Randomized placebo-controlled cross-over designs in clinical trials : a gold-standard to be reassessed

Placebo effects are well-known phenomena in medicine and biology. In fact, placebos are used as control conditions in randomized cross-over clinical trials to validate new treatments. Only recently, however, has it become apparent that the conditioning and/or expectation effects provided by the experience of placebos can influence the results of clinical trials. It seems that combining shams and sequences has prejudiced the conclusions provided by cross-over designs. Frighteningly, this bias is always in the same direction, namely to increase the risk of rejecting potentially valid treatments. New models for clinical trials should be encouraged if we wish to market new and truly valid treatments

Deciphering the role of endogenous opioids in high frequency TENS using low and high doses of naloxone

Abstract : Previous human studies have shown that the analgesic effect of high frequency TENS could not be reversed by low doses of naloxone. The aim of the present study was to reinvestigate the possible contribution of opioid receptors in high frequency TENS analgesia by using low (0.02 mg/kg) and high (0.14 mg/kg) doses of naloxone. Naloxone (high and low doses) and saline were administered intravenously to young healthy adults using a double-blind randomised cross-over design. For each visit, TENS (100 Hz, 60 sec) was applied for 25 minutes to the external surface of the left ankle. TENS intensity was adjusted to obtain strong but comfortable (innocuous) paresthesias. Experimental pain was evoked with a 1 cm2 thermode applied on the lateral aspect of the left heel. Subjective pain scores were obtained before, during and after TENS. Because preliminary analyses showed that the order of presentation affected the pattern of results, only the first visit of every participant could be analyzed without fear of contamination from possible carry-over effects. These revealed that TENS maintained its analgesic properties following the injection of saline (p<.001) and the injection of a low dose of naloxone (p<.05). However, when a high dose of naloxone was administered, TENS analgesia was completely blocked (p=.20). These results strongly suggest that high frequency TENS involves opioid receptors. An insufficient amount of opioid antagonist likely prevented previous human studies from discovering the importance of opioid receptors in producing high frequency/ low intensity TENS analgesia

Evidence of descending inhibition deficits in atypical but not classical trigeminal neuralgia

Abstract : Trigeminal neuralgia (TN) is a rare neuropathic facial pain disorder. Two forms of TN, classical TN (CTN) and atypical TN (ATN), are reported and probably have different aetiologies. The aim of the present study was to evaluate the functional integrity of the diffuse noxious inhibitory controls (DNIC) in (1) a group of patients with classical trigeminal neuralgia (CTN), (2) a group of patients with atypical trigeminal neuralgia (ATN), and (3) a group of healthy controls in order to determine if a descending pain modulation deficit could participate in the pathophysiology of TN pain. DNIC responses of 14 CTN patients, 14 ATN patients and 14 healthy controls were obtained by comparing thermode-induced facial heat pain scores before and after activating DNIC. DNIC was triggered using a standard counter-irritation paradigm (i.e., immersion of the arm in painfully cold water). General sensitivity to pain was also evaluated by measuring mechanical pain thresholds over 18 points located outside the trigeminal territory. Healthy participants and CTN patients showed a 21% and 16% reduction in thermode-induced pain following the immersion, respectively (all p-values <.01), whereas ATN patients experienced no change (p=.57). ATN patients also had more tender points (mechanical pain thresholds < 4.0 kg) than CTN and healthy controls (all p-values < .05). Taken together, these results suggest that the underlying physiopathology differs between CTN and ATN and that a deficit in descending inhibition may further contribute to the pain experienced by patients with ATN

Effect of pulsed electromagnetic field therapy on experimental pain : a double-blind, randomized study in healthy young adults

Abstract : Past studies have suggested that pulsed electromagnetic field (PEMF) therapy can decrease pain. To date, however, it remains difficult to determine if the analgesic effect observed in patients are attributable to a direct effect of PEMF on pain or to an indirect effect of PEMF on inflammation and healing. In the present study, we used an experimental pain paradigm to evaluate the direct effect of PEMF on pain intensity, pain unpleasantness and temporal summation of pain. Twenty-four healthy subjects (mean age 22 ± 2 years; 9 males) participated in the experiment. Both real and sham PEMF were administered to every participant using a randomized, double-blind, cross-over design. For each visit, PEMF was applied for 10 minutes on the right forearm using a portable device. Experimental pain was evoked before (baseline) and after PEMF with a 9 cm2 Pelletier type thermode, applied on the right forearm (120 sec stimulation; temperature individually adjusted to produce moderate baseline pain). Pain intensity and unpleasantness were evaluated using a 0-100 numerical pain rating scale. Temporal summation was evaluated by comparing pain intensity ratings obtained at the end of tonic nociceptive stimulation (120 sec) with pain intensity ratings obtained after 60 sec of stimulation. When compared to baseline, there was no change in pain intensity and unpleasantness following the application of real or sham PEMF. PEMF did not affect temporal summation. The present observations suggest that PEMF does not directly influence heat pain perception in healthy individuals

Altered autonomic nervous system reactivity to pain in trigeminal neuralgia

BACKGROUND: In the last two decades, there has been increasing evidence to suggest that trigeminal neuralgia (TN) may be linked to a dysfunction of the autonomic nervous system (ANS). The aim of the present study was to formally test this hypothesis by comparing the reactivity of the ANS to experimental pain in a population of TN patients and healthy controls. METHODS: Twelve patients diagnosed with classical TN and 12 healthy controls participated in the study. Cardiac activity was assessed while participants were instructed to rest and again during a cold pressor test (CPT). Heart rate variability analyses were performed off-line to obtain parasympathetic (high-frequency) and sympathetic (low-frequency) indices. RESULTS: At baseline, ANS measures did not differ between healthy controls and TN patients, and both groups showed a similar increase in heart rate during the CPT (all p-values > .05). However, TN patients showed a greater increase in cardiac sympathetic activity and a greater decrease in cardiac parasympathetic activity during CPT compared to healthy controls (all p-values < .05). Importantly, changes in sympathetic reactivity, from baseline to CPT, were negatively associated with the number of pain paroxysms experienced each day by TN patients in the preceding week (r = -.58, p < .05). CONCLUSION: These results suggest that TN, like many other short-lasting, unilateral facial pain conditions, is linked to ANS alterations. Future studies are required to determine if the altered ANS response observed in TN patients is a cause or a consequence of TN pain

Unpredictable pain timings lead to greater pain when people are highly intolerant of uncertainty

Abstract : Background and purpose: Many psychological factors are known to influence pain perception. Amongthem, intolerance of uncertainty (IU) may play a key modulating role in situations where uncertaintyprevails, especially uncertainty regarding the timing of painful events. The objective of this study was toexplore the impact of individual differences in IU on pain perception during predictable and unpredictablestimulation timings. We hypothesized that people with high IU, as opposed to those with low IU, wouldperceive more pain when the timing of painful stimulations cannot be predicted, as compared to whenthey can.Methods: Twenty (20) healthy adults, aged between 18 and 35 years old, were recruited. Painful sensa-tions were provoked using transcutaneous electrical stimulations of the right sural nerve. By measuringIU (Intolerance of Uncertainty Scale) and subjective pain (verbal numerical rating scale), it was possibleto test the relationship between IU and pain perception, by simulating predictable and unpredictablepainful experiences. This was done through cued shock interval (CSI) blocks, with either variable timingor fixed timings (long or short time frame). Self-administered questionnaires were also used to measurepain hypervigilance, pain catastrophizing, state anxiety, and trait anxiety.Results: Pearson correlations confirmed the presence of an association (r = 0.63) between IU and thechange in pain intensity provoked by unpredictable stimulation timings. Importantly, this associationwas significant only for stimulations provided at long CSIs, indicating that higher IU scores predictedhigher pain intensity scores when stimulation timings became unpredictable, and when the cued delaywas long. No association was found between pain scores and other psychological variables.Conclusions: Our results show that IU moderately correlates to the change in pain intensity provokedby unpredictable stimulation timings. High IU scores were associated with a worsening of the subjectivepain experience, especially during long delays in an unpredictable situation. These observations suggestthat IU could be considered as a psychological variable that is able to influence pain perception in certainsituations.Implications: Assessing and addressing IU could be an added value in pain-related therapy, especially in chronic pain

Unravelling the effect of experimental pain on the corticomotor system using transcranial magnetic stimulation and electroencephalography.

Abstract : The interaction between pain and the motor system is well-known, with past studies showing that pain can alter corticomotor excitability and have deleterious effects on motor learning. The aim of this study was to better understand the cortical mechanisms underlying the interaction between pain and the motor system. Experimental pain was induced on 19 young and healthy participants using capsaicin cream, applied on the middle volar part of the left forearm. The effect of pain on brain activity and on the corticomotor system was assessed with electroencephalography (EEG) and transcranial magnetic stimulation (TMS), respectively. Compared to baseline, resting state brain activity significantly increased after capsaicin application in the central cuneus (theta frequency), left dorsolateral prefrontal cortex (alpha frequency), and left cuneus and right insula (beta frequency). A pain-evoked increase in the right primary motor cortex (M1) activity was also observed (beta frequency), but only among participants who showed a reduction in corticospinal output (as depicted by TMS recruitment curves). These participants further showed greater beta M1-cuneus connectivity than the other participants. These findings indicate that pain-evoked increases in M1 beta power are intimately tied to changes in the corticospinal system, and provide evidence that beta M1-cuneus connectivity is related to the corticomotor alterations induced by pain. The differential pattern of response observed in our participants suggest that the effect of pain on the motor system is variable from on individual to another; an observation that could have important clinical implications for rehabilitation professionals working with pain patients

Electrophysiological evidence for an early processing of human voices

<p>Abstract</p> <p>Background</p> <p>Previous electrophysiological studies have identified a "voice specific response" (VSR) peaking around 320 ms after stimulus onset, a latency markedly longer than the 70 ms needed to discriminate living from non-living sound sources and the 150 ms to 200 ms needed for the processing of voice paralinguistic qualities. In the present study, we investigated whether an early electrophysiological difference between voice and non-voice stimuli could be observed.</p> <p>Results</p> <p>ERPs were recorded from 32 healthy volunteers who listened to 200 ms long stimuli from three sound categories - voices, bird songs and environmental sounds - whilst performing a pure-tone detection task. ERP analyses revealed voice/non-voice amplitude differences emerging as early as 164 ms post stimulus onset and peaking around 200 ms on fronto-temporal (positivity) and occipital (negativity) electrodes.</p> <p>Conclusion</p> <p>Our electrophysiological results suggest a rapid brain discrimination of sounds of voice, termed the "fronto-temporal positivity to voices" (FTPV), at latencies comparable to the well-known face-preferential N170.</p