Placebo effects on cutaneous pain and itch: a systematic review and meta-analysis of experimental results and methodology

Supplemental Digital Content is Available in the Text.


Figure S1
Note. Funnel plot of studies included in the pain classical conditioning with verbal suggestion meta-analysis. Outer, dashed line indicates a 95% confidence interval. Inner, dotted line indicates a 99% confidence interval.

Figure S2
Note. Funnel plot of studies included in the pain verbal suggestion meta-analysis. Outer, dashed line indicates a 95% confidence interval. Inner, dotted line indicates a 99% confidence interval.

Figure S3
Note. Funnel plot of studies included in the pain observational learning meta-analysis. Outer, dashed line indicates a 95% confidence interval. Inner, dotted line indicates a 99% confidence interval.

Figure S4
Note. Funnel plot of studies included in the itch verbal suggestion meta-analysis. Outer, dashed line indicates a 95% confidence interval. Inner, dotted line indicates a 99% confidence interval. Within subjects W Participants were also told that the experiment would identify the effects of medicines with different potencies, prescribed by doctors at different s tages of their careers . They were informed that the one potent placebo analgesic was 100 times less potent than the 100 potent placebo analges ic. Furthermore, they were told that the medicines were very short-acting analgesics which would take effect immediately after administration, would have a peak effect 10-20 s after administration, and then would expire 10 s later. Participants were not aware that the goal of the experiment was to inves tigate placebo analges ia Both the placebo uninformed and informed groups were told that we were testing the effects of an ointment on pain and given the suggestion of an active agent.In stage 2, the subjects in the placebo informed and uninformed conditions were provided with instructions regarding the nature of the experiment. They were told, ''The agent you have just been given is known to significantly reduce pain in some patients''.
They were also informed that the level of stimulation during this session would remain constant 0-10 VAS pain intensity Average of 4 trials. not reported not reported 8 (4P / 4C) Calibration aimed for pain of 0-2 for placebo and 4-6 for moderate pain 3 merobinson@ufl.edu 10/5/2020 Reminder sent 30.11.2020 Colagiuri, Ben and Quinn, Veronica F.
2018 Autonomic arousal as a mechanism of the persistence of nocebo hyperalgesia 65 19M / 46F 20.2 CC+VS Electrical pain Open label sham conditioning control W-B Before the dummy TENS device was attached, they received a 1-page handout including sections "What is TENS used for?," "How does TENS work?," and "What's so good about TENS?" The handout suggested that TENS was effective for reducing pain by "sending stimulation to block or reduce pain signals going to the brain" (placebo group). Participants were later told, "This is the TENS electrode [res earcher s hows participant the stimulator]. TENS stands for transcutaneous electrical nerve stimulation. TENS can reduce pain by sending out a pulse that then alters the firing rates of neurons to weaken the pain signals as they travel up your arm and into your brain [researcher follows the path from the electrode placement up the participant's arm]. You'll still be able to feel that you've received a shock if the TENS is switched on, but the pain will be much less intense. More s pecifically, the s ubjects were informed that the activation of electrodes attached to the ankle (actually, two sham electrodes), would reduce their perception of non-painful and painful stimuli, when a green light was displayed on the computer screen, whilst it would increase their non-painful or painful perception when a red light was displayed. Additionally, they were told that a yellow light would indicate the deactivation of the ankle electrodes and thus that no treatment would be given. Thermal pain Within subjects W We then treated subjects with two identical (pharmacologically inactive) creams , which were however pres ented as "lidocaine cream" and "control cream" and were kept in professionally labelled tubes. We told subjects that they would receive lidocaine cream on the skin areas outlined in green and that they would receive a completely inactive sensory control cream on the skin areas outlined in red. sham conditioning w-b "this study investigates how different doses of a painkiller affects cold pain. The painkiller has been shown to effectively reduce other forms of pain, and is now being tested on cold pain. Some persons will receive the drug, others will not receive the drug." The information was the same for all groups. Participants receiving placebo treatment were informed that the cream may or may not possess analgesic properties. Participants in the control group were informed that the cream was inactive and will have no effect on pain.
0-10 pain intensity NRS Effect is meas ured as the pre to post change in pain ratings (10 stimuli preconditioning, 10 stimuli postconditioning/test phase) not reported not reported 20 (10P / 10C) Participants were instructed that 4/10 indicated "just painful" (pain threshold?) 7/10 was used as moderate pain stimuli, 3/10 used as the placebo stimuli.

(10M / 22F) 3/34 1 Checked -I would include this
Hunter, T., Siess, F. and Colloca, L. Within subjects W Participants were told that the goal of the study was to evaluate how the brain responds to thermal stimulation when it is paired with topical application of either a pain-relief medication or a control liquid that does not contain medication. The Placebo was identified as Lidocaine, a powerful topically active, liquid analgesic. The Control was identified as water, which would not affect pain but otherwise would provide a sensory experience similar to that of the purportedly active medication. Participants were told that responses to acupuncture can be positive or neutral, and that a person's response tends to remain consistent across sessions. Participants then viewed a traditional Chinese medicine meridian diagram and were told that acupuncture could only produce analgesia on the side of the arm through which the meridian passed (the "treated" side, where the needles would be placed) but not on the other side of the arm (the "untreated" side).

0-20 Sensory box scale (Gracely s cale)
Effect was meas ured as the magnitude of a placebo effect before and after conditioning treatments and compared between active and sham conditioning groups. Number of trials not clearly specified not reported not reported Not reported Low pain (placebo) was calibrated to a temperature that evoked pain of 8-11 (0-20 scale) and high pain was calibrated to 14-17 on the 0-20 scale. You will participate in a study in which we will be testing the efficacy of a new analgesic technique on the experience of pain and on brain activity. During the experiment we will deliver thermal (laser) stimuli which can induce pricking and hot sensations. These sensations may be interpreted as painful depending on your very personal estimate. Importantly, we will use only one stimulus energy during the experiment, which will correspond to what you will judge as a moderate sensation of pain. We will spread one cream on one limb and the other cream on another limb. It will take about 10 minutes to come into action. Afterwards we will rub it off from your skin and start with the stimulation protocol" You will participate in a study in which we will be testing the efficacy of a new analgesic technique on the subjective experience of pain. During the experiment we will deliver two types of sensory stimulation, thermal (laser) and electrical. The thermal stimulus elicits pain, while the electrical stimulus is the analgesic technique that reduces pain. When occurring concomitantly with laser stimulation, very low electrical stimulation has been observed to reduce the pain sensation elicited by the laser. Importantly, the electrical stimulation will be so low that you will not perceive it. Thus, you will not be aware of this electrical stimulation. Both laser and the electrical stimuli will be delivered on your right hand. Only one laser intensity will be used throughout the experiment and we will es tablis h it before s tarting the experiment Between ''Now I will apply the same gel to the other forearm, but I added an pain-reducing substance to this gel, which reduces itch in such a way that nearly all healthy people do not experience pain anymore.'' In the pain placebo control condition, subjects received the following suggestions, ''Now I will apply the same gel to the other forearm. Nearly all healthy people experience pain from these stimuli, while hardly anyone experiences itch.'' Prior to the commencement of tes ting, each s ubject completed a consent form which contained the verbal manipulation as part of the instructions about the nature of the experiment. There were 2 versions of the form, one for subjects in groups 1 and 2 (which instructed them to expect that the cream was a powerful analgesic which would provide pain relief) and one for subjects in groups 3 and 4 (which told them that they were in a control group which was using a neutral cream and that they should expect no relief) Specifically, participants in the placebo condition were told that the res earcher was interes ted in a new topical, local anes thetic that was being tested for its pain-reducing effects. Participants were told the drug's name was Trivaricane and that the drug had been effective in reducing pain in studies at other universities. Participants were further informed that this topical drug was very powerful and would eliminate much of the pain usually caused by the cold pressor task.

15-60 SF-MPQ
Effect is meas ured as the difference in SF-MPQ s cores between placebo and control groups after 1 cold pressor task. Thermal pain Within subjects W Participants were told that the goal of the study was to evaluate how the brain responds to thermal stimulation when it is paired with topical application of either a pain-relief medication or a control liquid that does not contain medication. The Placebo was identified as Lidocaine, a powerful topically active, liquid analgesic. The Control was identified as water, which would not affect pain but otherwise would provide a sensory experience similar to that of the purportedly active medication. Within subjects W Prior to the experiment, participants read an information sheet about the medication, its analgesic properties (''highly effective in reducing pain on many body parts, including heat pain''), the onset (''about 11 minutes after oral administration''), and duration (''2-4 hours'') of these effects. ''This is a capsule of an effective pain reliever. In 10-15 minutes the medication will be fully effective, and notably decrease your sensitivity to the thermal heat pain'' (Placebo condition) or ''This is a capsule without any effective drug, needed as a control. It will not decrease your sensation of pain nor induce any other effects'' (Control condition) Neutral VS Between participants in the two expectation conditions (the choice condition and the no choice condition) were told that the study involved ''product testing'' for novel painrelieving treatments (actually inert ointments). The two products were described briefly and were subtly distinguished from one another. Specifically, the first product was described as warming a participant's hand and protecting it like a glove, whereas the second product was briefly described as blocking the pain receptors in the hand. Half of the AD and half of the HC were given the information that they belonged to the group that had received the ointment with the analgesic effect (''the ointment reduces pain''). The other half were told they had received the ''ointment with no effect'' (''ointment is neutral'').
Nine-point scale (0 = not noticeable, 1 = just about perceivable, 2 = clearly perceivable, 3 = strongly perceivable but not painful, 4 = strongly perceivable, noticeably painful, 5 = clearly painful, 6 = strongly painful, 7 = very strongly painful, and 8 = immensely painful) D ifference in the mean rating of 5 control stimuli and 5 placebo stimuli 12 difference s co not reported 10 (5P / 5C) Control pain was set to 2x pain threshold, placebo pain set to pain threshold. Temperatures for "pain" stimuli used during the baseline fMRI visit were determined for each individual based on the lowest temperature rated between 40 and 60. The highest temperature with a VAS score ≤20 was used as the "placebo" temperature during the subsequent placebo-conditioning visit.

Placebo effects in laser-evoked pain potentials.
39 25M / 4F 23.2 5 CC+VS Las er Within subjects W Participants were told that they were taking part in a study that compared brain responses to an analgesic cream (Lidocaine) with a control cream (ineffective). In reality both creams were ineffective (Vaseline skin cream).
a 13-point numerical ratings scale ranging from -2 to 10, with anchor points described by the following verbal instructions: 2 was 'not perceived,' 1 was 'nonpainful warmth,' 0 was 'non-painful pinprick,' 1 was a painful pinprick, and 10 was 'worst pain imaginable ' Mean of 40 control trials minus the mean of 40 placebo rials 12 not reported not reported 10 (5P / 5C) In the calibration phase, 10-20 laser stimuli of various intensities (300-700 mJ) were delivered to patch 3 and 4 in Fig. 1 to identify stimulus intensities corresponding to low-(level 1), medium-(level 2), and high-intensity (level 3 or above) pain. a 13-point numerical ratings scale ranging from -2 to 10, with anchor points described by the following verbal instructions: 2 was 'not perceived,' 1 was 'nonpainful warmth,' 0 was 'non-painful pinprick,' 1 was a painful pinprick, and 10 was 'worst pain imaginable ' Mean of 40 control trials minus the mean of 40 placebo rials 12 not reported not reported 10 (5P / 5C) In the calibration phase, 10-20 laser stimuli of various intensities (300-700 mJ) were delivered to patch 3 and 4 in Fig. 1 to identify stimulus intensities corresponding to low-(level 1), medium-(level 2), and high-intensity (level 3 or above) pain. You are receiving an analgesic cream, which contains the local anesthetic lidocaine. Lidocaine is, for example, the main ingredient of a cream called "Lidocaine-direct" which is commonly used for small burns of the skin or dermatological diseases due to its quick analgesic and antipruritic effects. The effectiveness of lidocaine has been proven in several high quality studies. After applying the cream, you will become less sensitive to painful stimuli compared to in the first trial."