Is predictability of the conditioning stimulus (CS) a critical factor in conditioned pain modulation (CPM)?

INTRODUCTION: Conditioned pain modulation (CPM) allows to investigate endogenous pain modulation and its clinical outcomes. Although co-activation of emotions has been shown to affect CPM, the impact of 'threat,' which may accompany CPM stimulation itself, has been mostly neglected. A critical factor for the threat level of the conditioning stimulus (CS) may be its predictability. METHODS: 38 healthy participants (18 female) took part in a CPM study with pressure stimulation on the leg (blood-pressure cuff) serving as CS and heat stimulation on the forearm (contact thermode; CHEPS) serving as test stimulus (TS). While CS varied in intensity and -as operationalisation of threat- in temporary predictability, TS was kept constant. CPM effects were studied by EEG parameters (N2P2) and pain ratings. RESULTS: We found a significant CPM effect when considering N2P2, with low CS predictability augmenting CPM inhibition; in contrast, a surprisingly facilitatory CPM effect occurred in pain ratings (in the high CS predictability condition). The threat manipulation was only partially successful because CS intensity increased the threat ratings but not -as intended- CS predictability. Correlations between subjective and psychophysiological CPM responses were low. DISCUSSION: The differing CPM effects in subjective and psychophysiological responses, with both inhibitory and facilitatory effects, is puzzling but has already been observed earlier. The consideration of the CPM stimulation as major threat that is emotionally active is theoretically clearly justifiable but the operationalisation by means of different levels of CS predictability as in the present study might not have been ideal. Thus, further attempts of experimental verification are warranted.

Counterirritation by pain inhibits the responsiveness to aversive loud tones: the role of state anxiety and state fear triggered in the NPU paradigm.

AIM OF THE STUDY: The application of a noxious stimulus reduces the perception and responsiveness to other pain stimuli. This inhibition can be experimentally assessed with a method called 'counterirritation'. The question arises if counterirritation acts also on the perception and responsiveness to aversive but non-nociceptive stimuli (e.g., loud tones). Since aversive stimulation is often associated with state anxiety or state fear, we investigated in addition the modulatory effects of these emotions on counterirritation. MATERIAL AND METHODS: 51 subjects participated in our study. We presented tones with aversive loudness (105 dB), first alone then during counterirritation (immersion of the hand in a hot water bath of 46 °C) to assess inhibition of loudness perception and responsiveness. Influences of state anxiety and state fear on counterirritation were investigated by using the Neutral-Predictable(fear)- Unpredictable(anxiety) Paradigm (NPU), which is based on classical conditioning. Loudness ratings (perception of the aversive tones) and startle reflex (defensive reaction to aversive tones) were assessed. RESULTS: Counterirritation reduced startle reflex amplitudes, but not the loudness ratings. Although state anxiety and state fear were successfully induced, counterirritation remained unaffected. CONCLUSIONS: Our study showed that pain inhibits the responsiveness to aversive stimuli (loud tones). Thus, the postulate that 'pain inhibits pain' might be better changed to 'pain inhibits aversiveness'. Consequently, our findings may also question the assumption of a clear pain specificity in inhibitory action as assumed by theoretical approaches like 'conditioned pain modulation' (CPM). Furthermore, counterirritation appeared one more time resistant to the influence of negative emotions.

Is conditioned pain modulation (CPM) affected by negative emotional state?

BACKGROUND: Conditioned pain modulation (CPM) is an experimental paradigm, which describes the inhibition of responses to a noxious or strong-innocuous stimulus, the test stimulus (TS), by the additional application of a second noxious or strong-innocuous stimulus, the conditioning stimulus (CS). As inadequate CPM efficiency has been assumed to be predisposing for clinical pain, the search for moderating factors explaining inter-individual variations in CPM is ongoing. Psychological factors have received credits in this context. However, research concerning associations between CPM and trait factors relating to negative emotions has yielded disappointing results. Yet, the influence of anxious or fearful states on CPM has not attracted much interest despite ample evidence that negative affective states enhance pain. Our study aimed at investigating the effect of fear induction by symbolic threat on CPM. METHODS: Thirty-seven healthy participants completed two experimental blocks: one presenting aversive pictures showing burn wounds (high-threat block) and one presenting neutral pictures (low-threat block). Both blocks contained a CPM paradigm with contact heat as TS and hot water as CS; subjective numerical ratings as well as contact-heat evoked potentials (CHEPs) were assessed. RESULTS: We detected an overall inhibitory CPM effect for CHEPs amplitudes but not for pain ratings. However, we found no evidence for a modulation of CPM by threat despite threat ratings indicating that our manipulation was successful. DISCUSSION: These results suggest that heat/thermal CPM is resistant to this specific type of symbolic threat induction and further research is necessary to examine whether it is resistant to fearful states in general. SIGNIFICANCE: The attempt of modulating heat conditioned pain modulation (CPM) by emotional threat (fear/anxiety state) failed. Thus, heat CPM inhibition again appeared resistant to emotional influences. Pain-related brain potentials proved to be more sensitive for CPM effects than subjective ratings.

Counterirritation by Pain Inhibits Responses to and Perception of Aversive Loud Tones.

The application of a noxious stimulus reduces the perception of other noxious stimuli, which can be assessed by an experimental method called "counterirritation." The question arises whether this type of inhibition also affects the processing of other aversive (but not nociceptive) stimuli, such as loud tones. If aversiveness or, in other words, negative emotional valence qualifies a stimulus to be affected by counterirritation, the general emotional context may also play a role in modulating counterirritation effects. We involved 63 participants in this study (M age = 38.8, SD = 10.5 years; 33 males, 30 females). We tried to counterirritate their perceptual and startle reactions to aversively loud tones (105 db) by immersing the hand into a painful hot water bath (46°C) in two emotional valence conditions (i.e., a neutral and a negative valence block in which we showed either neutral pictures or pictures of burn wounds). We assessed Inhibition by loudness ratings and startle reflex amplitudes. Counterirritation significantly reduced both loudness ratings and startle reflex amplitudes. The emotional context manipulation did not affect this clear inhibitory effect, showing that counterirritation by a noxious stimulus affects aversive sensations not induced by nociceptive stimuli. Thus, the assumption that "pain inhibits pain" should be widened to "pain inhibits the processing of aversive stimuli." This broadened understanding of counterirritation leads to a questioning of the postulate of clear pain specificity in paradigms like "conditioned pain modulation" (CPM) or "diffuse noxious inhibitory controls" (DNIC).

The induction of social pessimism reduces pain responsiveness.

OBJECTIVES: Past work has found that optimism reduces a person's responsiveness to pain, but the effects of pessimism are not clear. Therefore, we gave pessimistic forecasts of participants' future social life and measured changes in their pain responsiveness. In particular, some participants were told that they would end up alone in life. METHODS: Seventy-five subjects were investigated in three conditions (negative forecast, positive forecast, no forecast) for changes in pain threshold and pain tolerance threshold. Pressure pain induction was accomplished by either human- or machine-driven algometers. A randomly assigned bogus forecast promising either a lonely or a socially satisfying future was ostensibly based on a personality questionnaire and an emotional dot-probe task. As potential covariates, questionnaires assessing dispositional optimism (LOT-R), pain catastrophizing (PCS), and self-esteem (SISE) were given. RESULTS: Pain thresholds suggested a change toward unresponsiveness only in the negative forecast condition, with only small differences between the modes of pain induction (i.e., human or machine). The results for pain tolerance thresholds were less clear also because of limiting stimulation intensity for safety reasons. The covariates were not associated with these changes. CONCLUSIONS: Thus, people expecting a lonely future became moderately less responsive to pain. This numbing effect was not modulated by personality measures, neither in a protective fashion via dispositional optimism and self-esteem nor in a risk-enhancing fashion via trait pain catastrophizing. Alternative mechanisms of action should be explored in future studies.

Attentional processing of pain faces and other emotional faces in chronic pain-an eye-tracking study.

Altered attentional processing of pain-associated stimuli-which might take the form of either avoidance or enhanced vigilance-is thought to be implicated in the development and maintenance of chronic pain. In contrast to reaction time tasks like the dot probe, eye tracking allows for tracking the time course of visual attention and thus differentiating early and late attentional processes. Our study aimed at investigating visual attention to emotional faces in patients with chronic musculoskeletal pain (N = 20) and matched pain-free controls (N = 20). Emotional faces (pain, angry, happy) were presented in pairs with a neutral face for 2000 ms each. Three parameters were determined: First fixation probabilities, fixation durations (overall and divided in four 500 ms intervals) and a fixation bias score as the relative fixation duration of emotional faces compared to neutral faces. There were no group differences in any of the parameters. First fixation probabilities were lower for pain faces than for angry faces. Overall, we found longer fixation duration on emotional compared to neutral faces ('emotionality bias'), which is in accord with previous research. However, significant longer fixation duration compared to the neutral face was detected only for happy and angry but not for pain faces. In addition, fixation durations as well as bias scores yielded evidence for vigilant-avoidant processing of pain faces in both groups. These results suggest that attentional bias towards pain-associated stimuli might not generally differentiate between healthy individuals and chronic pain patients. Exaggerated attentional bias in patients might occur only under specific circumstances, e.g., towards stimulus material specifically relating to the specific pain of the patients under study or under high emotional distress.

Decoding of facial expressions of pain in avatars: does sex matter?

OBJECTIVES: The decoding of facial expressions of pain plays a crucial role in pain diagnostic and clinical decision making. For decoding studies, it is necessary to present facial expressions of pain in a flexible and controllable fashion. Computer models (avatars) of human facial expressions of pain allow for systematically manipulating specific facial features. The aim of the present study was to investigate whether avatars can show realistic facial expressions of pain and how the sex of the avatars influence the decoding of pain by human observers. METHODS: For that purpose, 40 female (mean age: 23.9 years) and 40 male (mean age: 24.6 years) observers watched 80 short videos showing computer-generated avatars, who presented the five clusters of facial expressions of pain (four active and one stoic cluster) identified by Kunz and Lautenbacher (2014). After each clip, observers were asked to provide ratings for the intensity of pain the avatars seem to experience and the certainty of judgement, i.e. if the shown expression truly represents pain. RESULTS: Results show that three of the four active facial clusters were similarly accepted as valid expressions of pain by the observers whereas only one cluster ("raised eyebrows") was disregarded. The sex of the observed avatars influenced the decoding of pain as indicated by increased intensity and elevated certainty ratings for female avatars. CONCLUSIONS: The assumption of different valid facial expressions of pain could be corroborated in avatars, which contradicts the idea of only one uniform pain face. The observers' rating of the avatars' pain was influenced by the avatars' sex, which resembles known observer biases for humans. The use of avatars appeared to be a suitable method in research on the decoding of the facial expression of pain, mirroring closely the known forms of human facial expressions.

Effects of oral alcohol administration on heat pain threshold and ratings of supra-threshold stimuli.

Background and aims Evidence for analgesic effects of oral alcohol consumption on heat pain has recently been documented in a placebo-controlled, randomized and double-blind design. We aimed at further investigating these effects and now set the focus on pain threshold and the ratings of supra-threshold pain to cover most of the pain range. Moreover, we now firstly evaluated sex differences in these effects. Methods We investigated 41 healthy participants (22 females) in a randomized, double-blind and placebo-controlled design and targeted two different moderate breath-alcohol levels of 0.06% and 0.08%. Before and after an alcoholic or placebo drink, contact heat was applied at the forearm. Subjects evaluated pain threshold (method of adjustment) and rated pain intensity and pain unpleasantness of supra-threshold stimuli (intensity: threshold +3 °C; duration: 5 s). Results Analgesic effects taking the form of increased pain thresholds were found after both alcohol doses, surprisingly with more pronounced effects for the lower dose. While the high alcohol dose exerted small analgesic effects on pain intensity ratings (i.e. decrease), slightly increased ratings of pain intensity and pain unpleasantness after the low alcohol dose rather suggest pain enhancement. Alcohol did not affect intensity vs. unpleasantness ratings differentially. We found no evidence for sex differences in any of these effects. Conclusions Overall, acute alcohol effects on pain were subtle. Our findings suggest that while low alcohol doses already exert analgesic effects on pain threshold, stronger doses are required for pain reduction on supra-threshold pain levels. Furthermore, sex differences could not be detected within our experimental paradigm but should be further explored in future research. Implications Analgesic effects of sub-toxic alcohol doses - as normally occurring during social drinking - might be weak; however, susceptibility to pain relieving effects of alcohol might be a risk factor for the use of alcohol as self-medication in acute pain states.

Acute alcohol effects on conditioned pain modulation, but not temporal summation of pain.

Although pain reduction after alcohol administration has repeatedly been demonstrated, alcohol effects on advanced and clinically relevant dynamic pain paradigms are still unknown. As such, temporal summation of pain (TSP) and conditioned pain modulation (CPM) indicate mechanisms of endogenous pain modulation and involve certain neurotransmitter systems crucially influenced by alcohol. Our study is the first to investigate acute alcohol effects on TSP and CPM. We investigated 39 healthy subjects in a placebo-controlled within-subject design and targeted alcohol levels of 0.06% (dose 1) and 0.08% (dose 2). Pain threshold, TSP, and CPM were evaluated before and after an alcoholic or placebo drink. Temporal summation of pain was assessed as enhanced pain response to 5 repetitive contact heat stimuli (threshold +3°C). Conditioned pain modulation was tested as pain inhibition when a conditioning stimulus (46°C hot water) was applied concurrently to a test stimulus (contact heat; threshold + 3°C). Both alcohol doses boosted CPM, with a greater effect size for the higher dose. Conditioning stimulus ratings increased after alcohol intake but were not correlated with CPM, suggesting independence of these effects. Temporal summation of pain was not affected by alcohol, and alcohol effects on pain threshold were small and limited to the higher dose. Our findings suggest that analgesic alcohol effects might be mainly driven by an enhancement of endogenous pain inhibition. The frequent use of alcohol as self-medication in chronic pain might be motivated by alcohol temporarily restoring deficient CPM, thus leading to pain relief in the short run and alcohol-related problems in the long run.

Interactive effects of conditioned pain modulation and temporal summation of pain-the role of stimulus modality.

Conditioned pain modulation (CPM) and temporal summation of pain (TSP) are 2 experimental paradigms capturing endogenous pain modulation, which have repeatedly demonstrated clinical relevance. Conditioned pain modulation describes the inhibition of the pain response to a test stimulus (Ts) when a second noxious stimulus, the conditioning stimulus (CS), is concurrently applied. Temporal summation of pain describes the enhanced pain response to a series of stimuli compared with single stimuli. Temporal summation of pain-limiting effects of CPM are likely but may depend on the stimulus modality of the Ts. This study aimed at investigating these differential effects of stimulus modality. Thirty-five healthy volunteers completed 2 experimental blocks (Ts modality: pressure vs heat) in balanced order. Both blocks consisted of 3 conditions: baseline (no CS), CPM1 (nonpainful CS: 42°C water bath), and CPM2 (painful CS: 46°C water bath). Single stimuli and series of stimuli were alternatingly applied to assess TSP by means of a Numerical Rating Scale. Both TSP and CPM were successfully induced with no difference between the 2 Ts modalities. We also detected a significant interaction between TSP and CPM, with higher pain reduction for a series of Ts compared with single Ts during the painful CS. Interestingly, this interaction was modality-dependent: TSP for heat Ts was completely abolished by CPM, whereas this was not the case for pressure Ts. Our findings suggest different forms of central sensitization induced by TSP using either heat or pressure stimuli, which differ in their susceptibility to CPM. Clinical implications and directions for future research are discussed.