# Placebo or Nocebo Interventions as Affected by Hypnotic Susceptibility
## 1 Introduction  
The non-pharmacological treatment of pain reflects the growing appreciation for the role that these interventions play in the therapeutic armamentarium for pain management [1]. Hypnosis was shown to be remarkably effective at alleviating both clinical and experimental pain [2]. A recent meta-analysis demonstrated the effectiveness of hypnotic susceptibility, with a 42% reduction in the intensity of pain in subjects with high hypnotic susceptibility [3]. Hypnotic analgesia significantly exceeded the effect of a placebo in highly hypnotizable (HH) subjects by utilizing ischemic pain [4, 5]. Painful electrical tooth-pulp stimulation had its panfulness markedly reduced under hypnotic analgesia in HH subjects, where the reduction significantly exceeded that of a placebo [6]. Focused hypnotic analgesia and hypnotic generalized relaxation produced differential hypnotic analgesia in response to ascending stimulus intensity, where the analgesic effect of the focused analgesia by far exceeded that of generalized relaxation in HH subjects but not in lowly hypnotizable (LH) subjects [7]. Furthermore, hypnotic relaxation demonstrated a constant pain reduction at all stimulus levels comparable to that under placebo analgesia [6]. It seems that generalized hypnotic relaxation evokes a sensory response similar to a placebo and bears no clear relationship to hypnotic susceptibility [7]. The interrelationship between hypnotic and placebo analgesia was further investigated in HH and LH subjects using two components of hypnotic analgesia: a local focus analgesia and a remote widespread analgesia [8]. Itwas found that pain reduction produced in the local site was significantly higher in HH subjects than in the remote site, but it did not differ in the LH group [8]. It was concluded that focused hypnotic analgesia in HH subjects was related to hypnotic suggestions, while the remote widespread analgesia was independent of hypnotic susceptibility and possibly a placebo effect [8; 9; 10]. Hypnotic analgesia differs from placebo analgesia in its underlying mechanisms. Thus, placebo analgesia is naloxone-reversed, pointing to the production of endogenous opiates, while hypnotic analgesia is not reversed by naloxone [11; 12; 13; 14]. Recently, [PERSON] demonstrated that hypnosis is not equal to a common placebo in terms of brain activity, thus questioning the hypothesis that the pain-reducing properties of hypnosis are just one form of a placebo effect [15]. Expectations for pain relief are likely to play a major role in the mechanisms of a placebo, and conditioning procedures that induce placebo analgesia are mediated by expectation [16; 17; 18]. Conditioning can be attained by the pairing of surreptitiously lowered pain stimulus intensity with placebo administration, which results in subsequent placebo analgesia [19]. It seems that verbally induced expectations of analgesia alone are not as effective as when paired with a conditioning procedure; the latter is believed to increase the expectation of analgesia [20]. Mechanisms underlying the placebo effect were widely studied, but its opposite effect, the nocebo, has only recently attracted attention [21; 22; 23]. Placebo and nocebo effects are not just identical opposites, and verbally induced expectations and conditioning procedures do not have the same effects on a placebo and a nocebo [24]. Conditioning was of great importance and the verbal information was of much smaller importance in the placebo group, while conditioning did not contribute to any significant nocebo effect [24; 25]. The fact that hypnotic analgesia is apparently not dependent on expectation [7; 8] makes the study of expectation and conditioning as related to a nocebo, a placebo, and hypnotic analgesia even more attractive. Hypnotic analgesia in HH subjects differs from that in LH subjects, but it is not clear whether HH subjects differ from LH subjects in their response to placebo analgesia or, for that matter, to nocebo hyperalgesia.