His and hers opioids – one size does not fit both

The American Pain Society held its annual conference in Honolulu this year.  I was fortunate enough to catch some of it. In the theme of blog posts about conference talks, started with our reflections on the NOI congress, this post is about a very interesting and enlightening talk I went to by the very impressive (on many counts) Jon Levine.  There is probably no one on the planet who would have contributed more to our current understanding of opioid use for analgesia than Prof Levine and his recent work sheds light on a question often raised – “Do men and women respond in the same way to opioids?” Well, he took a while to get there (and it was a most enjoyable journey) but the short answer is ‘No’.

Prof Levine reminded us that humans have a long relationship with opioids – the Greeks were using poppy juice in the 3rd century – but morphine was only isolated from opium at the turn of the 19th century and opioid receptors were not discovered until 1970 – perhaps to coincide with, or compensate for, my arrival on the planet.  The role of opioid receptors in placebo analgesia was uncovered when I was 8, but I may be taking a slightly narcissistic perspective on it so I will quit the history thing now.

Levine was focusing on Kappa opioids, which work mainly at kappa receptors, although also at mu opioid receptors, where they can antagonize morphine. The trials of kappas are equivocal – some show good analgesia, some show nothing – in fact some show an algesic effect – so they were more or less dumped. However, Levine (or someone to whom he spoke perhaps – I missed the details in the rush to fire up my computer) observed that the studies that showed good effects involved female participants – most notably labour pain, and the studies that showed bad effects involved male participants.  He put the question to the scientists doing the studies “Do you think there might be a difference in how men and women respond to these opioids? The answer was a resounding ‘No way’.

Then Levine did some experiments in men and women after they had their wisdom teeth dug out of their jaw bone (he showed a particularly gruesome picture of this – it should, by my reckoning, hurt a bit afterwards). I will try to get the results right here –

For a clinical dose of kappa opioid, women responded quite well but men didn’t respond at all. Neither responded to placebo (which actually whispers in my mind as to whether the placebo was credible – most placebo’s if truly concealed will have some analgesic effect). When the dose was doubled, the analgesic effect in women is reduced and the men got a slight analgesic effect.  When the dose was halved, the men got worse and the women didn’t respond at all.  This dodgy dose titration strongly implies that there are two receptors involved, so Levine et al tested it  – they combined the kappa with naloxone and there it was – some analgesic effects in both men and women.

There is actually a growing body of literature showing different opioid responses in boy and girl rats and experimental cold pressor tolerance studies are building the evidence in humans. So, it is probably fair to conclude that when it comes to opioids, we might have to think of a his and hers twin set, rather than just sharing the pack.

Jon Levine is Professor of Medicine, Oral & Maxillofacial Surgery
 and Director, NIH Pain Center at University of California San Francisco. He has written over 300 papers and, based on citations of his work, is in the top 0.5% of all scientists on the planet. He has a long list of achievements, but suffice here to say that he really is one of the pain world’s superstars.

About Lorimer Moseley

Lorimer Moseley1 280x300 His and hers opioids – one size does not fit bothLorimer is NHMRC Senior Research Fellow with twenty years clinical experience working with people in pain. After spending some time as a Nuffield Medical Research Fellow at Oxford University he returned to Australia in 2009 to take up an NHMRC Senior Research Fellowship at Neuroscience Research Australia (NeuRA). In 2011, he was appointed Professor of Clinical Neurosciences & the Inaugural Chair in Physiotherapy at the University of South Australia, Adelaide. He runs the Body in Mind research groups. He is the only Clinical Scientist to have knocked over a water tank tower in Outback Australia.

Link to Lorimer’s published research hereDownloadable PDFs here.


  1. Harry Eeman says:

    Interesting stuff! I wonder whether lack of (or perhaps loss of) placebo response wasn’t mediated by the kappa opioid pathway. As you know the placebo response can sometimes be reversed by administering naloxone demonstrating the role of endogenous opioids in placebo analgesia. (Jon Levine’s group worked this out in the late 70s). Naloxone is a weak kappa antagonist. Is there a link between kappa receptors and the neurobiology of the placebo response?


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