Is there a standard about maximal caffeine concentration for synergistic painkiller preparations?

Question

Synergistic painkiller preparations are common world wide in the following combination drug forms, for example:

paracetamol-ibuprofen-caffeine
paracetamol-codeine-caffeine
aspirin-paracetamol-caffeine
aspirin-caffeine

My problem

From reviewing different brands I get the impression that caffeine amount moves between 35mg to 65mg, but I might be wrong.

My question

Is there a standard about maximal caffeine concentration for synergistic painkiller preparations (by which manufacturers work worldwide)?

Answer 1

According to the U.S. Food and Drug Administration (FDA), 2017:

The GRASE dose for caffeine is established in the Stimulant Final Monograph as 100-200 mg not more often than every 3-4 hours.

GRASE (generally recognized as safe and effective) is a safety designation the FDA uses for over-the-counter drugs (FDA.gov, Wikipedia).

According to a systematic review Caffeine as an analgesic adjuvant for acute pain in adults (Cochrane, 2014):

The addition of caffeine (≥ 100 mg) to a standard dose of commonly used analgesics provides a small but important increase in the proportion of participants who experience a good level of pain relief. It confers an additional benefit amounting to an extra 5% to 10% of patients achieving a good level of pain relief.

Over the dose range of 65 mg to 200 mg, no increase in adjuvant effect was noted with increasing caffeine dose.

So, if there is no better effect from 65 mg than from 200 mg of caffeine, then there is no good reason to use more than 65 mg.