Why isn't paracetamol routinely combined with n-acetylcysteine?

Question

Whether it's acute large dose paracetamol or long term regular dosage of paracetamol usage, it is a problem for the liver, ototoxic and even potentially life-threatening.

While one might question the use of paracetamol at all, for acute symptoms and occasional use it seems to have a place in being overall well tolerated in short term usage scenarios.

But the problematic aspects of the drug leaves me wondering:

one mechanism for paracetamol induced damage is reactive oxygene overproduction and glutathione depletion. This is one of the reasons why N-acetylcysteine (NAC) is an effective treatment in paracetamol overdose scenarios.

So it seems as if combining paracetamol with NAC would be a good idea to prevent the problems from paracetamol use.

The fact that it isn't done, neither in formulas nor in prescription routines, is puzzling.

NAC seems to be very well tolerated if taken orally and even sold as a nutritional supplement. It seems to be quite problematic if injected or taken after alcohol consumption. But alcohol and paracetamol would be a bad idea in itself.

Seeing that paracetamol still is combined with for example hydrocodone, a combination that is now clearly shown to be highly problematic for example for hearing is just confusing.

In fact, it is an old idea that has been studied to be an effective combination:

Effects of legislation restricting pack sizes of paracetamol and salicylate on self poisoning in the United Kingdom: before and after study (Package paracetamol with its antidote, 2001, 2011)

Co-administration of N-Acetylcysteine and Acetaminophen Efficiently Blocks Acetaminophen Toxicity. (2015)

For the unpopularity of 'paracetamol plus NAC' it seems I must have overlooked something.

What are or would be the downsides of combining paracetamol routinely with NAC?

Answer 1

Several combinations between analgesics and other compounds could be interesting for medical treatment and used in pain treatments, however, the logic isn't only effectiveness. For a medication to be approved by regulatory authorities, such as FDA, as over the counter or under prescription, pharmaceutical companies look first on the ROI (return of investment), as any other intervention planned in health care. If the study cost to prove its efficacy is too high, or the market for the new compound not profitable, or the new product could not be patented, then the combination would not go to market. Paracetamol + N-AcetylCysteine seems to be an interesting combination, but the study to prove it is less harmful would have to include thousands of patients, because the number needed to harm is high, so the sample size calculation would go to very high numbers. Maybe someone from the industry after seeing your post do the calculations and start a project...