Experimental Pain Reporting Accuracy and Placebo Response

Instruments and procedures:

Instruments All stimuli were applied by a contact-heat Thermal Sen-sory Analyzer 2001 system (Medoc, Ramat-Yishai, Israel) with a 30 x 30mm Peltier surface stimulator, which was attached by Velcro straps to the volar surface of the forearm of the subjects' hand.

Familiarization session At the beginning of the experimental session, all subjects underwent short training in order to familiarize them with the device and with the sensations evoked by the painful stimulation, and to train them to report their perceived pain intensity using the numerical pain scale. The training included exposure to three short contact-heat stimuli (44, 46.5, and 48°C), each lasting for 7 seconds from the time that the stimulation intensity reached the destination temperature. The thermode was moved following each stimulus to a completely distinct, adjacent area of skin. Subjects were asked to report the numerical pain score (NPS), on a scale ranging from 0, denoting no pain, to 100, denoting the worst pain imaginable, induced by each stimulus.

Pain reporting accuracy assessment:

The subject's pain reporting accuracy skills was assessed by the FAST, which is based on recording a subject's pain reports in response to repeated administration of thermal noxious stimuli of various intensities. During the FAST procedure the thermode was attached to the ventral surface of the subject's non-dominant arm and the temperature was raised from a baseline of 32°C, peaked for 3 seconds at 1 of 7 designated temperatures (44°C, 45°C, 46°C, 47°C, 48°C, 49°C, and 50°C), and then decreased down to the baseline. Stimulus rate of rise and fall was kept constant at 8°C/seconds. Subjects were asked to rate the peak pain intensity of each stimulus verbally using the NPS. Each temperature was presented 7 times in a random block-ordered design (49 stimuli in total). Inter-stimulus intervals of 20 seconds allowed the subject sufficient time to rate the pain they perceived during each stimulus. The location of the thermode was adjusted every 10 stimuli to minimize sensitization and/or habituation effects. The duration of the FAST procedure is \~25 minutes.

Placebo assessment:

The placebo effect was assessed using tonic heat delivered at fixed temperature of either 44, 46.5, and 48°C. As was shown by previous studies, these temperatures evokes mild, moderate and severe pain sensations. During the stimuli, the thermode was attached to the volar surface of the forearm of the subjects' dominant hand. Baseline temperature was 32.0 °C, with an increasing temperature rate of 2°C/s and a return-to-baseline temperature rate of 8°C/s. Pain intensity ratings of heat stimuli were assessed verbally using NPS, at 2, 10 and 20 sec after the initiation of the stimulus.

Placebo procedure:

Each subject received clinical trial-type instructions before receiving the placebo so that the condition of the study would be similar to those encountered in typical drug trials. Subjects consented to participate in a study examining the analgesic effects of a well-known established pain relief medication. The subjects were told that they were about to receive a pain relief medication, which is commonly used in clinical practice. Possible adverse effects of the substance in question were then described, but it was indicated that the investigators did not typically observe significant adverse effects. Actual pharmacological agents were not administered.

Study design:

All experiments were conducted in the same setting, by the same investigator. The experiment was performed in a quiet room with an ambient temperature of 23°C. After the familiarization stage, the experiment begun with delivery of the FAST. After a 10 min break, subjects received the three tonic heat stimuli, each lasting 20 sec long, in a pseudo-random order with 60 sec break between each stimulus. Thereafter each subject was given a placebo pill. In order to evaluate placebo effect, the tonic heat stimuli were administered 20 minutes after placebo intake maintaining the same stimuli order.

The net placebo effect (Δ) was calculated as the difference between the mean NPS of the mild, moderate, and severe pain stimuli administrated before the placebo (Pre-placebo) minus the same after placebo (Post-placebo). The placebo effect in percent was calculated as the ratio of Post-placebo to Pre-placebo double 100. Positive values indicate efficient placebo effect.

The total duration of the experimental session was approximately 1 hours and 30 minutes.