Pain: perception, expectation, meaning – it’s all important

I regularly scour the literature for the latest studies that look at pain mechanisms. Firstly I am fascinated by the science and philosophy of pain, both personally as it is so intrical to life and living, and because I need to understand the current thinking in pain to be effective as a clinician–one day I will post a picture of my study that is largely held together by books, journals and papers. Secondly, and related to the first reason, is because we simply must maintain a contemporary perspective and keep up to date with the rapidly developing knowledge base that crosses basic sciences, neuroscience, cognitive sciences and other fields that together can provide explnantion for the complex experience that is pain.

Ulrike Bingel has done some fascinating work and here are some of the abstracts with my brief comments following:


Neurogastroenterol Motil. 2012 Oct;24(10):935-e462. doi: 10.1111/j.1365-2982.2012.01968.x. Epub 2012 Jul 2.

Perceived treatment group affects behavioral and neural responses to visceral pain in a deceptive placebo study.

Kotsis V, Benson S, Bingel U, Forsting M, Schedlowski M, Gizewski ER, Elsenbruch S.


To assess effects of perceived treatment (i.e. drug vs placebo) on behavioral and neural responses to rectal pain stimuli delivered in a deceptive placebo condition. Methods  This fMRI study analyzed the behavioral and neural responses during expectation-mediated placebo analgesia in a rectal pain model. In N = 36 healthy subjects, the blood oxygen level-dependent (BOLD) response during cued anticipation and painful stimulation was measured after participants were informed that they had a 50% chance of receiving either a potent analgesic drug or an inert substance (i.e., double-blind administration). In reality, all received placebo. We compared responses in subjects who retrospectively indicated that they received the drug and those who believed to have received placebo. Key Results  55.6% (N = 20) of subjects believed that they had received a placebo, whereas 36.1% (N = 13) believed that they had received a potent analgesic drug. Subjects who were uncertain (8.3%, N = 3) were excluded. Rectal pain-induced discomfort was significantly lower in the perceived drug treatment group (P < 0.05), along with significantly reduced activation of the insular, the posterior and anterior cingulate cortices during pain anticipation, and of the anterior cingulate cortex during pain (all P < 0.05 in regions-of-interest analyses).

Conclusions & Inferences

Perceived treatment constitutes an important aspect in placebo analgesia. A more refined understanding of individual treatment expectations and perceived treatment allocation has multiple implications for the design and interpretation of clinical trials and experimental studies on placebo and nocebo effects.

RS: The way in which we interact (therapist/doctor and patient) alongside the expectations that are brought along to the session need due consideration. This includes the language used to educate and explain pain and symptoms, the way in which it is delivered, the context and environment where the delivery takes place and preceeding events such as previous consultations and the journey to the appointment.


Curr Biol. 2012 Jun 5;22(11):1019-22. doi: 10.1016/j.cub.2012.04.006. Epub 2012 May 17.

Attention modulates spinal cord responses to pain.

Sprenger C, Eippert F, Finsterbusch J, Bingel U, Rose M, Büchel C.


Reduced pain perception while being distracted from pain is an everyday example of how cognitive processes can interfere with pain perception. Previous neuroimaging studies showed distraction-related modulations of pain-driven activations in various cortical and subcortical brain regions, but the precise neuronal mechanism underlying this phenomenon is unclear. Using high-resolution functional magnetic resonance imaging of the human cervical spinal cord in combination with thermal pain stimulation and a well-established working memory task, we demonstrate that this phenomenon relies on an inhibition of incoming pain signals in the spinal cord. Neuronal responses to painful stimulation in the dorsal horn of the corresponding spinal segment were significantly reduced under high working memory load compared to low working memory load. At the individual level, reductions of neuronal responses in the spinal cord predicted behavioral pain reductions. In a subsequent behavioral experiment, using the opioid antagonist naloxone in a double-blind crossover design with the same paradigm, we demonstrate a substantial contribution of endogenous opioids to this mechanism. Taken together, our results show that the reduced pain experience during mental distraction is related to a spinal process and involves opioid neurotransmission.

RS: Nervous system activity takes place on a spectrum. the peripheral nerves at one end, the spinal cord in the middle and the brain on top. Ascending and descending mechanisms are key players in the overall perception of pain which is why we can distract ourselves and feel less pain for example, or indeed by re-evaluating the meaning of our pain, we can use parts of our brain to facilitate the flow of messages down to the spinal cord to influence danger signals coming up from the tissues. In central sensitisation though, we can see facilitation of the flow of danger signals, this being one of the mechanism based features of chronic and persisting pain.


J Neurosci. 2010 Dec 1;30(48):16324-31.

Anterior insula integrates information about salience into perceptual decisions about pain.

Wiech K, Lin CS, Brodersen KH, Bingel U, Ploner M, Tracey I.


The decision as to whether a sensation is perceived as painful does not only depend on sensory input but also on the significance of the stimulus. Here, we show that the degree to which an impending stimulus is interpreted as threatening biases perceptual decisions about pain and that this bias toward pain manifests before stimulus encounter. Using functional magnetic resonance imaging we investigated the neural mechanisms underlying the influence of an experimental manipulation of threat on the perception of laser stimuli as painful. In a near-threshold pain detection paradigm, physically identical stimuli were applied under the participants’ assumption that the stimulation is entirely safe (low threat) or potentially harmful (high threat). As hypothesized, significantly more stimuli were rated as painful in the high threat condition. This context-dependent classification of a stimulus as painful was predicted by the prestimulus signal level in the anterior insula, suggesting that this structure integrates information about the significance of a stimulus into the decision about pain. The anticipation of pain increased the prestimulus functional connectivity between the anterior insula and the midcingulate cortex (MCC), a region that was significantly more active during stimulation the more a participant was biased to rate the stimulation as painful under high threat. These findings provide evidence that the anterior insula and MCC as a “salience network” integrate information about the significance of an impending stimulation into perceptual decision-making in the context of pain.

RS: The anticipation and expectation of pain play a role in the end perception of pain, this study illustrating the connectivity within important brain regions known to be active in pain. Salience is key. The meaning that we give to the pain plays such a significant role in the threat level: how dangerous is this? Really? The brain has to answer this question biologically and on concluding that there is a problem, pain is an output in response. An amazing device that protects us and is vital for survival.


Sci Transl Med. 2011 Feb 16;3(70):70ra14.

The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil.

Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC, Ploner M, Tracey I.


Evidence from behavioral and self-reported data suggests that the patients’ beliefs and expectations can shape both therapeutic and adverse effects of any given drug. We investigated how divergent expectancies alter the analgesic efficacy of a potent opioid in healthy volunteers by using brain imaging. The effect of a fixed concentration of the μ-opioid agonist remifentanil on constant heat pain was assessed under three experimental conditions using a within-subject design: with no expectation of analgesia, with expectancy of a positive analgesic effect, and with negative expectancy of analgesia (that is, expectation of hyperalgesia or exacerbation of pain). We used functional magnetic resonance imaging to record brain activity to corroborate the effects of expectations on the analgesic efficacy of the opioid and to elucidate the underlying neural mechanisms. Positive treatment expectancy substantially enhanced (doubled) the analgesic benefit of remifentanil. In contrast, negative treatment expectancy abolished remifentanil analgesia. These subjective effects were substantiated by significant changes in the neural activity in brain regions involved with the coding of pain intensity. The positive expectancy effects were associated with activity in the endogenous pain modulatory system, and the negative expectancy effects with activity in the hippocampus. On the basis of subjective and objective evidence, we contend that an individual’s expectation of a drug’s effect critically influences its therapeutic efficacy and that regulatory brain mechanisms differ as a function of expectancy. We propose that it may be necessary to integrate patients’ beliefs and expectations into drug treatment regimes alongside traditional considerations in order to optimize treatment outcomes.

RS: Again this emphasises the point that we must address belief systems and expectations that patients bring along as an integral part of who they are as an individual. What we observe and what the patient experiences are key factors that require ‘marrying’ in order to target this interface with education, strategies, training and treatment. But, it has to make sense to the patient and fit with their belief system. In many cases this may require shifts in thinking to promote healthier behaviours and habits for moving forwards.

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