Open Administration of Placebos Greatly Increases Effectiveness

In postoperative pain following the extraction of the third molar (Levine et al., 1981; Levine and Gordon, 1984), a hidden intravenous injection of 6–8 mg morphine corresponded to an open intravenous injection of saline solution in full view of the patient (placebo).

In other words, telling the patient that a painkiller was being injected (with what was actually a saline solution) is as potent as 6–8 mg of morphine. The investigators concluded that an open injection of morphine in full view of the patient is more effective than a hidden one because in the latter the placebo component is absent.

Careful analysis of the differences between open (expected) and hidden (unexpected) injections in postoperative settings was performed for five widely used painkillers (morphine, buprenorphine, tramadol, ketorolac, metamizole) (Fig. 4.3) (Amanzio et al., 2001; Benedetti et al., 2003a; Colloca et al., 2004).

A doctor carried out the open administration, telling the patient (at the bedside) that the injection was a powerful analgesic and that the pain was going to subside in a few minutes. In contrast, hidden injections of the same analgesic at the same dose were performed by an automatic infusion machine that started the painkilling infusion without any doctor or nurse in the room; these patients were completely unaware that analgesic therapy had been started.

One analysis found that the analgesic dose needed to reduce the pain by 50% (AD50) was much higher with hidden infusions than with open ones for all five painkillers, indicating that hidden administration is less effective than open administration (Fig. 4.3A).

Another analysis found that the time course of post-surgical pain was significantly different between open and hidden injections. In fact, during the first hour after administration, pain ratings were much higher with a hidden injection than with an open one (Fig. 4.3B).

Fig. 4.3 Part (A) shows the analgesic dose of buprenorphine, tramadol, ketorolac, and metamizole needed to reduce pain by 50% (AD50), obtained by means of either open or hidden infusions in postoperative patients. Note that in the hidden conditions, the AD50 increased. Reproduced from Martina Amanzio, Antonella Pollo, Giuliano Maggi, and Fabrizio Benedetti, Response variability to analgesics: a role for non-specific activation of endogenous opioids, Pain, 90 (3), pp. 205–15 Copyright 2001, The International Association for the Study of Pain, with permission. DOI: http://dx.doi.org/10.1016/S0304–3959(00)00486–3 Part (B) shows the time course of analgesia for buprenorphine, tramadol, ketorolac, and metamizole. Note that the analgesic response was smaller with hidden injections. In addition, open injections produced an analgesic response as soon as 15 minutes after administration, while hidden injections did not, indicating that this early analgesic response was due, at least in part, to a placebo effect. Reproduced from Martina Amanzio, Antonella Pollo, Giuliano Maggi, and Fabrizio Benedetti, Response variability to analgesics: a role for non-specific activation of endogenous opioids, Pain, 90 (3), pp. 205–15 Copyright 2001, The International Association for the Study of Pain, with permission. DOI: http://dx.doi.org/10.1016/S0304-3959(00)00486-3

References

Benedetti, Fabrizio. Placebo Effects (pp. 120-121). OUP Oxford.

Amanzio M, Pollo A, Maggi G and Benedetti F (2001). Response variability to analgesics: a role for non-specific activation of endogenous opioids. Pain, 90, 205-15.

Benedetti F, Maggi G, Lopiano L et al. (2003a). Open versus hidden medical treatments: the patient’s knowledge about a therapy affects the therapy outcome. Prevention & Treatment, 6(1).

Colloca L, Lopiano L, Lanotte M and Benedetti F (2004). Overt versus covert treatment for pain, anxiety and Parkinson’s disease. Lancet Neurology, 3, 679-84.

Levine JD, Gordon NC, Smith R and Fields HL (1981). Analgesic responses to morphine and placebo in individuals with postoperative pain. Pain, 10, 379-89.

Levine JD and Gordon NC (1984). Influence of the method of drug administration on analgesic response. Nature, 312, 755-6.