Facilitation of pain in the human spinal cord by nocebo treatment

Abstract

Nocebo hyperalgesia is an increase in subjective pain perception after a patient or subject underwent an inert treatment without any active ingredient. For example, verbal suggestion of increased pain can enhance both pain experience and responses in pain-related cortical brain areas. However, changes in cortical pain responses may be secondary to earlier amplification of incoming pain signals within the spinal cord. To test for a potential early enhancement of pain signals in the dorsal horn of the spinal cord, we combined a nocebo heat pain paradigm with spinal functional magnetic resonance imaging in healthy volunteers. We found that local application of an inert nocebo cream on the forearm increased pain ratings compared with a control cream, and also reduced pain thresholds on the nocebo-treated skin patch. On the neurobiological level, pain stimulation induced a strong activation in the spinal cord at the level of the stimulated dermatomes C5/C6. Comparing pain stimulation under nocebo to a control pain stimulation of the same physical intensity revealed enhanced pain-related activity in the ipsilateral dorsal horn of the spinal cord. Importantly, the activation of the main effect of pain and the nocebo effect spatially overlapped. The current study thus provides direct evidence for a pain-facilitating mechanism in the human spinal cord before cortical processing, which can be activated by cognitive manipulations such as nocebo treatments.

Figure 1.

Experimental design. A, Four patches on subjects' volar forearm were treated with identical inert creams, but subjects were led to believe that the nocebo cream would increase heat pain perception. Subjects were correctly informed that the control cream did not contain any active ingredient and would thus not affect pain perception. During the manipulation phase, we surreptitiously increased the temperature on the nocebo patch (filled red square on the forearm sketch), thereby simulating an effective treatment. During the fMRI test phase, temperatures were identical. Temperatures were individually calibrated to elicit an average pain rating of 60 on a VAS of 0–100 during the test phase. Each manipulation session consisted of two blocks of six nocebo trials and six control trials. During the fMRI session, subjects rated 15 painful heat stimuli in each condition. The stimulation order (nocebo first vs control first), and the assignment of conditions to patches (nocebo upper vs control upper) was counterbalanced across subjects. B, During each trial, a fixed anticipation period of 6 s was followed by 20 s heat pain stimulation. After a variable delay of 6–10 s, a VAS rating appeared on the screen and subjects rated the perceived pain intensity of the preceding stimulus. The ITI duration was adjusted in such a way that each trial lasted a total of 60 s.

Figure 2.

Behavioral results. A, Subjects perceived heat stimuli on the nocebo patch as more painful than on the control patch (t₍₁₉₎ = 2.54; p = 0.02). B, Pain ratings over trials were stable, but the nocebo effect (dashed line) decreased slightly over time (b = −0.36; t₍₁₃₎ = 2.83; p = 0.01). C, Pain thresholds obtained immediately before the test stimulation inside the fMRI scanner were lower on the nocebo patch than on the control patch (t₍₁₉₎ = 2.61; p = 0.017), indicating increased thermal sensitivity due to nocebo treatment. *Indicates a significant difference at p < 0.05. Error bars represent SEM after correction for between-subject variability (see Behavioral analyses).

Figure 3.

fMRI results. A, Main effect of painful stimulation overlaid on a sagittal slice of the averaged T1-weighted images and axial sections of the mean functional image. One contiguous pain cluster at the level of C5/C6 was observed at the set threshold of p < 0.005. Peak location was in the left ipsilateral hemicord on the axial section 2. B, Parameter estimates for the pain stimulation extracted from the left dorsal quadrant of the spinal cord. Parameter estimates were higher for pain stimulation under nocebo compared with control (t₍₁₉₎ = 2.32; p = 0.016). *Indicates a significant difference at p < 0.05. Error bars represent SEM after correction for between-subject variability (see Behavioral analyses). C, The contrast (nocebo > control) masked with the main effect of pain revealed a nocebo-induced signal increase in the left ipsilateral dorsal horn. Statistical t maps are thresholded at p < 0.005.

Figure 4.

Time course of the spinal response to pain. Parameter estimates were extracted for both conditions at the peak voxel of the nocebo > control contrast. The shaded area indicates the SEM, and the gray line marks the time of heat stimulation.