Current Pain and Headache Reports (2020) 24: 19

https://doi.org/10.1007/s11916-020-00852-0

OTHER PAIN (AD KAYE AND N VADIVELU, SECTION EDITORS)

A Comprehensive Review of Over-the-counter Treatment for Chronic

Migraine Headaches
Jacquelin Peck 1 & Ivan Urits 2 & Justin Zeien 3 & Shelby Hoebee 3 & Mohammad Mousa 3 & Hamed Alattar 3 & Alan D. Kaye 4 &
Omar Viswanath 5,6,7

Published online: 21 March 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Purpose of Review Migraine headaches are a neurologic disorder characterized by attacks of moderate to severe throbbing
headache that are typically unilateral, exacerbated by physical activity, and associated with phonophobia, photophobia, nausea,
and vomiting. In the USA, the overall age-adjusted prevalence of migraine in female and male adults is 22.3% and 10.8%,
respectively.
Recent Findings Migraine is a disabling disease that ranks as the 8th most burdensome disease in the world and the 4th most in
women. The overarching hypothesis of migraine pathophysiology describes migraine as a disorder of the pain modulating
system, caused by disruptions of the normal neural networks of the head. The activation of these vascular networks results in
meningeal vasodilation and inflammation, which is perceived as head pain. The primary goals of acute migraine therapy are to
reduce attack duration and severity. Current evidence-based therapies for acute migraine attacks include acetaminophen, four
nonsteroidal anti-inflammatory drugs (NSAIDs), seven triptans, NSAID–triptan combinations, dihydroergotamine, non-opioid
combination analgesics, and several anti-emetics.
Summary Over-the-counter medications are an important component of migraine therapy and are considered a first-line therapy
for most migraineurs. These medications, such as acetaminophen, ibuprofen, naproxen, and aspirin, have shown strong efficacy
when used as first-line treatments for mild-to-moderate migraine attacks. The lower cost of over-the-counter medications
compared with prescription medications also makes them a preferred therapy for some patients. In addition to their efficacy
and lower cost, over-the-counter medications generally have fewer and less severe adverse effects, have more favorable routes of
administration (oral vs. subcutaneous injection), and reduced abuse potential. The purpose of this review is to provide a
comprehensive evidence-based update of over-the-counter pharmacologic options for chronic migraines.

Keywords Pharmacology . Chronic pain . Migraine . Headache

This article is part of the Topical Collection on Other Pain

* Jacquelin Peck 3
University of Arizona College of Medicine-Phoenix, Phoenix, AZ,
Jacquelin.peck@msmc.com USA
4
Department of Anesthesiology and Pharmacology, Toxicology, and
Alan D. Kaye Neurosciences, Louisiana State University School of Medicine,
akaye@lsuhsc.edu; alankaye44@hotmail.com Shreveport, LA, USA
5
Department of Anesthesiology, University of Arizona College of
1
Department of Anesthesiology, Mount Sinai Medical Center, 4300 Medicine-Phoenix, Phoenix, AZ, USA
Alton Road, Miami Beach, FL 33140, USA 6
Department of Anesthesiology, Creighton University School of
2 Medicine, Omaha, NE, USA
Department of Anesthesia, Critical Care, and Pain Medicine, Beth
7
Israel Deaconess Medical Center, Harvard Medical School, Valley Anesthesiology and Pain Consultants, Envision Physician
Boston, MA, USA Services, Phoenix, AZ, USA
19 Page 2 of 9
Introduction
Migraine headaches are a neurologic disorder characterized
by attacks of moderate to severe throbbing headache that are
typically unilateral, exacerbated by physical activity, and as-
sociated with phonophobia, photophobia, nausea, and
vomiting [1]. In the USA, the overall age-adjusted prevalence
of migraine in female and male adults is 22.3% and 10.8%,
respectively. Migraine prevalence peaks between the ages of
18–44 for both sexes affect Caucasians at a higher rate and is
inversely proportional to income and educational attainment
[2••]. Migraine is a disabling disease that ranks as the 8th most
burdensome disease in the world and the 4th most in women
[3]. Nearly, 50% of those afflicted by migraine experience a
50% reduction in work or school productivity during attacks,
with absenteeism at work or school at least 1 day every
3 months [4]. Migraine also has a profound impact on health
care costs, accounting for an estimated annual direct cost of
$17 billion in the USA, not including the indirect costs of lost
productivity and reduced quality of life [5].
The overarching hypothesis of migraine pathophysiology
describes migraine as a disorder of the pain modulating sys-
tem, caused by disruptions of the normal neural networks of
the head [6]. Current research demonstrates that diencephalic
and brainstem nuclei modulate the activation of the
trigeminovascular system. This system consists of efferent
neurons innervating vascular networks in the head and affer-
ent neurons from these networks feeding information to the
trigeminal nucleus caudalis [6, 7]. The activation of these
specific vascular networks results in meningeal vasodilation
and inflammation, which is perceived as head pain [8, 9].
Neurotransmitters, such as serotonin, play a significant role
in the pathophysiology and accordingly, the treatment of mi-
graine. Serotonin binds primarily to G protein-coupled recep-
tors (except receptor 5-HT3, which is a ligand-gated cation
channel) and initiates an intracellular second messenger cas-
cade, resulting in either excitatory or inhibitory neurotrans-
mission. These serotonin receptors are dispersed throughout
the head, including along cranial blood vessels and pain sig-
naling circuits. Migraine therapies, such as triptans, have been
designed to stimulate serotonin receptors, particularly 5-
HT1b, 5-HT1d, and 5-HT1f receptors. This amplification of
the serotonin signal leads to pain relief through vasoconstric-
tion of cranial blood vessels and inhibition of peptides such as
calcitonin gene-related peptide (CGRP) [10] and substance P
[11].
The primary goals of acute migraine therapy are to reduce
attack duration and severity [12]. Other secondary objectives
of acute therapy include restoring patient’s ability to function,
minimizing the use of back-up and rescue medications, pro-
moting cost-effectiveness for overall management, and having
minimal or no adverse events [13]. Current evidence-based
therapies for acute migraine attacks include acetaminophen
Curr Pain Headache Rep (2020) 24: 19
[14••, 15], four nonsteroidal anti-inflammatory drugs
(NSAIDs) (ibuprofen, acetylsalicylic acid (ASA), naproxen
sodium, and diclofenac potassium) [16••, 17–19], seven
triptans (almotriptan, eletriptan, frovatriptan, naratriptan,
rizatriptan, sumatriptan, and zolmitriptan) [20, 21••],
NSAID–triptan combinations [22, 23], dihydroergotamine
[24], non-opioid combination analgesics (acetaminophen,
ASA, and caffeine) [25], and several anti-emetics
(metoclopramide, chlorpromazine, and prochlorperazine)
[26–28]. Although opioids such as butorphanol, codeine/acet-
aminophen, and tramadol/acetaminophen have shown effica-
cy, their benefit fails to surpass that of NSAIDs [29], and they
are not recommended for regular use due to the frequent de-
velopment of medication overuse headache (MOH) [12, 30].
Moreover, opioids should be avoided related to the risk for
addiction [13], potential for development of central sensitiza-
tion to opioid medications [31], and potential for reducing the
efficacy of other migraine therapies, such as triptans [32].
Over-the-counter medications are an important component
of migraine therapy and are considered a first-line therapy for
most migraineurs [33]. These medications, such as acetamin-
ophen, ibuprofen, naproxen, and aspirin, have shown strong
efficacy when used as first-line treatments for mild to moder-
ate migraine attacks [12]. The lower cost of over-the-counter
medications compared with prescription medications also
makes them a preferred therapy for some patients [34]. In
addition to their efficacy and lower cost, over-the-counter
medications generally have fewer and less severe adverse ef-
fects, have more favorable routes of administration (oral vs.
subcutaneous injection), and reduced abuse potential [12, 33].
The following comprehensive review breaks down the specif-
ic categories of over-the-counter pharmacologic options for
chronic migraine treatment with focus on background infor-
mation, systematic reviews and meta-analysis, and recent
trials.
Acetaminophen
Background
Acetaminophen, also known as paracetamol, is an antipyretic
agent and non-opioid analgesic that can be used to treat fever
and pain. As a single agent, acetaminophen is indicated for the
treatment of mild to moderate migraine [12]. The mechanism
of action of acetaminophen is not fully understood, but it acts
through inhibition of the cyclooxygenase (COX-1 and COX-
2) resulting in inhibition of prostaglandin synthesis.
Prostaglandins are significant mediators of the body’s inflam-
matory response. Unlike NSAIDs, acetaminophen only in-
hibits the COX pathways in the central nervous system, not
in peripheral tissues [35].
Curr Pain Headache Rep (2020) 24: 19
Formulations currently available in the USA for treatment
of migraine include 325 mg or 500 mg tablets as well as
combination pharmaceutical including acetaminophen in
combination with aspirin, caffeine, codeine, or tramadol
[12]. Adverse effects include headache, insomnia, nausea,
vomiting, constipation, itching, and atelectasis. Rare and seri-
ous adverse effects include toxic epidermal necrolysis, acute
generalized exanthematous pustulosis, Stevens-Johnson syn-
drome, liver failure, and pneumonitis. Contraindications to
acetaminophen use include hypersensitivity to acetaminophen
and severe liver disease [36].
Systematic Reviews
A 2013 Cochrane systematic review explored the efficacy and
tolerability of paracetamol alone, or in combination with an
antiemetic, compared with placebo and other medical inter-
ventions in the treatment of migraine in adults. Eleven studies
(2942 participants and 5109 migraine attacks) were included
in the review. For all studies, paracetamol was superior to
placebo when taken for moderate to severe pain in all three
pre-determined primary outcomes: 2-h pain-free, 2-h head-
ache relief, and 1-h headache relief. For the 2-h pain-free
outcome, paracetamol response was 19% versus 10% with
placebo with a number needed to treat (NNT) of 12. For 2-h
headache relief, the paracetamol response was 56% versus
36% with placebo with NNT of 5. For 1-h headache relief,
the paracetamol response was 39% versus 20% with placebo
with NNT of 5.2. Paracetamol 1000 mg plus metoclopramide
10 mg was not significantly different from oral sumatriptan
100 mg for 2-h headache relief. Adverse event rates were
similar between paracetamol and placebo, and between para-
cetamol plus metoclopramide and sumatriptan. Paracetamol
use alone did not result in any severe adverse events [37].
Another Cochrane systematic review in 2016 assessed the
efficacy and safety of paracetamol in the acute treatment of
frequent tension-type headache (TTH) in adults. Twenty-three
studies (8079 participants) were included in the review; how-
ever, only about 6000 participants were involved in compari-
sons between paracetamol 1000 mg and placebo. The primary
outcomes were 2-h pain-free and 2-h pain-free or 2-h mild
pain. For the 2-h pain-free outcome, the paracetamol response
was 24% versus 19% with placebo with NNT of 22. For 2-h
pain-free or 2-h mild pain, the paracetamol response was 59%
versus 49% with placebo with NNT of 10. The efficacy of
paracetamol 500 to 650 mg was not superior to placebo and
paracetamol 1000 mg was similar to ketoprofen 25 mg and
ibuprofen 400 mg in the treatment of TTH, although there was
low quality evidence supporting these results. Adverse events
were similar between paracetamol 1000 mg and placebo (RR:
1.1); 10% of participants taking paracetamol 1000 mg report-
ed an adverse event compared with 9% for those taking the
Page 3 of 9 19
placebo. There were no reported serious adverse events in
either treatment arm [38].
Recent Trials
A double-blind, placebo-controlled multicenter RCT by
Diener et al. found a significant difference in time to 50% pain
relief between patients taking paracetamol and the placebo
group. A total of 1743 patients from 133 medical centers with
an acute headache attack were enrolled in the study and were
randomized into six treatment groups: two tablets of 250 mg
aspirin (ASA) + 200 mg paracetamol + 50 mg caffeine;
250 mg ASA + 200 mg paracetamol; 2 tablets of 500 mg
ASA; two tablets of 500 mg paracetamol; two tablets of
50 mg caffeine; and placebo. The paracetamol treatment
group consisted of 276 patients. Although paracetamol was
superior to placebo for the primary outcome “time to 50%
pain relief” (81 min vs. 133 min), the combination of ASA
+ paracetamol + caffeine was superior to all other groups
(65 min). ASA + paracetamol (73 min) and ASA (79 min)
were also superior to paracetamol in time to 50% pain relief,
but paracetamol was shown to be superior to caffeine (81 min
vs. 107 min). Patients in the paracetamol group had the lowest
rate of adverse events at 5.8% with only 0.4% experiencing
severe adverse events [25].
A single-blind RCT by Gallelli, et al. concluded that acet-
aminophen significantly reduces the pain intensity of mi-
graines in children. One hundred sixty children diagnosed
with migraine and presenting to an outpatient center were
included in the study and randomized into four treatment
groups: acetaminophen 15 mg/kg, ibuprofen 10 mg/kg, acet-
aminophen 15 mg/kg with magnesium 400 mg, and ibuprofen
10 mg/kg with magnesium 400 mg. Both acetaminophen and
ibuprofen significantly decreased the pain intensity of the mi-
graine, but there was no reduction in migraine frequency. The
decrease in pain was significantly faster with ibuprofen than
with acetaminophen (mean 31.95 vs. 48.5 min). The addition
of magnesium to the acetaminophen and ibuprofen treatment
groups also led to a significant reduction in migraine pain
intensity. However, the addition of magnesium decreased pain
relief timing only for the acetaminophen group (from 48.5 to
35.42 min) [39].
The results from both RCTs conclude that acetaminophen
is superior to placebo in treating acute migraine attacks. Other
medications, such as ibuprofen and combination drugs, have
been shown to be more effective than acetaminophen alone for
the outcome time to headache relief. These two trials are also
concordant with the latest Cochrane reviews which show no
significant difference in the adverse events between paraceta-
mol and placebo [37, 38].
A double-blind RCT by Zhang, et al. found greater efficacy
of propacetamol (prodrug form of paracetamol) for 60-min
pain relief from acute migraine compared with rizatriptan. A
19 Page 4 of 9
total of 148 patients presenting to the emergency department
(ED) with an acute migraine attack were included in the study
and were randomized into two treatment groups:
propacetamol and rizatriptan. The propacetamol group re-
ceived propacetamol 1 g dissolved in 100-mL normal saline
(NS) infused intravenously over 30 min. Patients in the
rizatriptan group received rizatriptan benzoate 5 mg tablet
once orally. Pain scores were assessed before and 30, 60,
and 120 min after treatment. Despite the greater efficacy of
propacetamol at 60 min, there were no differences in pain
relief between the two treatment groups at 30 and 120 min
post-treatment [40]. These results differ from published liter-
ature which generally demonstrates that triptans are superior
to paracetamol in several outcomes, including pain-free at 2 h
and headache relief at 2 h [37]. However, results may also
reflect differing modes of delivery (intravenous vs. oral).
Summary
Acetaminophen is an effective therapy for treatment of acute
migraine attack. Most evidence demonstrates that acetamino-
phen is superior to placebo in decreasing migraine pain inten-
sity and migraine pain duration. Acetaminophen use also has a
low risk of adverse events and nearly negligible risk for severe
adverse events. Acetaminophen treatment may also benefit
children with migraine, though further evidence is warranted
[41], as a acetaminophen is a relatively low-risk and inexpen-
sive over-the-counter medication that has proven to be effec-
tive in the treatment of acute migraine attack.
Nonsteroidal Anti-Inflammatory Drugs
(NSAIDs)
Ibuprofen
Ibuprofen is commonly used in the treatment of chronic mi-
graine because of its analgesic, anti-inflammatory, and anti-
pyretic properties [42]. Ibuprofen is the most commonly used
drug of the nonsteroidal anti-inflammatory drug (NSAID)
class, which works to non-selectively inhibit
cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2)
[43]. These two enzymes are involved in the synthesis of
prostaglandins, which play a large role in pain, fever, and
inflammation.
In the USA, ibuprofen is available in over-the-counter
(OTC) 200-mg oral tablets with a maximum recommended
daily dose of 2400 mg [43]. Peak serum concentration is 1–
2 h with a half-life of 2–4 h [43]. The most common adverse
effects of ibuprofen include gastric discomfort, gastric ulcers,
rash, heartburn, nausea, and vomiting [42]. Ibuprofen is con-
traindicated in patients with recognized hypersensitivity to
NSAIDs or aspirin, NSAID/aspirin-induced asthma, active
Curr Pain Headache Rep (2020) 24: 19
gastrointestinal bleeding or peptic ulceration, and in the third
trimester of pregnancy [43].
Currently, ibuprofen is recommended as an abortive treat-
ment for mild to moderate migraine headaches or if triptans
are ineffective or contraindicated [44]. It is recommended that
the ibuprofen be taken as early on as possible after onset of
migraine at a dose of 400 mg [44].
Systematic Review and Meta-analysis
A 2017 Cochrane review included 9 randomized, double-
blind, placebo-controlled studies (4373 participants) to com-
pare the efficacy and tolerability of ibuprofen at different dos-
ages vs. placebo for treatment of adult migraine [45]. The
review found that both 400 mg and 200 mg of ibuprofen were
superior to placebo at 2 h pain-free (26% vs. 12%), 2 h head-
ache relief (57% vs. 25%), and 24 h sustained headache relief
(45% vs. 19%). Two hundred milligrams was also more effec-
tive than placebo at 2-h pain-free (20% vs. 10%) and 2-h
headache relief (52% vs. 37%). The number needed to treat
(NNT) for the 400 mg was lower than 200 mg (7.2, 3.2, 4.0 vs.
9.7 and 6.3, respectively) [45]. Thus, this review showed that
while ibuprofen is an effective treatment for acute migraine
headache, it only provided full relief in 50% patients. Adverse
events were mild and similar between placebo and treatment.
A 2016 meta-analysis comparing the efficacy and tolera-
bility of NSAIDs vs. triptans showed that triptans appeared to
be more effective at treating migraines when compared with
ibuprofen, though ibuprofen is a great alternative due to its
excellent tolerability [46]. Ibuprofen was shown to be signif-
icantly better than placebo at treating migraines with weighted
odds ratio (OR) for 1-h pain-free of 3.14 (1.31–7.54), 1-h pain
relief of 2.77 (1.68–4.55), 2-h pain-free of 2.31 (1.70–3.14),
and 2-h pain relief of 1.83 (1.32–2.53) [46].
Summary
Based on the most recent evidence, ibuprofen is a safe, cost-
effective, and efficacious treatment for migraines in most pa-
tients. Ibuprofen has been shown to be a strong alternative to
triptans and continues to be recommended as an over-the-
counter treatment for migraines.
Naproxen
Naproxen is another propionic acid derivative in the NSAID
class that is used to treat pain, inflammation, and fever [7].
Naproxen is available as a free acid and sodium salt with the
salt being more quickly absorbed in the gastrointestinal tract
and preferred for analgesia. It can be bought OTC in the USA
in both immediate release (IR) and delayed release (DR) for-
mulations of 250 mg, 220 mg, or 500 mg. Effects can be felt
within 1 h of ingestion with duration of action lasting between
Curr Pain Headache Rep (2020) 24: 19
8 and 12 h [47]. Naproxen has a half-life of 15 h, which is
much longer-lasting than ibuprofen.
Currently, naproxen is recommended for early treatment of
acute migraine attacks with a dosage of 500–550 mg IR for
migraines of all severity. Common side effects associated with
naproxen include dizziness, headache, bruising, heart burn,
gastric ulcers, and gastrointestinal bleeding [47]. There is a
higher risk of gastric ulcers when taking naproxen vs. ibupro-
fen [48]. As with ibuprofen, naproxen is contraindicated in
patients with known hypersensitivity to aspirin or NSAIDs,
NSAID/aspirin induced asthma, active gastrointestinal bleed-
ing/ulceration, or while in the third trimester of pregnancy
[49].
Systematic Reviews
A 2013 Cochrane systematic review (2735 participants)
found that naproxen was statistically superior to placebo
for treating acute migraines in adults, though this was a
weak effect [50]. Only 17% of patients were pain-free
after 2-h vs. 8% with placebo (RR 2, CI 1.6–2.6,
NNT = 11). Fifty percent of patients reported headache
relief with naproxen vs. 30% with placebo. Sustained
headache relief at 24 h for naproxen was 30% vs. 18%
with placebo and NNT of 8.3. Compared with ibuprofen
and sumatriptan, naproxen was not as effective [50].
There is a lack of studies that focus solely on naproxen for
treating migraines. Naproxen sodium with sumatriptan
(Treximet) is a common medication combination used for
migraines treatment. An update to the previous 2013
Cochrane review done in 2016 found that the combination
was marginally better than sumatriptan alone but much more
effective than naproxen monotherapy when compared with
placebo [51]. At 2-h, 50% of combination-treated patients
with mild headache intensity were pain-free compared with
18% of placebo. Fifty-eight percent of patients with moderate-
severe pain had pain reduced to mild or none at 2 h when
treated with combination compared with 27% with placebo,
52% sumatriptan monotherapy, and 44% with naproxen
monotherapy. Though combining naproxen with sumatriptan
appears to be more clinically effective, there is an associated
increase of adverse events such of dizziness, somnolence, par-
esthesias, and nausea [51].
Summary
Overall, naproxen appears to be a safe, inexpensive, and read-
ily available treatment option for patients experiencing chron-
ic migraine. It is more effective when used in combination
therapy, though this may result in greater risk for adverse
effects.
Page 5 of 9 19
Aspirin
Aspirin is an analgesic commonly used in the treatment of
chronic migraine headaches, with benefit both as a solitary
modality and in combination with other drugs [52, 53].
Aspirin irreversibly inhibits cyclooxygenase enzymes
(COX-1 and COX-2) resulting in decreased prostaglandin
synthesis and, therefore, modulation of inflammation and pain
[52, 54]. COX inhibition also hinders thromboxane synthesis,
and aspirin may also be used for anti-platelet therapy, often at
lower doses that are used for analgesia [55, 56]. For this rea-
son, patients at increased risk for complications related to
bleeding disorders should not take aspirin. Additional contra-
indications include age less than 12, aspirin-exacerbated re-
spiratory disease, and existing peptic ulcer disease. Well-
described complications of chronic aspirin use include peptic
ulcers, bleeding, and nephrotoxicity.
Aspirin is currently available in oral and intravenous for-
mulations. Over-the-counter (OTC) formulations for platelet
therapy are typically equal to or less than 325 mg. For pain
relief, doses are typically between 500 and 1000 mg [52].
Aspirin may also arrive in formulation combined with caf-
feine, acetaminophen, and clopidogrel.
Systematic Reviews and Meta-analyses
A 2010 Cochrane review assessed the use of aspirin for acute
migraine headaches in adults. The authors included thirteen
randomized, double-blind, controlled studies (4222 patients)
that compared aspirin (900 to 1000 mg, with or without
metoclopramide 10 mg) with placebo or other active compar-
ators such as sumatriptan 50 mg or 100 mg [57]. All treatment
branches were superior to placebo for all efficacy outcomes,
including 2-h headache relief, 2-h pain-free, and 24-h head-
ache relief. Aspirin was similarly effective when compared
with sumatriptan 50 mg. However, sumatriptan 100 mg was
slightly more effective in achieving 2-h pain-free outcomes,
but not 2-h headache relief. The addition of metoclopramide
to aspirin treatment branched slightly reduced nausea and
vomiting, but not pain.
A 2013 update on the Cochrane review found no additional
studies for inclusion and again concluded that aspirin was ef-
fective in the treatment of migraine headaches and was similar
in efficacy to sumatriptan 50 mg or 100 mg [58]. Authors also
reported that adverse events were transient and mild, with ad-
verse events following aspirin use more commonly than place-
bo but less commonly than following the use of sumatriptans.
In a 2017 systematic review including 8 studies with over
28,326 participants, Baena et al. reported that aspirin appears
to reduce the frequency of migraines when used for migraine
prophylaxis [59]. The findings from this review are promising,
but limited by inconsistent dosing across studies (50-650 mg/
day).
19 Page 6 of 9
Recent Trials
Recent studies show that aspirin may be effective in the treat-
ment of chronic migraines as well as tension headaches and
caffeine withdrawal headaches [60]. The 2015 “Clopidogrel
for the Prevention of New-Onset Migraine Headache
Following Transcatheter Closure of Atrial Septal Defects”
(CANOA) trial was conducted on 160 patients and showed a
significant decrease in the occurrence and new onset migraine
headaches within 3 months of the procedure among patients
receiving aspirin in addition to clopidogrel [61].
Summary
Current evidence demonstrates that aspirin is an effective over-
the-counter medication for the treatment of migraine headaches. It
is similarly effective when compared with sumatriptan and has a
favorable safety profile. Coadministration with metoclopramide
reduces migraine-associated nausea and vomiting.
Aspirin, Acetaminophen, and Caffeine Triple
Therapy
Background
Aspirin, acetaminophen, and caffeine are frequently used in
combination as a triple therapy for chronic migraines.
Multiple studies have shown that combinations of these med-
ications have an additive response on their analgesic effect
[62]. Indications for use are typically for acute headaches,
both for tension-type headaches and migraines [63, 64].
Triple therapy is typically in a single combination pill of
250 mg aspirin, 250 mg acetaminophen, and 65 mg caffeine
[64]. There are slight variations to these dosages currently on
the market. Studies have shown that combinations of aspirin,
acetaminophen, and caffeine as well as the combination of
acetaminophen and caffeine have been more effective than
monotherapy of either medication.
Each therapy plays an additive role both in its analgesia and
contraindications. Patients who are intolerant to caffeine or
adolescents with high risk of repetitive brain injuries should
avoid the use of triple therapy due to its caffeine component.
Patients with hepatic insufficiency should use this therapy
with caution and minimize their dosage to the acetaminophen.
Patients below the age of 12 (due to fear of Reye syndrome),
adults with asthma, and patients with peptic ulcer disease
should avoid use of triple therapy due to its aspirin compo-
nent. Adverse effects are similarly additive, and caffeine can
lead to various cardiac symptoms such as arrhythmias, while
acetaminophen can lead to acute liver failure, and excess as-
pirin can lead to symptoms of salicylate toxicity.
Curr Pain Headache Rep (2020) 24: 19
Recent Studies
In a randomized control trial published in 2014, triple therapy
with aspirin, acetaminophen, and caffeine was shown to be
more effective than use of ibuprofen as monotherapy. While
ibuprofen was effective in treating an acute migraine attack,
the use of triple therapy proved to be much quicker and more
effective [65]. In a 2017 study, Voicu et al. reported the effects
of using chlorpheniramine, an antihistamine, in addition to the
triple therapy in the treatment of migraines. Results showed
that the use of chlorpheniramine allowed for a decrease in
dosing of triple therapy which led to a decrease in the side
effects from the components of the triple therapy [66].
Summary
Overall, though few studies currently evaluate triple therapy,
existing evidence suggests that triple therapy using acetamin-
ophen, aspirin, and caffeine may be more effective than mono-
therapy of any individual component. It, therefore, appears to
be a viable option for treatment of chronic migraines.
However, utility may be limited by additive contraindications
to use from each component of the triple therapy.
Melatonin
Background
Melatonin, a hormone released by the pineal gland, regulates
the circadian rhythm. This hormone works by acting on the
MT1 and MT2 melatonin receptors in the suprachiasmatic nu-
cleus (SCN) of the hypothalamus to promote sleep [67]. As a
supplement, it is indicated for short-term treatment of insom-
nia but is also emerging as a complementary treatment for
migraine prevention.
Currently, there is insufficient evidence to support a strong
recommendation for using melatonin as episodic migraine
prophylaxis, though it is suggested as a therapy to consider.
The mechanism of action for melatonin’s role in improving
migraines is not fully known, though there are many theories
such as its anti-inflammatory effect, free radical scavenging,
nitric oxide synthase activity, and dopamine release inhibition
[67]. Immediate and extended release melatonin supplements
are available in the USA OTC in various concentrations from
0.5–10 mg with dosages varying based on reason for usage
[68]. For migraine prophylaxis, a dose of 3 mg IR is recom-
mended [69]. The most common adverse events of melatonin
include daytime drowsiness, abdominal cramps, and dizzi-
ness. Contraindications to taking melatonin include pregnancy
and breastfeeding [70].
Curr Pain Headache Rep (2020) 24: 19
Recent Studies
In 2016, a randomized, double-blind, placebo-controlled study
(196 participants) was done to compare 3 mg melatonin with
25 mg amitriptyline and placebo for migraine prevention [71].
Melatonin significantly reduced migraine frequency when
compared with placebo (p = 0.009), but not to amitriptyline
(p = 0.19). Furthermore, a greater proportion of patients expe-
rienced at least 50% reduction in migraine frequency in the
melatonin group than in the amitriptyline group. The number
of adverse events with melatonin was also lower than both
placebo and amitriptyline (16, 17, and 46, respectively) with
most adverse events being mild to moderate in intensity [71].
Overall, melatonin was found to be better than placebo and
non-inferior to amitriptyline with a better adverse event profile.
In 2017, another double-blind, randomized, placebo-
controlled clinical trial (192 patients) sought to compare mel-
atonin vs. valproic acid in prophylaxis of migraine headache.
Patients were treated with baseline therapies of nortriptyline
(10–25 mg) and propranolol (20–40 mg) with daily adjuvant
3 mg of melatonin, 200 mg of valproate, or placebo. After
2 months of treatment, monthly migraine attack frequency in
both melatonin (2.5) and valproic acid (2.3) was significantly
less than in placebo (3.8). At 1 and 2 months, duration of
migraine was also decreased for melatonin (10.1 and 8.7)
and valproic acid (10.2 and 8.8) compared with placebo
(15.4 and 14.1). These results showed melatonin to be non-
inferior to valproic acid as adjuvant therapy for chronic mi-
graines, though superior to placebo with a more favorable side
effect profile than valproate [72].
Summary
Melatonin treatment for migraine prophylaxis has shown to be
extremely favorable based on recent study outcomes. In addi-
tion to its efficacy and tolerability, melatonin is also extremely
cost-effective when compared with other migraine treatments.
There is a growing literature regarding melatonin and other
complementary treatments for migraine prophylaxis.
Currently, studies are still limited in terms of their quality,
but emerging evidence is pointing towards melatonin being
a promising alternative to current prophylaxis.
Conclusion
Migraine is a common disorder that affects millions of men and
women of all ages across the USA. Many therapies exist for
acute migraine attacks; however, over-the-counter medications
are generally preferred over prescription medications because
they are more accessible and cost-effective. Commonly used
over-the-counter medications include acetaminophen, NSAIDs
such as ibuprofen, naproxen, aspirin, caffeine, acetaminophen/
Page 7 of 9 19
aspirin/caffeine triple therapy, and melatonin. Acetaminophen
is a cost-effective therapy for the treatment of acute migraine
attack with minimal risk for adverse events.
Compliance with Ethical Standards
Conflict of Interest Jacquelin Peck, Ivan Urits, Justin Zeien, Shelby
Hoebee, Mohammad Mousa, Hamed Alattar, and Omar Viswanath de-
clare no conflict of interest. Alan Kaye is a section editor for Current
Headache and Pain Reports. He has not been involved in the editorial
handling of this manuscript. Dr. Kaye is also a speaker for Merck.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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