Note: Depending on where you live paracetamol is also known as acetaminophen, APAP and Tylenol. 

I have had a version of the following conversation a surprising number of times:

"I have a headache."

"Aah, that sucks. Did you take some paracetamol?"

"Yes, but it still hurts."

"How many did you take?"

The fact that I even ask this question is because I have been noticing a trend. 

"One."

"You should take two, it makes a big difference."

"Nah, I'm fine with one."

"But you still have a headache."

"Yeah, but it doesn't make much of a difference. Paracetamol just doesn't work that well for me."

Everyone is free to choose how many paracetamol they take, but I've always had this hunch that there is a big difference between taking one or two paracetamol. Where taking one has almost no effect on my headaches, but taking two makes a big difference. Effectively I'm making two claims:

1. 1000mg paracetamol works better than 500mg paracetamol.
2. 500mg paracetamol doesn't work much better than placebo. 

Today I chose to finally resolve this mystery and laugh in the face of my friends! Or I will admit in shame that I was wrong...

Claim 2: 500mg vs placebo

There is a Cochrane Review from 2016 that tries to answer exactly my question.^[1] The review looks at pain relief with paracetamol for tension-type headaches, the most common form of headaches. They reference two studies that have compared 500mg/650mg with placebo that also fit their inclusion criteria. 

Steiner 2003^[2], which comes to the following conclusion:

They didn't find a significant result when comparing 500mg paracetamol and placebo! But they did find a significant result when comparing 1000mg paracetamol and placebo.

Dahlöf 1996 is less conclusive. This study only contains 29 participants, where only 14 of them took paracetamol at a dose of 500mg. 

In this study both 500mg and 1000mg performed equally well, but with the low participant numbers it is hard to draw any conclusions. 

The Cochraine Review itself comes to the conclusion that they couldn't find a significant difference between 500mg paracetamol and placebo, but that the quality of evidence is low.

Claim 1: 1000mg vs 500mg

The same Cochrane Review concludes that a 1000mg paracetamol outperforms placebo. There is high quality evidence for this being the case when looking at 

• Pain-free at two hours: the proportion of attacks/participants who were pain-free at two hours with paracetamol.
• Pain-free or mild pain at two hours: the proportion of attacks/participants who were pain-free or had only mild pain at two hours with paracetamol.

There is moderate quality evidence for this being the case when looking at

• Pain-free at one hour: The proportion of attacks/participants who were pain-free or had only mild pain at one hour with paracetamol.
• Pain-free at four hours: The proportion of attacks/participants who were pain-free at four hours with paracetamol.

Although it might seem that I'm moving towards a clear win for my case, I'm afraid I have to highlight one interesting point which is exemplified by the work of Steiner 2003^[2]. 

Their data leads to three seemingly incompatible statements:

• They find a significant difference between 1000mg paracetamol and placebo.
• They don't find a significant difference between 500mg paracetamol and placebo.
• They don't find a significant difference between 500mg and 1000mg paracetamol.

It is funny that these three statements can all true at the same time. At this point in time we don't have the data to show that a 1000mg outperforms 500mg.

Conclusion

To be honest, I didn't expect the results I found. In hindsight it is obvious that these statements can all be true at the same time, but when starting out I hadn't considered it an option. 

I think I can safely say the following going forward:

• Take two paracetamol, there is good evidence that it will help you with your headache.
• You can take one paracetamol, but we simply don't know if it works.

Edits: I have edited this post quite intensively based on the comment of Lao Mein. They correctly spotted that one of the journals I quoted from, Open Pain Journal, has an impact factor of 0.11. I have removed this reference and I've based the article fully on the Cochrane Review.

1. ^{^}

   Stephens, G., Derry, S., & Moore, R. A. (2016). Paracetamol (acetaminophen) for acute treatment of episodic tension‐type headache in adults. Cochrane Database of Systematic Reviews, (6).

2. ^{^}

   Steiner, T. J., Lange, R., & Voelker, M. (2003). Aspirin in episodic tension-type headache: placebo-controlled dose-ranging comparison with paracetamol. Cephalalgia, 23(1), 59-66.

3. ^{^}

   Gaul, C., & Eschalier, A. (2018). Dose Can Help to Achieve Effective Pain Relief for Acute Mild to Moderate Pain with Over-the-Counter Paracetamol. The Open Pain Journal, 11(1).