Previous experience can also influence the magnitude of placebo analgesia. In one study, the intensity of painful stimulation was reduced surreptitiously after placebo administration, so leading subjects to believe that an analgesic treatment was effective (Colloca and Benedetti, 2006) (Fig. 4.2C).
Fig. 4.2 C. Variability in magnitude of placebo analgesia. Part (C) shows different degrees of placebo responses (small, medium, and large) elicited in different experimental conditions: 1, natural history; 2, placebo right after conditioning; 3, placebo 1 week after conditioning; 4, placebo after verbal suggestions alone; 5, placebo after conditioning and previous negative therapeutic experience. Reproduced from Luana Colloca and Fabrizio Benedetti, How prior experience shapes placebo analgesia, Pain, 124 (1), pp. 126–33 Copyright 2006, The International Association for the Study of Pain, with permission. DOI: http://dx.doi.org/10.1016/j.pain.2006.04.005
This procedure induced strong placebo responses after minutes, and these responses, albeit reduced, lasted up to 4–7 days. In a second group of subjects, this procedure was repeated 4–7 days after a totally ineffective analgesic treatment.
The placebo responses were markedly reduced compared to the first group. Thus, small and large placebo responses were obtained that depended on several factors, such as previous positive or negative experiences of analgesic treatment and the time lag between the treatment and the placebo responses. These findings indicate that placebo analgesia is finely tuned by prior experience and that these effects may last, albeit reduced, for several days.These results emphasize that the placebo effect may represent a learning phenomenon involving several factors and may explain the large variability in the magnitude of placebo responses among studies.
The strength of previous experience is a crucial factor which contributes to the magnitude of the placebo response. In fact, the number of learning trials that are carried out in a conditioning procedure is related to the subsequent magnitude of the placebo effects. Colloca et al. (2010) tested the effects of either one or four sessions of conditioning on the modulation of both nonpainful and painful stimuli delivered to the dorsum of the foot.
Placebo and nocebo manipulations were obtained by pairing green or red light to a series of stimuli that were made lower or higher with respect to a yellow light associated with a series of control stimuli. Subjects were told that the lights would indicate a treatment that would reduce or increase nonpainful and painful stimuli to the foot.
They were randomly assigned to two groups: group 1 underwent one session of conditioning whereas group 2 received four sessions of conditioning. It was found that one session of conditioning-induced nocebo responses, but not placebo responses in the no-painful condition.
After one session of conditioning, both nocebo and placebo responses to painful stimulation were observed; however, these effects extinguished over time. Conversely, four sessions of conditioning-induced robust placebo and nocebo responses to both nonpainful and painful stimuli that persisted over the entire experiment, which suggests that the strength of learning plays a key role.
Not only is learning important for psychophysical measurements such as pain rating, but it also affects neurophysiological parameters, like laser evoked potentials (Colloca et al., 2008b). Colloca and Benedetti (2009) showed that social observational learning, whereby placebo responses can be learned by merely observing others, plays an important role as well .
The strength of learning may have profound implications both in medical practice and in the setting of clinical trials. A representative example is provided by the timing of either placebo administration or repetitive transcranial magnetic stimulation (rTMS) of the motor cortex for neuropathic pain relief.
Andrè-Obadia et al. (2011) performed a randomized controlled study including 45 patients, in which they compared the analgesic effects of sham rTMS that either preceded or followed an active rTMS, which could be itself either successful or unsuccessful.
Placebo analgesia differed significantly when the sham rTMS session followed a successful or an unsuccessful active rTMS. Placebo sessions induced significant analgesia when they followed a successful rTMS (mean pain decrease of 11%), whereas they tended to worsen pain when following an unsuccessful rTMS (pain increase of 6%). Only when the sham intervention was applied before any active rTMS were placebo scores unchanged from the baseline.
André-Obadia N, Magnin M and Garcia-Larrea L (2011). On the importance of placebo timing in rTMS studies for pain relief. Pain, 152, 1233-7.