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Three Part Question

1) In [adult patients with acute migraine or tension-type headache]
2) Are [over-the-counter analgesics more efficacious when combined with caffeine]
3) At [reducing pain]

Clinical Scenario

A young female adult attends the emergency department complaining of a severe headache associated with nausea and sensitivity to light. A diagnosis of acute migraine is made and her symptoms improve in the department following analgesia. She has frequent headaches and does not want to keep attending the emergency department. She does not wish to take prescription medications. She asks you which over the counter medications are most effective and work quickest.

Search Strategy

Ovid MEDLINE 1946-2020 database:

(Caffeine/) AND [(Migraine Disorders/) OR (Tension-Type Headache/)]

The Cochrane Library:

migraine OR headache AND caffeine

Search Outcome

Ovid MEDLINE yielded 221 results. 6 papers identified that were relevant to question.

No relevant publications identified from The Cochrane Library

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Migliardi JR et al. 1994	4 studies comprising 1811 patients. Outpatients aged 18-65 who reported an average of 6-7 tension-type headaches per month in the previous year that responded to OTC analgesics were included. Patient were randomised to receive 2 of either placebo, acetaminophen (APAP) alone, or acetaminophen/aspirin/caffeine (AAC) combination. One medication was used for 2 episodes, and then the other medications was given for use for another 2 episodes.	Randomised, double-blind, two-period crossover studies	Patient-reported pain intensity and pain relief using 4 and 5 point ordinal scales respectively	AAC showed significantly greater pain intensity difference, pain relief and total pain relief (P<0.001)	Dietary caffeine was only limited within 4hr study window. No comparison of the same analgesic with and without caffeine.
Diamond et al. 2001	385 adult patients with history of acute TTH. Patients were given single-dose of ibuprofen and caffeine, ibuprofen alone, caffeine alone or placebo. Took medication when experienced an at least moderate severity tension-type headache.	Randomised, double-blind, parallel, single-dose, placebo-controlled trial	Patient-measured time to first onset of perceptible pain relief and first onset of meaningful pain relief.	Significantly more patients achieved meaningful pain relief with ibuprofen + caffeine than all other groups. Meaningful pain relief was achieved significantly quicker with ibuprofen + caffeine compared to placebo or ibuprofen alone	Dietary caffeine only limited in 4 hours prior to onset of headache
			Patient-rated pain relief and pain intensity	Ibuprofen + caffeine showed significantly greater pain relief compared to all other treatments (p<0.05)
Pini et al. 2008	93 patients aged 18-65 with history of TTH. Treated 3 consecutive TTH attack with the 3 different study medications (paracetamol 1g + caffeine 130mg (PCF), naproxen 550mg (NAP), or placebo (PLA)). Patients were randomised to 6 different sequences of treatment.	Multicentre, randomised, double-blind, double-dummy, crossover, placebo-controlled trial	Patient-reported pain intensity and pain relief at using 4- and 5-point scales respectively, at 1, 2, 3 and 4 hr post-ingestion	Both PCF and NAP achieved significantly better pain intensity difference and total pain relief compared to placebo (p<0.05). PCF and NAP. No significant difference between PCF and NAP.	No comparison of the same analgesic with and without caffeine. Sponsored by Angelini Farmaceutici.
Goldstein et al. 2014	660 adult patients with diagnosis of migraines. Randomised to receive single dose containing acetaminophen/aspirin/caffeine (AAC), ibuprofen (IB), or placebo.	Multicentre, double-blind, randomised, parallel-group, placebo-controlled, single-dose study	Subjective pain intensity, pain relief, functional disability, nausea, vomiting, photo/phonophobia at intervals for 3hr post-ingestion	AAC achieved significantly faster onset of meaningful relief than IB. AAC showed significantly greater total pain relief and pain intensity difference than both IB and placebo (p<0.05). No consistent significant difference between AAC and IB in associated features and functional disability	No comparison of same analgesic with/without caffeine.
Diener et al. 2005	1743 adult patients who met diagnostic criteria for TTH or migraine. Three independent headache episodes treated. First episode treated with patient’s usual non-prescription analgesic. Randomised to treat following 2 episodes with either aspirin+paracetamol+caffeine, aspirin+paracetamol, aspirin alone, paracetamol alone, caffeine alone, or placebo.	Randomised, placebo-controlled, double-blind, multi-centre, parallel group trial.	Primary endpoint was time to 50% pain relief based on patient-rated intensity using visual analogue scale for 4hr post-ingestion.	ASA+PAR+CAF was significantly superior to all other treatments (p<0.05).
Jafari et al. 2018	60 adult patients with diagnosed migraines. 2 medications prescribed for 4 consecutive episodes - ibuprofen 400mg or acetaminophen+aspirin+caffeine.	Double-blind clinical trial	Pain perception using 11-point Box Scale recorded prior to dose, at 2hr and 6hr.	Pain severity significantly lower in those taking AAC (p<0.05) at 2hr and 6hr post-dose.	Treatment protocol unclear. Not placebo controlled. Results do not take pre-dose pain level into account.

Comment(s)

There are multiple studies in the literature addressing the efficacy of caffeine as an analgesic adjunct in the treatment of acute migraine and/or tension-type headache. These were of varying quality. All studies included were interventional with clear primary outcomes. One of the studies, however, was not placebo controlled. Additionally, a number of the studies did not compare like analgesics with and without caffeine, making it difficult to identify caffeine as the agent responsible for increased efficacy. Diener et al. and Diamond et al. presented large studies which did compare like analgesics, reporting significantly greater efficacy with caffeine as an adjunct.

Clinical Bottom Line

These studies provide evidence that addition of caffeine to over-the-counter analgesics can provide significantly greater pain relief in tension-type headaches and migraines, as well as significantly reducing the time taken to achieve meaningful pain relief. Based on this, it would be reasonable to advise our patient that using over the counter caffeine-containing analgesics could result in faster and more effective symptom relief than her previous choice analgesics. One could surmise that this greater home symptom control could decrease this patient’s number of ED attendances, although this theory has not been specifically investigated in these studies.

References

1. Migliardi JR et al. Caffeine as an analgesic adjuvant in tension headache Clin Pharmacol Ther (1994); 56(5):576–586
2. Diamond et al. The use of Ibuprofen plus caffeine to treat tension-type headache. Current Pain and Headache Reports (2001); 5:472-478
3. Pini et al. Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised, double-blind, double-dummy, cross-over study versus placebo and naproxen J Headache Pain (2008) 9:367-373
4. Goldstein et al. Results of a multicenter, double-blind, randomised, parallel group, placebo controlled, single-dose study comparing the fixed combination of acetaminophen, acetylsalicylic acid and caffeine with ibupr Cephalagia (2014) Vol. 34(13):1070-1078
5. Diener et al. The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-b Cephalalgia (2005); 25(10):776–787
6. Jafari et al. Comparison of ibuprofen and AAC (acetominaphen, aspirin, caffeine) for treating acute migraine episodes Journal of Basic and Clinical Pathophysiology (2018); Vol. 6(2):1-6