The Rising Placebo Effect

By Derek Lowe October 15, 2015

The placebo effect has many interesting and annoying features, among them the way that it varies so much among different therapeutic areas. There is no placebo effect for a broken leg, or for pancreatic cancer: these things are going to play out the way that they do, regardless of what you think about them. But for the pain of a broken leg, there you might have something. In general, the things tied most closely to self-awareness (pain, mood, etc.) show the strongest placebo effects.

Now a new analysis of clinical trials for pain medication shows that the placebo effect in this area has been getting stronger. (Here’s a Nature News article on the subject). The same also seems to be true for antipsychotics and antidepressants, but this effect seems to be mainly (or only) visible in large-scale US trials:

“We were absolutely floored when we found out,” says Jeffrey Mogil, who directs the pain-genetics lab at McGill University in Montreal and led the analysis. Simply being in a US trial and receiving sham treatment now seems to relieve pain almost as effectively as many promising new drugs. Mogil thinks that as US trials get longer, larger and more expensive, they may be enhancing participants’ expectations of their effectiveness.

That certainly could be it. People may also be raising their expectations of what modern medical science is capable of, and figure that in these days of modern times (as the Firesign Theater used to put it), new drugs must be quite a bit better than the old stuff. In a way, they’re right – that Jack Scannell article I linked to yesterday talks about what he’s called the “Better Than the Beatles” problem in drug discovery. That’s the competition we always face against our greatest hits, effective medications that have gone generic and are now cheap and well-proven. For simple pain relief, it’s not easy to beat the likes of aspirin, ibuprofen, naproxen et al.. so if you’re going into that market, you’d better have something good. Unfortunately, the harder-to-treat forms of pain are really, really hard to treat. And if you’d like to treat them without the possibility of addiction, then that’s just too bad. There’s not a heck of a lot between ibuprofen and opiates, although not for lack of trying.

So people may be expecting more out of pain medication trials, but they’re not getting it. This new study found that against neuropathic pain (a large and terribly underserved market), the drugs studied over the last 23 years have all been about the same: not too effective. But the placebo responses in these trials have been creeping up the whole time – well, the placebo responses in the US. Asia and Europe have been flat.

Thatsuggests placebo and drug responses may not always be strictly additive. This isn’t entirely unexpected, Mogil argues, because both placebos and pharmaceutical painkillers tap into similar biological mechanisms — such as the release of endorphins in the brain. But if true, it suggests that growing placebo responses are masking real painkilling effects. “There are a lot of people in the pain field who believe the drugs that are failing clinical trials actually work, it’s just that the trials can’t show it,” he says.

Hmm. I see where he’s coming from, but I think that’s a dangerous line of thought. If they worked really well, we wouldn’t be having this argument at all. If you start throwing out clinical trial results because the drug “actually works” anyway, where is there an end to it? I suppose one could draw some sort of placebo-control cutoff and say that if the placebo group responds to some high level, then the drug. no, actually, I still can’t see it. I’m going to remain an absolutist for now: if your drug can’t beat placebo, then there’s no way to say that your drug does anything for patients.