculate NNTB, NNTp, and NNTH with 95% CIs using the pooled number of events (Cook 1995).

We will use the z‐test to determine significant differences between NNTB, NNTp, or NNTH for different groups in subgroup and sensitivity analyses (Tramèr 1997).

We will compare dipyrone and different controls (i.e. placebo or active intervention) separately. We will not pool data from adult and children's populations in the analyses:

• Dipyrone only versus placebo (any route of administration)

• Dipyrone only versus other active intervention (any route of administration)

We will follow the Cochrane Handbook guidance on data from comparisons and outcomes that cannot be analysed in meta‐analyses (McKenzie 2023). For example, we will narratively describe data from comparisons and outcomes with only one study or fewer than 200 participants and include them in dedicated tables (different from the summary of findings tables) for information and comparison, but we will not analyse them quantitatively.

Subgroup analysis and investigation of heterogeneity

We will conduct subgroup analyses when at least ten eligible studies with a minimum of 200 participants are available to evaluate the following:

• Administration (any route)

• Type of migraine (with aura versus without aura)

Subgroup analyses aim to determine whether there is a more efficacious route of administration, and if the intervention works better in either of the two major classes of migraine.

Sensitivity analysis

We will perform sensitivity analyses to investigate the impact of heterogeneity on our review findings. These analyses will be conducted only when there are at least two eligible studies, each with a minimum of 200 participants, to include in the meta‐analysis within either subgroup. Our assessment of considerable or substantial heterogeneity will follow the methods outlined in the Assessment of heterogeneity section.

Summary of findings and assessment of the certainty of the evidence

Two review authors (ALR, MNS) will independently rate the certainty of the body of evidence for the outcomes listed below. We will use the GRADE approach to rate the certainty of the evidence using GRADEpro GDT software (GRADEpro GDT), and guidelines provided in the CochraneHandbook (Schünemann 2023), and in the GRADE Handbook (Schünemann 2013).

GRADE considers risk of bias, inconsistency, indirectness, imprecision, and publication bias to determine the certainty of evidence for each outcome. Well conducted randomised controlled trials provide high certainty evidence, and can be downgraded for important limitations.

Based on our GRADE assessment, we will assign a level of certainty (e.g. high, moderate, low, or very low) to the evidence for each outcome. High‐certainty evidence implies greater confidence in the effect estimate, while low‐certainty evidence suggests uncertainty.

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

• Serious or very serious study limitations (risk of bias);

• Important or serious inconsistency of results;

• Some or major indirectness of evidence;

• Serious or very serious imprecision;

• Probability of publication bias.

The grades of evidence are:

• High certainty: we are very confident that the true effect lies close to that of the estimate of the effect;

• Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different;

• Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect;

• Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.

We plan to include at least two summary of findings tables to present the main findings for dipyrone versus each comparison.

• Dipyrone only versus placebo (any route of administration)

• Dipyrone only versus other active intervention (any route of administration)

We will include key information concerning the certainty of the evidence, the magnitude of the effect of dipyrone comparisons, and the sum of the available data on these outcomes:

• Pain relief at two hours after treatment

• Absence of the most bothersome migraine‐associated symptom at two hours after treatment

• Adverse events during the 24 hours after treatment

• Pain‐free response at two hours after treatment

• Sustained pain freedom at 24 hours after treatment

• Relief of other symptoms associated with migraine at two hours after treatment

• Functional disability at conclusion of the intervention

Appendices

Appendix 1. MEDLINE search strategy

1. Dipyrone/

2. (dipyrone or met?amizole).tw.

3. (6429l0l52y or 68‐89‐3 or algopyrin or analgin or biopyrin or dipyrone or dipyronium or methampyrone or narone or noramidopyrine methanesulfonate or normelubrine or novalgetol or novalgin or novamidazophen or novaminsulfone or optalgin or pyralgin or sulpyrin* or vsu62z74on).tw.

4. 1 or 2 or 3

5. (headache* or migrain* or cephalgi* or cephalalgi*).tw.

6. exp Headache Disorders/

7. 5 or 6

8. 4 and 7

Contributions of authors

All authors (ML, ALR, LL, MNS, SJ) contributed to the discussion of the PICO criteria, methodology, and development of the protocol draft.

Sources of support

Internal sources

• Cochrane Pain Palliative and Supportive Care Review Group / Cochrane Central Editorial Service, UK

  Cochrane

• Instituto Conci Carpinella, Argentina

  Protected research time and technical support.

• University of the West of England, UK

  Protected research time

• Institute of Psychiatry, Psychology and Neuroscience, King's College, UK

  Protected research time

External sources

• National Institute for Health Research (NIHR), UK

  Cochrane Infrastructure funding to the Cochrane Pain, Palliative and Supportive Care Review Group (PaPaS)

Declarations of interest

Marco Lisicki is a neurology specialist physician and works with people with migraine. He has received speaker honoraria and congress travel grants from Novartis, Teva, Pfizer, and Allergan/Abbvie. He also received honoraria for participating on advisory boards for Allergan/Abbvie and Pfizer.

Marcio Nattan Souza is a neurology specialist physician and works with people with migraine. He has received honoraria from Sanofi for an advisory board regarding new molecules for migraine treatment (no relation to dipyrone) and speaker honoraria from Novartis, TEVA, Lilly, Pfizer, Lundbeck, Libbs, and Allergan/Abbvie.

Alejandro Labastida‐Ramírez has no conflicts to declare.

Lucas David Llenas is an anaesthesiology specialist physician and works with people with several types of pain.

Sadia Janjua has no conflicts to declare.

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