I've no doubts that your comments are correct and what you say makes sense, but in the light of those facts why then isn't methadone substituted in place of codeine in low-dose opiate/paracetamol and other NSAID-like combination painkillers that are approved for OTC sale?

(If you read my reply to the above comment, you'll note the significant rebound effect I suffered from codeine in that it significantly increased the frequency of my headaches.)

It has only just occurred to me to ask this question after reading your comment and my logic for doing so is thus:

(a) Compared to certain other opiates, codeine isn't a particularly powerful painkiller, presumably this is why it's been licensed for inclusion in weak amounts in combination with NSAID painkillers in a number of countries (although I realize that in some places the rules concerning the sale of these OTC drugs have been tightened in recent years).

(b) The codeine 'rebound problem' (presumably caused by its activation of NMDA receptors) could be eliminated if codeine were to be substituted with low-dose methadone in these combination painkillers.

(c) As it has little or no NMDA activity, substituting low-dose methadone may alleviate or reduce some of the overdose problem from paracetamol overdoses (paracetamol poisoning occurs when people overdose on it in their attempt to get a bigger hit from the codeine component - or when they find that the painkillers are no longer working effectively and increase the dose above recommended amounts).

(d) Again, as methadone doesn't have any NMDA activity, its effective level could be increased in comparison to that which has been traditionally considered safe for OTC codeine preparations. In essence, for an equivalent level of risk/narcotic side effects, OTC low-dose methadone/NSAID combination painkillers could be made more effective than their codeine equivalents.

Thinking quickly through this some objections are immedately clear, the most obvious being that (from memory) methadone has a similar analgesic threshold to morphine (albeit its overall effectiveness is somewhat less for other reasons).

As methadone's analgesic threshold much higher than that of codeine (perhaps by as much as five times) it's traditionally said to be highly addictive in its own right and thus significantly more so than codeine.

The question arises that given its lack of activation of NMDA receptors how effective would it be in low-dose preparations. If there is little NMDA response one would expect little addictive risk at these low leveks. Of course, the argument against that is that the higher analgesic threshold would negate the benefits as consumers could actually get bigger hits by taking larger amount of these painkillers (that argument is used correctly with other opiates such as heroin which has an analgesic threshold of about three times that of morphine).

However, as you point out, this shouldn't happen with methadone given its lack NMDA action (especially so in small amounts).

Even if it did, would we be faced with methadone addiction kicking in first or would abusers of these painkillers succumb and die from paracetamol poisoning (as they often do now with codeine combinations)?

There's another option that is also worth considering in this debate and that's the inclusion of a small quantity of atropine in OTC preparations that include narcotic drugs such as with the anti-diarrhea drug diphenoxylate (aka Lomotil). The inclusion of atropine has proved highly effective in discouraging deliberate overdosage of diphenoxylate, as beyond a certain threshold level it makes one feel quite I'll.

No doubt, the wider use of opiates such a methadone is both a complex and very emotive subject. Moreover, it worries me that the very mention of the word 'opiate' is enough to close down sensible debate on the subject. We need a much more sophisticated and nuanced approach to the use of opiates than we have at present and I can't help feel that we're not getting it because of a silly non rational approach to the problem. Mentioning methadone for instance has widespread connotations with drug abuse and these are usually negative - even though the drug is usually used to improve the lives of people.

BTW, let it not be said that I'm advocating a wider more laissez faire approach to opiate use, I'm certainly not. What I want to see is more science and less emotion in the debate.

Moreover, if you look back on my old HN comments about such matters, you'd find few other posters whose comments were more critical over the opioid epidemic than I have been. In my opinion, the behavior of Purdue Pharmaceuticals and the Sacklers has been nothing short of criminal and the fact that they have been let off lightly is a national disgrace.