Placebo or Nocebo Interventions as Affected by Hypnotic Susceptibility

Round 1

Reviewer 1 Report (Previous Reviewer 1)

Now the limitations of the study design are clearly described and the discussion is adequate. Congratulations!

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 2 Report (New Reviewer)

Overall, I felt this was a very competently conceptualized, conducted, and reported study with a potentially quite useful practical implication: that the analgesic effect of hypnosis can be increased in low-hypnotizability subjects to that of high-hypnotizability subjects by combining it with a credible placebo. 

My suggestions here are relatively minor: 

1.  If I am reading correctly, the Y-axis in Figures 1 and 2 seems to be mislabeled.  The Y-axis seems to be the Mean Absolute VAS Score rather than "% of pain reduction" as given. 

2.  Line 283:  The p-value given in the text (0.092) seems at variance with the corresponding number in Table 3 (0.084).  Please forgive me if I am misreading. 

3.  Methods section:  I think it would be helpful for future replication to know the interstimulus interval (vs. the 0.2 msec interpulse interval).  As you know, this has bearing on windup, temporal summation. 

4.  Methods section.  I see from the end of the article that there was, of course, informed consent and IRB approval.  I think it would be helpful to include this in the Methods section as well.  Also, as the experimental design involved deception (appropriately), were the subjects debriefed?  Please forgive me if I missed this. 

5.  Methods section.  I was surprised that the VAS was anchored with respect to "sensation" rather than "pain."  Could you give a few words about this choice? 

Overall, though, I felt this was a very competently conducted, worthwhile study. I wish you good success. 

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Reviewer 3 Report (New Reviewer)

Dear Authors, 

thank you for submitting your paper. I experienced serious difficulties trying to find the scientific soundness of the paper: the population is made by payed volunteers, susceptible to bias; the same is for hypnosis, all non-objectifiable parameters. 

 

About the manuscript: 

- the introduction is too long

- reduce the use of "we" with a more objective and non in-first-person style

- the division in paragraphs and sub-paragraphs is messy; consider to adopt roman numbers ( I, II, III)

In conclusion, the paper is well structured and the idea is interesting but need more objective considerations.

Author Response

Please see the attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report (New Reviewer)

I don’t agree with you: all the scientific production considers that the reader could not be expert in a particular filed. For this reason, I suggest you again to modify the wall of text made with the introduction, it doesn’t encourage reading. 

Author Response

Thanks for your remark. I see your point in the possible discouraging of reading. Introduction was shortened as suggested. See attached file.

Author Response File: Author Response.docx

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The authors of the manuscript address an important topic. I see a major problem in the issue the authors state in the end of the manuscript:

"lack of an experiment of our subject under hypnosis with no placebo or nocebo interventions"

It is very hard to interpret the data as in every session, participants first had the placebo/nocebo condition and then the hypnosis analgesia. So we never know how the hypnosis analgesia works alone.

Maybe the authors can work around this and think about a possibly interesting question about a combination of placebo and hypnotic analgesia.

On the other hand, as the authors combine both placebo/nocebo and hypnotic analgesia, you would expect a condition where participants are suggested during hypnosis that pain gets more intensive so you have the counterpart to nocebo effect without hypnosis.

I like the question if placebo/nocebo works better with or without hypnosis. Maybe the authors can frame the manuscript like that.

I missed the citaton of the recent meta analysis on hypnosis and analgesia (Thompson et al, 2019) https://doi.org/10.1016/j.neubiorev.2019.02.013

saying that hypnotic analgesia works better for highly suggestible participants.

I was wondering why hypnotic suggestibility was not assessed with the HGSHS but instead with the arm levitation test. Please justify!

The blockade of sensory stimuli under hypnosis was shown in a series of studies justifying the method of blocking pain sensation under hypnosis 

https://doi.org/10.1371/journal.pone.0257380

https://doi.org/10.1371/journal.pone.0240832

https://doi.org/10.1038/s41598-017-05195-2

Also, the seminal study by Pierre Rainville showing the disentangling of sensory and affective pain processing under hypnosis should be cited 

https://www.science.org/doi/full/10.1126/science.277.5328.968

Comments on the figures:

Figure 1 and 2 need better x and y-axis labeling to understand what is going on. I expect a description of the numeric scale on the y-axis (VAS pain ratings from 0-100) and then the full range of possible ratings on the figure, not only until 60/70. On the x-axis, I expect full names like "baseline".

Also, there is no error bar or confidence interval in the figures. That sould be definetly added to interpret the variation of ratings!

Figure 3 is very confusing as the 2006 data are added without a lot of explanation.

Over all, I have troubles with the conclusion the authors make. "High hypnotizable (HH) subjects seem unresponsive to placebo or nocebo interventions, and hypnotisability is not synonymous with suggestibility. It seems that HH subjects are more "tuned" to an inner trait that makes them less susceptible to contextual cues, and therefore more resistant to placebo/nocebo interventions."

I don't think you can draw this conclusion from the data as "we performed placebo or nocebo interventions within the same session in which hypnotic relaxation and hypnotic analgesia took place as well, and subjects were aware of this fact."

That brings me back to my major point in the beginning. The authors should find a way to interpret the data in light of this confound.

Author Response

Answer for Reviewer 1 is attached  
Thank you

Author Response File: Author Response.docx

Reviewer 2 Report

Overview: The authors present a study in which participants were screened for hypnotic susceptibility and allocated to high or low susceptibility groups. Participants then underwent two sessions differing in whether a placebo or nocebo treatment was applied. In both sessions, participants reported pain on a VAS to electrical stimulation, calibrated at the start of each session. In each session after baseline, participants underwent placebo/nocebo conditioning, placebo/nocebo test, hypnotic relaxation, hypnotic analgesia, and post hypnosis placebo/nocebo. The results indicated that high hypnotic susceptibility individuals were unresponsive to the placebo/nocebo effects, while displaying reductions in pain to hypnotic relaxation, and hypnotic analgesia. In contrast, low susceptibility individuals were responsive to both the placebo and nocebo effects, with the combination of placebo and hypnotic relaxation and hypnotic analgesia producing similar rates of analgesia to high susceptibility participants. Hypnotic relaxation and analgesia appeared to attenuate the nocebo effect in low susceptibility individuals.

Comments:

Introduction:

• The introduction could benefit from a brief description of the difference between hypnotic analgesia and hypnotic relaxation for readers.
• The authors provide an interesting discussion as to whether effects such as hypnotic relaxation or wide spread analgesia are actually hypnotic phenomenon based on their previous research findings and relate such findings to discussions on the nature of hypnosis and the placebo effect as related (or unrelated) phenomena. These discussions have quite a rich history (e.g. Barber, 1960; Kirsch, 1996). Contemporary accounts of placebo analgesia highlight the role of endogenous opioids. While under-examined, opioid antagonists such as naloxone do not appear to attenuate hypnotic analgesia (Goldstein & Hilgard, 1975; Moret et al., 1991). The authors may wish to include such discussion to distinguish between these phenomena.

Methods:

• The relationship between pain report and stimulus intensity is typically non-linear. The authors placed the experimental intensity at 50% intensity between pain threshold and pain tolerance. This is a somewhat uncommon procedure, what was the rationale behind it?
• Page 3, line 142. The authors mention that participants marked VAS during the pain threshold/tolerance procedure. Is this correct?
• The authors applied the experimental stimulus 6 times, were these pain reports averaged for each condition for analysis?
• The authors report not asking participants to record VAS during placebo/nocebo conditioning, simply whether a change had occurred. This is somewhat uncommon in the literature, both as a means of demonstrating the effect of the surreptitious conditioning on pain report and avoiding interruption to the experimental procedure and alerting participants to possible deception.
• The order of conditions did not seem to be counterbalanced between participants (i.e. participants seemed to go from placebo/nocebo to hypnotic relaxation, to hypnotic analgesia, to post-hypnotic placebo/nocebo). While I appreciate that the sample size is small and that the authors aim was to examine the placebo and nocebo effect under hypnotic induction, the methodology would have been improved by the use of as much counterbalancing as possible.
• The authors state that the aim of the study was to examine the placebo and nocebo effects under hypnotic induction.
• The authors state they did not control for multiple comparisons, why?
• The authors state that the participants were from a medical background. Were any details provided to the participants on the nature of the placebo/nocebo treatments as part of the study? Such as drug names, dosage, etc?

Results:

• Could the authors include what measure of variance was reported in Table 2? Was this standard deviation or standard error? The figures would also benefit from the inclusion of error bars.

Discussion:

• Figure 3 is somewhat unclear in its labelling. I presume P and N refer to placebo and nocebo? It is also unclear from the discussion what the conditions were in this study the authors are comparing the present data to. The authors later mention that this data was included to overcome the lack of results for hypnotic relaxation and hypnotic analgesia without the presence of placebo/nocebo manipulations. This point could be addressed more clearly earlier.
• Page 10, line 340. I am not sure I follow the authors discussion on how differences in the role of conditioning between the placebo and nocebo effects played a role in the apparent attenuation of the nocebo effect by hypnotic relaxation.
• The authors discuss that high susceptibility individuals were unresponsive to the placebo/nocebo effect. However, post-hypnotic ratings of the placebo/nocebo effects were still substantially below baseline ratings. While a difference would be expected between groups as an indication of the placebo/nocebo effects, how would the authors explain this continued reduction in pain? Habituation?

 

Author Response

Answer for Reviewer 2 is attached  
Thank you

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

I am sorry but the response of the authors did not convince me that the serious confound is addressed appropriately. Therefore, I do not recommend the paper to be published.