Headache Medicine 2021, 12(3):168-181 p-ISSN 2178-7468, e-ISSN 2763-6178

168

ASAA

DOI: 10.48208/HeadacheMed.2021.31

Headache Medicine

Review

Pizotifen for the treatment of migraine. A systematic review and

meta-analysis

Yara Dadalti Fragoso , Giullia C. Mangas Lopes , Giovanna Marcilio Santos , Paula Carturan ,

Ana Luiza C. Martimbianco

Universidade Metropolitana de Santos, São Paulo, Brazil

Abstract

Introduction

Pizotifen is an oral drug developed many years ago for the prophylaxis of migraine. Trials on

pizotifen are decades old, and there has never been a systematic review and meta-analyses

of data from these clinical studies.

Methods

This is a systematic review and meta-analyses on pizotifen's efcacy and safety for prophylac-

tic migraine treatment. We considered for inclusion only randomized clinical trials (RCTs).

A comprehensive electronic search was performed without language, date or publication

status restrictions in the formal electronic databases, clinical trial registration platforms and

grey literature.

Results

There were eight RCTs of pizotifen compared either to placebo or to other drugs. Very low

certainty of evidence showed that pizotifen seems to be superior to placebo regarding clinical

symptoms improvement (Relative risk [RR] 6.00; 95% Condence interval [CI] 1.63 to 22.03;

p = 0.007), but not inferior to naproxen, unarizine, valproate or clonidine. Weight gain

was the most frequent adverse event of pizotifen but there was no difference with placebo

(RR 1.92; 95% CI 0.30 to 12.38; 2 RCTs; 142 participants; I2 = 67%; p = 0.49).

Conclusion

The RCTs of pizotifen were decades old. It is a safe and potentially efcacious inexpensive

drug that deserves a better designed, modern clinical trial before being dismissed as an

option for migraine therapy. PROSPERO Register: CRD42020194347.

Yara Dadalti Fragoso

Universidade Metropolitana de

Santos (UNIMES)

Avenida Conselheiro Nebias,

536 - Encruzilhada, Santos - SP,

11045-002

Phone: +55 (13) 3228-3400

yara@bsnet.com.br

Edited by:

Marcelo Moraes Valença

Keywords:

migraine

pizotifen

headache

systematic review

evidence-based medicine

Received: April 9, 2021

Accepted: September 30, 2021

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Fragoso YD, Lopes GCM, Santos GM, Carturan P, Martimbianco ALC

Pizotifen for the treatment of migraine. A systematic review and meta-analysis

Introduction

igraine affects over 10% of adults and can limit their

activities both at home and at work.

The socioeco-

nomic costs of migraine are remarkably high, and patients

tend to overuse medications for the pain if the headache is

not properly treated.

This disease is an important cause of

absenteeism and presentism at work, missed days at school

and excessive numbers of medical consultations and exam-

inations.

Although several medications have been used for

prophylaxis of migraine attacks, only two classes of drugs

presently commercialized have been specically developed

for this condition. One of the drugs is the relatively old

pizotifen and the other is the monoclonal antibody (MAb)

anti-CGRP. Small oral molecules with anti-CGRP effect are

undergoing clinical trials.

Anti-CGRP monoclonal antibodies have a strong placebo

and weak nocebo effect.

This, in addition to their good

safety prole [Hou], makes these drugs successful in

controlling migraine. The complicating aspect of this

treatment is its cost of circa USD 200/month per patient.

In places with high

per capita

income and/or in countries

with healthcare systems providing reimbursement of the

drug, use of anti-CGRP MAbs can thrive.

Pizotifen, on the other hand, costs little. The only bothersome

adverse event caused by pizotifen is weight gain, which

can be tolerated by some patients if they know what

to expect. It is hard to nd pharmacies selling branded

pizotifen: it is mostly available online and at compounding

pharmacies. Pizotifen may decrease migraine attacks at a

fraction of the price of some other drugs. There has never

been a systematic review and meta-analysis on pizotifen for

the treatment of migraine.

Apart from pizotifen and anti-CGRP MAbs, other drugs are

used in migraine prophylaxis, like tricyclic antidepressants,

calcium channel blockers, betablockers and anticonvulsants.

For all these drugs, the prole of adverse events is worse

than that of pizotifen or anti-CGRP MAbs.

Should pizotifen prove to be an efcient and safe

prophylactic drug for migraine, many individuals who

cannot afford the expensive new therapy could benet

from the older one. Thus, the objective of this systematic

review was to assess the effects (benets and harms) of

pizotifen for treating migraine in adults.

Methods

This systematic review followed the methodological

recommendations of the Cochrane Handbook for

Systematic Reviews of Interventions

and the PRISMA

statement (Preferred Reporting Items for Systematic

Reviews and Meta-Analyses) to ensure the quality of the

report.

This systematic review protocol was prospectively

registered in the PROSPERO (International Prospective

CRD42020194347.

Criteria for including studies for this review

We considered randomized clinical trials (RCTs) with

parallel design, assessing the effects (benets and harms)

of pizotifen for treating migraine in adults (over 18 years),

who reported episodic or chronic migraine with or without

aura. Studies that included any other headache condition

were excluded if data were not presented separately for

patients with migraine. The RCTs included compared any

dose or scheme of pizotifen with placebo, no intervention,

or another active drug treatment.

Types of outcome measurements

Primary outcomes

-Reduction of frequency and/or severity and/or

duration of migraine attacks.

-Reduction of medications taken to treat a migraine

attack.

-Adverse events: proportion of participants with at least

one adverse event resulting from the use of pizotifen

(for example, any gastrointestinal events or allergy).

Secondary outcomes:

-Patients' satisfaction and preferences.

-Tolerability of weight gain.

We considered all time points reported by the RCTs, but

we only pooled similar time points: short term (up to 8

weeks of treatment), intermediate-term (9 to 16 weeks of

treatment) and long term (over 16 weeks of treatment).

Search methods for identification of studies

A comprehensive electronic search was performed on July

20, 2020, and was updated on February 18, 2021. There

were no restrictions regarding language, date or publication

status. Sensitive search strategies were developed for

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Pizotifen for the treatment of migraine. A systematic review and meta-analysis

the following databases: The Cochrane Central Register

of Controlled Trials (CENTRAL) (via Wiley); MEDLINE

(via PubMed); EMBASE (via Elsevier); Literatura Latino

Americana em Ciências da Saúde e do Caribe - LILACS

(via Biblioteca Virtual em Saúde - BVS); and PsycINFO (via

EBSCO). We also searched for clinical trial registration

platforms: Clinical Trials.gov (https://ClinicalTrials.gov/)

and WHO International Clinical Trials Registry Platform

(ICTRP) (https://www.who.int/ictrp/search/en/). The

grey literature was searched via OpenGrey (http://www.

opengrey.eu/). Hand searching was done by verifying the

lists of references from relevant studies. Search strategies

for each database were presented in the Supplementary

material 1.

Data collection and analysis

Selection of studies and data extraction

All titles and abstracts obtained through the search

strategies were included in a reference management

program (Endnote ) where duplicates were removed.

Two authors independently selected titles and abstracts

of the references retrieved using the software Rayyan.

All

references classied as 'potentially eligible' were read in

full text to conrm their eligibility.

The data extraction process was carried out by three

independent authors using a pre-established data extraction

form. Two other authors resolved all discordance in the

selection and extraction process. When necessary, the

authors of the trials included in the review were contacted

for additional information.

Risk of bias (quality) assessment

Two independent authors assessed the methodological

quality of the studies included using the Cochrane Risk

of Bias (RoB) table

, which classify each of the following

domains as presenting a high, low or unclear risk of bias: (1)

random sequence generation; (2) allocation concealment;

(3) blinding of participants and personnel; (4) blinding

of outcome assessors; (5) incomplete outcome data; (6)

selective reporting of outcomes; and (7) other potential

sources of bias (for example, baseline imbalances). A third

author was consulted in cases of disagreement.

Data synthesis

We planned to calculate risk ratios (RR) for dichotomous

outcomes and mean differences (MD) for continuous

outcomes, or the standard mean difference (SMD), if any

outcome of interest had been measured using different

scales or questionnaires (95% condence interval). When

possible (if data were available and homogeneous),

treatment effects were combined using a random-

effects model meta-analysis in the Review Manager

5.4.1 software. The heterogeneity between the studies

included was evaluated according to the clinical and

methodological characteristics. Statistical heterogeneity

was assessed through visual inspection of forest plots. We

calculated a chi² test, considering p > 0.1 as indicative

of statistical heterogeneity, and an I² test for measuring

inconsistency across studies (we dened I² > 50% as

indicative of signicant inconsistency).

Subgroup and sensitivity analysis

We planned to assess subgroups for all primary outcomes,

comparing separated results between adults and children.

We also planned to conduct a sensitivity analysis in which

RCTs with a high risk of bias (selection, detection and

attrition bias) would be excluded from the meta-analysis.

Publication bias assessment

Publication bias would be investigated through analysis of

funnel plots if there had been meta-analyses with at least

ten studies.

Assessment of the certainty of the evidence

Two independent authors assessed the certainty of the

body of evidence for primary outcomes from the main

comparison: pizotifen versus placebo, using the GRADE

approach (Grading of Recommendations, Assessment,

Development and Evaluations).

We summarized the

evidence in the 'Summary of ndings table' (SoF table)

through the GRADEpro GDT platform.

Results

Search results

The results from the search strategies, retrieved 749

records. After removing 104 duplicates, 645 were

analyzed using the title and abstract. Of these, 623 did

not full the inclusion criteria and were excluded. Twenty-

two studies were analyzed using the full text, and nine

10-

were excluded (crossover trials). Five studies

19-23

were

classied as 'awaiting classication studies' because their

randomization was not clear, and we did not nd the

authors' contact details to request additional information.

Contacts with the editors of the journals in which these

papers were published were fruitless. Therefore, in the

end, eight RCTs were included in this review.

24-31

Figure 1

summarizes the study selection process.

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Pizotifen for the treatment of migraine. A systematic review and meta-analysis

Figure 1. PRISMA owchart.

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Fragoso YD, Lopes GCM, Santos GM, Carturan P, Martimbianco ALC

Pizotifen for the treatment of migraine. A systematic review and meta-analysis

Characteristics of the studies included

Table 1

summarizes the main characteristics of the eight RCTs included.

Table 1. Main characteristics of the included studies.

Study, year,

country

Study

design

Participants Intervention Comparator(s) Outcomes of interest

Time

points

Funding

sources

Behan 1985

Scotland

RCT

n = 60

common migraine

>2 episodes/ month

mean 30 years

predominantly female (% NR)

Pizotifen 1.5 mg

(once, at night)

(n = 30)

Clonidine 25ug

twice/d

(n = 30)

* Number of episodes

* Duration of episodes

* Severity of episodes

* Adverse events (weight gain)

2 mo NR

Behan 1986

Scotland

RCT

n = 67

common migraine (dened by

WFN)

frequent migraine episodes >

2 years

age NR

82% female

Pizotifen 0.5 mg

three times/d

(n = 35)

Naproxen

sodium

550 mg twice/d

(n = 32)

* Number of episodes

* Duration

* Severity (excellent, moderate, mild, no

change or worse)

* Adverse events

(weight gain, nausea, vomiting)

* Analgesic medication required

3 mo NR

Bellavance et

al., 1990

Canada

RCT

n = 176

Common migraine (dened by

AHC), mean duration 11.9 years

6.7 episodes/month

mean 32.5 years

79% female

Pizotifen 0.5 mg

three times/d (0.5

mg at bedtime and

gradually titrated

up over 7 d to 0.5

mg three times/d)

(n = 55)

Naproxen

sodium 550 mg

twice/d

(n = 60)

Placebo

(n = 57)

* Frequency, duration and severity of

episodes (Headache Unit Index)

* Severity (rate of pain intensity, vomiting

episodes)

* Analgesic medication required

* Adverse events (weight gain,

gastrointestinal, skin effects)

* Patient’s global assessment

3 mo NR

Cerbo et al.,

1985

Italy

RCT

n = 30

4 to 14 episodes/month

> 6 episodes, last 6 months

aged 23 to 54 years

53.3% male

Pizotifen 1.5 mg

nightly, for 2 mon

(n=15)

Flunarizine 15

mg nightly, for 2

mo (n=15)

* Number of episodes (per month)

* Duration (per month)

* Severity (total hours of intense pain

per month)

* Adverse events (weight gain, daytime

sedation)

2 mo NR

Chitsaz et al.,

2012

Iran

RCT

n = 42

Common migraine (dened

by IHS)

frequent migraine episodes >

1 year

4 to 14 episodes/month, last 3

months

aged 23 to 54 years

57.1% female

Pizotifen 0.5 mg

(bedtime) in the

rst week; 1.5

mg (bedtime) in

the second and

subsequent weeks

(n = 21)

Sodium

valproate

200 mg twice/d

(n = 21)

* Number of episodes

* Duration

* Severity (VAS)

* Adverse events (weight gain, nausea,

vomiting)

3 mo

Isfahan

University

of Medical

Sciences,

Iran

Lawrence et

al., 1977

England

RCT

n = 36

Common migraine (dened by

AHC), mean duration 15.9 years

>4 episodes/ month

mean age 16-64 years

72.2% female

Pizotifen 0.5 mg

once/d (days 1-2),

twice/d (days 3-4),

three times (days

5-15), two tablets,

three times/d for

10 wks (n=14)

Placebo

same scheme

(n = 14)

* Headache index (number of episodes

x severity)

* Adverse events (weight gain)

3 mo NR

Louis et al.,

1982

Belgium and

Netherlands

RCT

n = 75

Common migraine (dened by

AHC)

> 6 episodes, last 6 months

mean age 37 years

55% female

Pizotifen 1 mg

nightly, and after

5 d, additional

0.5 mg capsules

twice/d, for 4 mo

(n=37)

Flunarizine

10mg nightly,

and after 5

d, additional

placebo capsules

twice/d for 4 mo

(n=38)

* Number of episodes

* Duration

* Severity (4-point scale)

* Adverse events (weight gain, daytime

sedation)

* Patient’s global assessment

4 mo NR

Rascol et al.,

1986

France

RCT

n = 35

Common migraine (dened by

AHC), >2 years

> 6 episodes, last 6 months

mean age 38 years

71% female

Pizotifen 0.73 mg

(days 1-2), 1.46

mg (days 4-6) and

2.19 mg (days

7-120), for 4 mo

(n=14)

Flunarizine 10

mg /d, for 4

months (n=21)

* Number of episodes

* Duration

* Severity (4-point scale)

* Adverse events (weight gain, changes

in blood pressure, hot ushes, drowsiness,

asthenia)

* Patient’s global assessment

4 mo NR

RCT: randomized clinical trial; n: number of participants; mg: milligrams; h: hours; NR: not reported; AHC: Ad Hoc Committee on Classication of

Headache; d: days; mo: months; WFN: World Federation of Neurology Research Group on Migraine and Headache; IHS: International Headache

Society; VAS: visual analogue scale.

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Pizotifen for the treatment of migraine. A systematic review and meta-analysis

Methodological quality assessment (risk of bias)

Figure 2

summarizes the review authors' judgments on each

risk-of-bias domain for each study included. The reasons

for each judgment are summarized in the "Risk of bias" is

detailed in

Supplementary Material 2

Regarding selection bias, only one study

reported using

an adequate method for generating the randomization

sequence, and this study was judged as presenting a low

risk of bias. In the other studies, insufcient information was

provided, and these were classied as having an unclear

risk of bias.

Regarding performance bias, three studies

24,25,28

were

classied as having high risk of bias because they were

single-blinded. Only one study

was considered as having

a low risk of bias regarding blinding of participants,

personnel and outcome assessors.

Four studies

24-26,29

had substantial losses of participants

during the study (16 to 44%) and were classied as

presenting high risk of attrition bias. Trial register protocols

were not available for any of the studies included, leading

to an overall unclear risk of reporting bias. Lastly, two

studies

27,29

did not describe the baseline characteristics

between groups and were judged as having unclear risk of

other sources of bias.

Figure 2. Risk-of-bias summary: review authors' judgments about each risk-

of-bias item for each study included.

Effects of interventions

Comparison 1. Pizotifen versus placebo

Frequency, intensity and duration of episodes

Two studies

26,29

evaluated these outcomes, and it was

not feasible to pool their results in a meta-analysis due

to their clinical diversity and the unavailability of data.

When possible, estimated effects were calculated using

individual study data.

Bellavance et al.

(112 participants) assessed a

headache unit index (sum of severity x duration of each

episode/number of treatment days) and reported that

use of pizotifen led to improvement after three months of

treatment, compared with placebo (mean of 3.27

versus

5.08 episodes per week). No difference was observed

regarding pain intensity (mean 1.80

versus

1.86),

severity of disability (mean 1.67

versus

1.77), duration

of episodes (mean 1.59

versus

1.55), use of migraine

rescue medication per week (mean 0.82

versus

1.26) and

vomiting episodes per week (mean 0.08

versus

0.48).

Lawrence et al. (1977)

(36 participants) assessed a

weekly headache index by multiplying the number of

episodes by their intensity, according to the following

scale: severe = 3, moderate = 2 and mild = 1. In the

pizotifen group, 85.7% (12/14) achieved complete

resolution of symptoms or progressive improvement after

three months of treatment, compared with 14.2% (2/14)

reporting slight improvement in the placebo group.

Pizotifen seemed to improve compared with placebo, but

this result was considered very imprecise due to the wide

condence interval (RR 6.00; 95% CI 1.63 to 22.03; p =

0.007).

Adverse events

The meta-analysis results showed no difference between

pizotifen and placebo regarding weight gain (ranging

from 0.5 to 4 kg) after three months of treatment. However,

an imprecision in this estimated effect was observed

due to the wide condence interval (RR 1.92; 95% CI

0.30 to 12.38; 2 RCTs; 142 participants; I

= 67%; p =

0.49) (

Figure 3

). Moreover, there was a slight statistical

heterogeneity (67%), which can be explained as possible

clinical differences between participants, including in the

treatment scheme with pizotifen.

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Pizotifen for the treatment of migraine. A systematic review and meta-analysis

Bellavance et al. (1990)

also presented a non-signicant

difference between their groups regarding the following

adverse events: gastrointestinal (7/58

versus

3/56); skin

(0/58

versus

1/56), and other (2/58

versus

4/56). The

adverse events informed by patients were generally of mild

or moderate intensity.

Patients' overall evaluation

In one study

, good or excellent ratings in the patients'

overall evaluation were reported by 68% of pizotifen-treated

participants and 36% of placebo-treated participants (p =

0.005).

Comparison 2: Pizotifen versus unarizine

- Frequency, intensity and duration of episodes

Regarding the severity of episodes measured on a pain

intensity scale, in one study

an improvement of 81% in

the unarizine group was observed, compared with 40% in

the pizotifen group (p < 0.01). The episodes' duration was

not signicantly changed by either pizotifen or unarizine

(mean 8.5

versus

31, respectively). Louis et al.

used a

4-point scale to assess the severity of the episodes, and no

difference was noted between pizotifen and unarizine,

considering the number of participants with migraine

grade 1 (mild) after four months of treatment (RR 0.14;

95% CI 0.02 to 1.06; p = 0.06). This effect was uncertain,

given the breadth of the condence interval. These authors

also stated that the episodes' duration was not changed by

either drug (no numerical data provided).

Three studies

27,30,31

assessed these outcomes, but it was not

possible to group their data in a meta-analysis or calculate

the estimated effects for most individual studies due to

missing numerical data.

One study

(75 participants) presented a mean reduction

in the number of migraine episodes of 54% for the

unarizine group and 45% for the pizotifen group after

four months. The authors stated that there was a signicant

difference between the groups (p < 0.001). Cerbo et

al.

(30 participants) reported that there was no difference

between drug treatments regarding the mean reduction in

the number of episodes per month (mean 2.67 pizotifen

versus 3.56 unarizine). Rascol et al.

(35 participants)

reported that the reduction in the unarizine group (65%)

was slightly greater than in the pizotifen group (45%),

but the intergroup difference was not signicant after two

months of treatment (p = 0.10).

Adverse events

Weight gain was reported in the three studies comparing

pizotifen with unarizine

27,30,31

, ranging from 4 to 11 kg.

The results from a meta-analysis showed that there was no

difference between the groups (RR 1.07; 95% CI 0.57 to

2.01; 3 RCTs; 140 participants; I

= 0%; p = 0.84) (

Figure

In two studies

27,30

, daytime sedation among the participants

in both groups was reported. The results from a meta-

analysis showed no difference between groups (RR 0.49;

95% CI 0.24 to 1.01; 2 RCTs; 105 participants; I

= 0%;

p = 0.48). Rascol et al.

found no difference between

the groups regarding occurrences of other adverse

events, including changes in blood pressure, hot ushes,

drowsiness and severe asthenia (1/14

versus

2/15; RR

2.00; 95% CI 0.20 to 19.78; p = 0.55). However, both

effect estimates had wide condence intervals and were

Figure 3. Meta-analysis of pizotifen versus placebo. Outcome: adverse events (weight gain).

Figure 4. Meta-analysis of pizotifen versus unarizine. Outcome: adverse events (weight gain).

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Pizotifen for the treatment of migraine. A systematic review and meta-analysis

highly imprecise.

Patients' overall evaluation

The participants in two studies

30,31

reported that the effects

from both treatments were positive, but there was no

signicant difference between the groups after 4 months

of treatment (RR 0.90; 95% CI 0.61 to 1.32; 2 RCTs; I2 =

0%; 101 participants; p = 0.40) (

Figure 5

The pooled results from two studies

26,27

showed that subjects

who received naproxen presented less weight gain than

those who received pizotifen. However, this meta-analysis

was very imprecise (RR 11.45; 95% CI 1.52 to 86.21; 2

RCTs; I2 = 0%; 183 participants; p = 0.90) (

Figure 6

In two studies

26,27

, other adverse events relating to the

treatments were reported. These included nausea,

Comparison 3: Pizotifen versus naproxen

- Frequency, intensity and duration of episodes

Two studies

25,26

assessed these outcomes, but it was not

possible to group their data in a meta-analysis because

the outcomes were measured using different methods. In

one study

(67 participants), no signicant differences

between the groups were found regarding frequency (MD

-0.10; 95% CI -0.68 to 0.48) or severity of episodes (MD

-0.20; 95% CI -0.93 to 0.53), after 3 months of treatment.

There were no signicant differences between the

groups regarding the duration of attacks or use of rescue

medication (no numerical data provided).

In another study

(115 participants), a headache unit

index (sum of severity and duration of each episode/

number of treatment days) was assessed, and no difference

was found between the groups after three months (mean

of 3.27

versus

2.85 episodes per week). There were also

no differences regarding pain intensity (mean 1.80

versus

1.64), severity of disability (mean 1.67

versus

1.58),

duration of episodes (mean 1.59

versus

1.35), migraine

rescue medication per week (mean 0.82

versus

0.73) or

vomiting episodes per week (mean 0.08

versus

0.25).

Adverse events

Figure 5. Meta-analysis on pizotifen versus unarizine. Outcome: patients' overall evaluation.

vomiting and gastrointestinal effects. However, there were

no differences between the groups observed.

Comparison 4: Pizotifen versus sodium valproate

- Frequency, intensity and duration of episodes

One study

(60 participants) assessed this comparison.

Signicant mean reductions in the frequency (MD 2.80;

95% CI 1.42 to 4.18) and severity (RR 1.30; 95% CI

0.61 to 1.99) of headaches were observed in the pizotifen

group, compared with the sodium valproate group, at the

end of three months. No difference in reducing headache

duration was found (RR 1.10; 95% CI -1.94 to 4.14).

Adverse events

Regarding safety, 30 participants presented one or more

adverse events during the study

: 18 in the pizotifen group

and 12 in the sodium valproate group. No difference in

weight gain was observed (RR 0.33; 95% CI 0.04 to

2.95). Sedation, nausea, and increased appetite were

the other adverse events observed after three months of

treatment, but no difference was noted between groups.

Comparison 5: Pizotifen versus clonidine

- Frequency, intensity and duration of episodes

One study

(60 participants) assessed this comparison

Figure 6. Meta-analysis on pizotifen

versus

naproxen. Outcome: adverse events (weight gain).

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and showed an overall greater improvement through

use of pizotifen than clonidine. After two months of

treatment, the authors reported that approximately 50%

of the participants who received pizotifen (6/14) had no

headaches, whereas only one participant who received

clonidine was completely headache-free (1/19). There

were overall reductions in the pizotifen group regarding

frequency, severity and duration of episodes and the

number of associated symptoms in most patients (RR 5.88;

95% CI 2.06 to 16.78; p = 0.0002).

Adverse events

The participants in the study by Behan et al.

presented

weight gains. However, no numerical data were provided,

and the authors reported that only in one case, was it

sufcient to cause the patient's withdrawal from the study.

No adverse events were seen in the clonidine group.

Certainty of the evidence

Based on the GRADE approach, the certainty the evidence

regarding pizotifen

versus

placebo was classied as

'very low'. It indicated that we had little condence in

the effect estimate. The evidence was downgraded due

to methodological limitations, inconsistency (substantial

heterogeneity between studies) and imprecision (wide

condence intervals and small sample size). The ndings

are summarized in a table of assessment details, which is

presented as

Supplementary Material 3

Discussion

Migraine is a burden for patients and society. The

socioeconomic costs of migraine are immense

, with

average direct costs of €2427/patient/year in the USA

and Canada

and €1222 to €1482/patient/year in

Europe.

34,35

These societies will invest in newer drugs

and will reimburse the costs of anti-CGRP MAbs so that

migraineurs will have lower nancial burdens and less

absenteeism and presenteeism. The same cannot be said

for developing countries, where treating migraine at the

cost of circa €1600/patient/year is unrealistic. Poorer

countries require efcient but inexpensive drugs that provide

effective migraine treatments. For this situation, pizotifen

may be an alternative. This systematic review has shown

that pizotifen is superior to placebo and not inferior to

naproxen, unarizine, valproate or clonidine. The ensuing

weight gain is not tolerated by all patients

, but it may be

acceptable in some cases and situations. An additional

benet of pizotifen is a very safe prole in pregnancy

cases (category B in the Food and Drug Administration

- FDA). All other prophylactic migraine treatments are at

least category C by the FDA.

The adverse events reported in pizotifen trials are essentially

restricted to weight gain. The prole of adverse events of

most prophylactic drugs for migraine leads to high rates of

discontinuation.

Even for erunumab, an anti-CGRP MAb,

the discontinuation rate over six months was 27.7% in real

life.

Trials on pizotifen were conducted decades ago, with low

numbers of participants and unclear risks of bias. The

patients with migraine included in most pizotifen studies

were not selected to take the International Headache

Society criteria into consideration criteria.

It is unlikely that

an inexpensive drug-like pizotifen will be tested in modern

trials. In an ideal scenario, a new trial should compare

pizotifen's efcacy and safety compared to another drug.

Despite the limitations mentioned above, we believe that

these meta-analyses' results are sufcient for pizotifen to be

considered in treatments for migraine for patients who are

not preoccupied with weight gain.

Conclusion

Pizotifen was superior to placebo and not inferior to

naproxen, unarizine, valproate or clonidine, for treating

migraine. The adverse events from the use of pizotifen were

restricted to weight gain. The clinical trials on pizotifen are

now a few decades old, and the body of evidence was

classied as 'very low' due to methodological limitations.

A new trial in the 21

century could render good evidence

for this inexpensive drug's safety and efcacy.

Funding: none.

Conflicts of interest/competing interests: none.

Authors contribution: all authors contributed to the study

concept and design and participated in searching and

selecting articles. ALCM, carried out meta-analyses; YDF,

paper draft and nal version.

Yara Dadalti Fragoso

https://orcid.org/0000-0001-8726-089X

Giullia C. Mangas Lopes

https://orcid.org/0000-0002-3223-9871

Giovanna Marcilio Santos

https://orcid.org/0000-0002-7195-339X

Paula Carturan

https://orcid.org/0000-0002-1533-2206

Ana Luiza C. Martimbianco

https://orcid.org/0000-0002-4361-4526

177

ASAA

Fragoso YD, Lopes GCM, Santos GM, Carturan P, Martimbianco ALC

Pizotifen for the treatment of migraine. A systematic review and meta-analysis

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179

ASAA

Fragoso YD, Lopes GCM, Santos GM, Carturan P, Martimbianco ALC

Pizotifen for the treatment of migraine. A systematic review and meta-analysis

Supplementary material 1. Search strategy for each electronic database (on 20 July 2020 and updated on 18 February 2021).

MEDLINE

(via Pubmed)

#1 "Migraine Disorders"[Mesh] OR (Disorder, Migraine) OR (Disorders, Migraine) OR (Migraine Disorder) OR Migraine OR

Migraines OR (Migraine Headache) OR (Headache, Migraine) OR (Headaches, Migraine) OR (Migraine Headaches) OR

(Acute Confusional Migraine) OR (Acute Confusional Migraines) OR (Migraine, Acute Confusional) OR (Migraines, Acute

Confusional) OR (Status Migrainosus) OR (Hemicrania Migraine) OR (Hemicrania Migraines) OR (Migraine, Hemicrania) OR

(Migraines, Hemicrania) OR (Migraine Variant) OR (Migraine Variants) OR (Variant, Migraine) OR (Variants, Migraine) OR

(Sick Headache) OR (Headache, Sick) OR (Headaches, Sick) OR (Sick Headaches) OR (Abdominal Migraine) OR (Abdominal

Migraines) OR (Migraine, Abdominal) OR (Migraines, Abdominal) OR (Cervical Migraine Syndrome) OR (Cervical Migraine

Syndromes) OR (Migraine Syndrome, Cervical) OR (Migraine Syndromes, Cervical)

#2 "Migraine with Aura"[Mesh] OR (Migraine with Auras) OR (Familial Hemiplegic Migraine) OR (Familial Hemiplegic

Migraines) OR (Hemiplegic-Ophthalmoplegic Migraine) OR (Hemiplegic Migraine, Familial) OR (Migraine with Typical

Aura) OR (Classical Migraine) OR (Migraine, Classical) OR (Migraine, Classic) OR (Classic Migraine) OR (Migraine with

Acute Onset Aura) OR (Acute Onset Aura Migraine) OR (Migraine with Prolonged Aura) OR (Migraine, Prolonged Aura) OR

(Prolonged Aura Migraine) OR (Complicated Migraine) OR (Migraine, Complicated) OR (Basilar-Type Migraine) OR (Basilar

Type Migraine) OR (Migraine, Basilar-Type) OR (Basilar Migraine) OR (Basilar Migraines) OR (Migraine, Basilar) OR (Basilar

Artery Migraine) OR (Migraine, Basilar Artery) OR (Migraine Aura without Headache) OR (Typical Aura without Headache)

#3 "Migraine without Aura"[Mesh] OR (Common Migraine) OR (Common Migraines) OR (Migraines, Common) OR (Migraine,

Common)

#4 #1 OR #2 OR #3

#5 “Pizotyline"[Mesh] OR Pizotifen OR Polomigran OR Sandomigran OR (BC-105) OR (BC 105) OR (BC105)

#6 #3 AND #4 (236)

Embase

(via Elsevier)

#1 'migraine'/exp OR 'Disorder, Migraine' OR 'Disorders, Migraine' OR 'Migraine Disorder' OR Migraine OR Migraines OR

'Migraine Headache' OR 'Headache, Migraine' OR 'Headaches, Migraine' OR 'Migraine Headaches' OR 'Acute Confusional

Migraine' OR 'Acute Confusional Migraines' OR 'Migraine, Acute Confusional' OR 'Migraines, Acute Confusional' OR 'Status

Migrainosus' OR 'Hemicrania Migraine' OR 'Hemicrania Migraines' OR 'Migraine, Hemicrania' OR 'Migraines, Hemicrania'

OR 'Migraine Variant' OR 'Migraine Variants' OR 'Variant, Migraine' OR 'Variants, Migraine' OR 'Sick Headache' OR

'Headache, Sick' OR 'Headaches, Sick' OR 'Sick Headaches' OR 'Abdominal Migraine' OR 'Abdominal Migraines' OR

'Migraine, Abdominal' OR 'Migraines, Abdominal' OR 'Cervical Migraine Syndrome' OR 'Cervical Migraine Syndromes' OR

'Migraine Syndrome, Cervical' OR 'Migraine Syndromes, Cervical'

#2 'migraine with aura'/exp OR 'migraine without aura'/exp

#3 #1 OR #2

#4 'pizotifen'/exp OR pizotyline OR polomigran OR sandomigran OR 'bc 105' OR bc105

#5 #3 AND #4

#5 AND [embase]/lim NOT ([embase]/lim AND [medline]/lim) (469)

Cochrane Central

Trials (CENTRAL)

#1 MeSH descriptor: [Migraine Disorders] explode all trees

#2 "Disorder, Migraine" OR "Disorders, Migraine" OR "Migraine Disorder" OR Migraine OR Migraines OR "Migraine

Headache" OR "Headache, Migraine" OR "Headaches, Migraine" OR "Migraine Headaches" OR "Acute Confusional

Migraine" OR "Acute Confusional Migraines" OR "Migraine, Acute Confusional" OR "Migraines, Acute Confusional" OR

"Status Migrainosus" OR "Hemicrania Migraine" OR "Hemicrania Migraines" OR "Migraine, Hemicrania" OR "Migraines,

Hemicrania" OR "Migraine Variant" OR "Migraine Variants" OR "Variant, Migraine" OR "Variants, Migraine" OR "Sick

Headache" OR "Headache, Sick" OR "Headaches, Sick" OR "Sick Headaches" OR "Abdominal Migraine" OR "Abdominal

Migraines" OR "Migraine, Abdominal" OR "Migraines, Abdominal" OR "Cervical Migraine Syndrome" OR "Cervical Migraine

Syndromes" OR "Migraine Syndrome, Cervical" OR "Migraine Syndromes, Cervical"

#3 MeSH descriptor: [Migraine with Aura] explode all trees

#4 "Migraine with Auras" OR "Familial Hemiplegic Migraine" OR "Familial Hemiplegic Migraines" OR "Hemiplegic-

Ophthalmoplegic Migraine" OR "Hemiplegic Migraine, Familial" OR "Migraine with Typical Aura" OR "Classical Migraine"

OR "Migraine, Classical" OR "Migraine, Classic" OR "Classic Migraine" OR "Migraine with Acute Onset Aura" OR "Acute

Onset Aura Migraine" OR "Migraine with Prolonged Aura" OR "Migraine, Prolonged Aura" OR "Prolonged Aura Migraine"

OR "Complicated Migraine" OR "Migraine, Complicated" OR "Basilar-Type Migraine" OR "Basilar Type Migraine" OR

"Migraine, Basilar-Type" OR "Basilar Migraine" OR "Basilar Migraines" OR "Migraine, Basilar" OR "Basilar Artery Migraine"

OR "Migraine, Basilar Artery" OR "Migraine Aura without Headache" OR "Typical Aura without Headache"

#5 MeSH descriptor: [Migraine without Aura] explode all trees

#6 "Common Migraine" OR "Common Migraines" OR "Migraines, Common" OR "Migraine, Common"

#7 #1 OR #2 OR #3 OR #4 OR #5 OR #6

#8 MeSH descriptor: [Pizotyline] explode all trees

#9 Pizotifen OR Polomigran OR Sandomigran OR BC-105 OR "BC 10 5" OR BC105

#10 #8 OR #9

#11 #7 AND #10 (in Trials) (78)

Literatura Latino-

Americana em

Ciências da Saúde e

do Caribe - LILACS (via

Biblioteca Virtual em

Saúde - BVS)

#1 MH: "Transtornos de Enxaqueca" OR "Migraine Disorders" OR "Trastornos Migrañosos" OR

C10.228.140.546.399.750

#2 MH: Pizotilina OR Pizotyline OR Pizotilina OR D02.886.778.580 OR D03.383.903.580

#3 #1 AND #2 (4)

PsycINFO (APA)

Any Field: migraine disorders AND Any Field: Pizotyline (10)

ClinicalTrials.gov

Pizotifen AND Migraine (0)

WHO/ICTPR

Pizotifen AND Migraine (0)

180

ASAA

Fragoso YD, Lopes GCM, Santos GM, Carturan P, Martimbianco ALC

Pizotifen for the treatment of migraine. A systematic review and meta-analysis

Supplementary material 2. Judgments and justications for risk of bias assessments.

Study

(author

year)

Sequence generation

Allocation

concealment

Blinding participants/

personnel

Blinding outcome assessors Incomplete outcome

Selective

reporting

Other bias

Behan

1985

UNCLEAR

No information on

random sequence

generation

UNCLEAR

information

on allocation

concealment

HIGH

Quote: "A randomised,

single-blind study"

UNCLEAR

Blinding of outcome

assessors was unconrmed.

Judgement of subjective

outcomes is likely to be

inuenced by the lack of

blinding.

HIGH

Substantial losses

(26.6%), with

reasons: no data at

all were available

for 6 and a further 2

did not

return after the

admission interview.

No ITT analysis.

UNCLEAR

Unavailable

trial

protocol

LOW

No other

potentially

sources of bias.

Behan

1986

UNCLEAR

No information on

random sequence

generation.

UNCLEAR

information

on allocation

concealment

HIGH

Quote: "A randomised,

single-blind study"

UNCLEAR

Blinding of outcome

assessors was unconrmed.

Judgement of subjective

outcomes is likely to be

inuenced by the lack of

blinding.

HIGH

Substantial losses

(44%), with reasons:

16 in the naproxen,

15 pizotifen (due

to poor response,

adverse event, loss to

follow up, remission).

No ITT analysis.

UNCLEAR

Unavailable

trial

protocol

LOW

No other

potentially

sources of bias.

Bellavance

1990

UNCLEAR

Quote:

'patients

were assigned to

receive, according

to a predetermined

randomization code'.

Comment: Insufcient

information on

random sequence

generation.

UNCLEAR

information

on allocation

concealment

UNCLEAR

Quote: "

The drugs were

taken three times daily

using a double placebo

method.

" Comment: There

was insufcient information

on how blinding of

participants and personnel

was performed.

UNCLEAR

Quote: "

The drugs were

taken three times daily

using a double placebo

method

." Comment: There

was insufcient information

on how blinding of outcome

assessors was performed.

HIGH

Substantial losses

(16.4%), with

reasons: 7 dropped

out due to adverse

reactions, 4 were lost

to follow-up, 4 were

noncompliant and

10 dropped out due

to reasons unrelated

to therapy. No ITT

analysis.

UNCLEAR

Unavailable

trial

protocol

LOW

No other

potentially

sources of bias.

Cerbo

1985

UNCLEAR

Quote: '

i pazienti

sono stati assegnati

in maniera

randomizzata a due

gruppi, per effettuare

un trattamento di

due mesi

'. Comment:

Insufcient information

on random sequence

generation.

UNCLEAR

information

on allocation

concealment

LOW

Quote: '

i farmaci erano

stati consegnati in boccette

di plastica indentiche,

denominate A (pizitifene)

e B (unarizina). All'inizio

dello studio né i medici

né il paziente sapevano

quali farmaci fossero

presenti nelle boccette A

e B.

'. Comment: adequate

blinding

LOW

Quote: '

La valutazione

dell'effetto prolattico è

stata effettuata per mezzo

di controlli mensili dei

pazienti, mettendo in

evidenza le variazioni

di grequenza, intensità

e durata degli attachi.

Comment: outcome

assessment was conducted

by the patients, that were

blinded by the allocation

group.

LOW

No substantial losses

(10%), with reasons

UNCLEAR

Unavailable

trial

protocol

UNCLEAR

The study did

not describe

the baseline

characteristics

between

groups.

Chitsaz

2012

UNCLEAR

No information on

random sequence

generation.

UNCLEAR

information

on allocation

concealment

HIGH

Quote: '

This was a single

blind, randomized,

parallel-group study.

LOW

Quote: '

A research assistant

who was blind to the

type of intervention made

all evaluations.

UNCLEAR

It was not clear if

there were no losses

after randomization.

UNCLEAR

Unavailable

trial

protocol

LOW

No other

potentially

sources of bias.

Lawrence

1977

UNCLEAR

No information on

random sequence

generation.

UNCLEAR

information

on allocation

concealment

UNCLEAR

Blinding of outcome

participants and personnel

was unconrmed.

Judgement of subjective

outcomes is likely to be

inuenced by the lack of

blinding.

HIGH

Quote: '

Information

about migraine attacks

was recorded daily on

record cards

'. Comment:

Outcomes results could be

inuenced by this fact.

HIGH

Substantial losses

(22%), with reasons:

5 on active treatment

stopped because of

failure to improve,

symptoms resolved,

complained of

depression, and

felt "muzzy", bad

tempered and was

excessively hungry.

Three patients on

placebo stopped

treatment because it

was ineffective

. No

ITT analysis.

UNCLEAR

Unavailable

trial

protocol

UNCLEAR

The study did

not describe

the baseline

characteristics

between

groups.

181

ASAA

Fragoso YD, Lopes GCM, Santos GM, Carturan P, Martimbianco ALC

Pizotifen for the treatment of migraine. A systematic review and meta-analysis

Louis

1982

UNCLEAR

No information on

random sequence

generation.

UNCLEAR

information

on allocation

concealment

UNCLEAR

Blinding of outcome

participants and personnel

was unconrmed.

Judgement of subjective

outcomes is likely to be

inuenced by the lack of

blinding.

UNCLEAR

Blinding of outcome

assessors was unconrmed.

Judgement of subjective

outcomes is likely to be

inuenced by the lack of

blinding.

LOW

No substantial losses

(8%), with reasons.

UNCLEAR

Unavailable

trial

protocol

LOW

No other

potentially

sources of bias.

Rascol

1986

LOW

Quote: '

According

to a computer-made

randomization list

Comment: Insufcient

information on

random sequence

generation.

UNCLEAR

information

on allocation

concealment

UNCLEAR

Blinding of outcome

participants and personnel

was unconrmed.

Judgement of subjective

outcomes is likely to be

inuenced by the lack of

blinding.

UNCLEAR

Blinding of outcome

assessors was unconrmed.

Judgement of subjective

outcomes is likely to be

inuenced by the lack of

blinding.

LOW

No substantial losses

(8.5%), with reasons.

UNCLEAR

Unavailable

trial

protocol

LOW

No other

potentially

sources of bias.

Supplementary material 3. Summary of ndings table: pizotifen versus placebo.

Pizotifen compared to placebo for migraine

Patient or population: migraine

Setting: outpatient

Intervention: pizotifen

Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect

(95% CI)

of participants

(studies)

Certainty of the evidence

(GRADE)

Comments

Risk with placebo Risk with Pizotifen

Frequency, intensity and

duration of migraine episodes

assessed with: Headache

index

follow up: mean 3 months

143 per 1.000

857 per 1.000

(233 to 1.000)

RR 6.00

(1.63 to 22.03)

(1 RCT)

VERY LOW a,b

Adverse events (weight gain)

follow up: mean 3 months

114 per 1.000

219 per 1.000

(34 to 1.000)

RR 1.92

(0.30 to

12.38)

142

(2 RCTs)

VERY LOW a,b,c

*The risk in the intervention group (and its 95% condence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Condence interval; RR: Risk ratio

GRADE Working Group grades of evidence

High certainty: We are very condent that the true effect lies close to that of the estimate of the effect

Moderate certainty: We are moderately condent 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 condence 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 condence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Explanations

a. We downgraded 2 levels due to methodological limitations (unclear risk for selection and performance bias; and high risk for detection and attrition bias.

b. We downgraded 2 levels due to a wide CI and small sample size.

c. We downgraded one level due to substantial heterogeneity (I2=67%)