Hadas Nahman-Averbuch

Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy

Summary Conditioned pain modulation (CPM) predicts efficacy of duloxetine in painful diabetic neuropathy; patients with less efficient CPM are more likely to benefit from the drug. ABSTRACT This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug’s mechanism of action with the patient’s pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study’s primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r = 0.628, P < .001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R2 = 0.673; P = .012) showed that drug efficacy was predicted only by CPM (P = .001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment‐induced improvement in CPM was correlated with drug efficacy (r = −0.411, P = .033). However, this improvement occurred only in patients with less efficient CPM (16.8 ± 16.0 to −1.1 ± 15.5, P < .050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision‐making process. This evaluative approach promotes personalized pain therapy.

Pain sensitivity is inversely related to regional grey matter density in the brain.

Summary Highly sensitive individuals had the least grey matter density in the bilateral precuneus, posterior cingulate cortex, posterior parietal cortex, and left primary somatosensory cortex. ABSTRACT Pain is a highly personal experience that varies substantially among individuals. In search of an anatomical correlate of pain sensitivity, we used voxel‐based morphometry to investigate the relationship between grey matter density across the whole brain and interindividual differences in pain sensitivity in 116 healthy volunteers (62 women, 54 men). Structural magnetic resonance imaging (MRI) and psychophysical data from 10 previous functional MRI studies were used. Age, sex, unpleasantness ratings, scanner sequence, and sensory testing location were added to the model as covariates. Regression analysis of grey matter density across the whole brain and thermal pain intensity ratings at 49 °C revealed a significant inverse relationship between pain sensitivity and grey matter density in bilateral regions of the posterior cingulate cortex, precuneus, intraparietal sulcus, and inferior parietal lobule. Unilateral regions of the left primary somatosensory cortex also exhibited this inverse relationship. No regions showed a positive relationship to pain sensitivity. These structural variations occurred in areas associated with the default mode network, attentional direction and shifting, as well as somatosensory processing. These findings underscore the potential importance of processes related to default mode thought and attention in shaping individual differences in pain sensitivity and indicate that pain sensitivity can potentially be predicted on the basis of brain structure.

Distinct Brain Mechanisms Support Spatial vs. Temporal Filtering of Nociceptive Information

Summary Endogenous analgesic mechanisms are intrinsically associated with the spatial and temporal filtering of afferent input and play a far greater role than simple gain modulation. ABSTRACT The role of endogenous analgesic mechanisms has largely been viewed in the context of gain modulation during nociceptive processing. However, these analgesic mechanisms may play critical roles in the extraction and subsequent utilization of information related to spatial and temporal features of nociceptive input. To date, it remains unknown if spatial and temporal filtering of nociceptive information is supported by similar analgesic mechanisms. To address this question, human volunteers were recruited to assess brain activation with functional magnetic resonance imaging during conditioned pain modulation (CPM) and offset analgesia (OA). CPM provides one paradigm for assessing spatial filtering of nociceptive information while OA provides a paradigm for assessing temporal filtering of nociceptive information. CPM and OA both produced statistically significant reductions in pain intensity. However, the magnitude of pain reduction elicited by CPM was not correlated with that elicited by OA across different individuals. Different patterns of brain activation were consistent with the psychophysical findings. CPM elicited widespread reductions in regions engaged in nociceptive processing such as the thalamus, insula, and secondary somatosensory cortex. OA produced reduced activity in the primary somatosensory cortex but was associated with greater activation in the anterior insula, dorsolateral prefrontal cortex, intraparietal sulcus, and inferior parietal lobule relative to CPM. In the brain stem, CPM consistently produced reductions in activity, while OA produced increases in activity. Conjunction analysis confirmed that CPM‐related activity did not overlap with that of OA. Thus, dissociable mechanisms support inhibitory processes engaged during spatial vs temporal filtering of nociceptive information.

Waning of “Conditioned Pain Modulation”: A Novel Expression of Subtle Pronociception in Migraine

To assess the decay of the conditioned pain modulation (CPM) response along repeated applications as a possible expression of subtle pronociception in migraine.

Psychological Factors and Conditioned Pain Modulation: A Meta-Analysis.

Objective:Conditioned pain modulation (CPM) responses may be affected by psychological factors such as anxiety, depression, and pain catastrophizing; however, most studies on CPM do not address these relations as their primary outcome. The aim of this meta-analysis was to analyze the findings regarding the associations between CPM responses and psychological factors in both pain-free individuals and pain patients. Materials and Methods:After a comprehensive PubMed search, 37 articles were found to be suitable for inclusion. Analyses used DerSimonian and Laird’s random-effects model on Fisher’s z-transforms of correlations; potential publication bias was tested using funnel plots and Egger’s regression test for funnel plot asymmetry. Six meta-analyses were performed examining the correlations between anxiety, depression, and pain catastrophizing, and CPM responses in healthy individuals and pain patients. Results:No significant correlations between CPM responses and any of the examined psychological factors were found. However, a secondary analysis, comparing modality-specific CPM responses and psychological factors in healthy individuals, revealed the following: (1) pressure-based CPM responses were correlated with anxiety (grand mean correlation in original units r=−0.1087; 95% confidence limits, –0.1752 to −0.0411); (2) heat-based CPM was correlated with depression (r=0.2443; 95% confidence limits, 0.0150 to 0.4492); and (3) electrical-based CPM was correlated with pain catastrophizing levels (r=−0.1501; 95% confidence limits, −0.2403 to −0.0574). Discussion:Certain psychological factors seem to be associated with modality-specific CPM responses in healthy individuals. This potentially supports the notion that CPM paradigms evoked by different stimulation modalities represent different underlying mechanisms.

The role of stimulation parameters on the conditioned pain modulation response

Abstract Background and purpose Conditioned pain modulation (CPM) is a testing paradigm representing features of diffuse noxious inhibitory control. There is large diversity in the paradigms applied to induce CPM, and the consistency in CPM responses assessed by different paradigms is largely unknown. We aimed to characterize and explore the associations between the CPM responses assessed by different paradigms in the same cohort. Methods Thirty-three healthy middle-aged subjects underwent six CPM paradigms. The ‘test-stimuli’, consisted of thermal and mechanical modalities, using pain thresholds, suprathreshold pain and temporal summation types of measurements. The ‘conditioning-stimulus’ consisted of a contact heat stimulus applied to the thener of the left hand for 60s at an intensity of 46.5°C. Results Large variability was observed among the responses to the different CPM paradigms. Surprisingly, no correlations were found between the various CPM responses. Conclusions The variability in the CPM responses may suggest that the capacity of pain modulation is a multifaceted trait, whose expression varies with the application of different CPM paradigms. Implications Considering that CPM responses may represent different processes when assessed by different paradigms, we encourage the use of more than one CPM paradigm.

Preoperative preemptive drug administration for acute postoperative pain: A systematic review and meta-analysis

Preoperative administration of pharmacological substances, such as non‐steroidal anti‐inflammatory drugs or opioids, has been gaining acclaim as a preemptive measure to minimize postoperative pain. This systematic review and meta‐analysis aimed at evaluating the effectiveness of this approach in adults undergoing surgical procedures. MEDLINE, EMBASE and the Cochrane Central Register were searched from inception through January 2015. Data from randomized placebo‐controlled trials were screened, extracted and assessed for risk of bias according to The Cochrane Collaborations Tool by two independent authors. The primary outcome measure was reduction in postoperative analgesic consumption during 24 h post surgery; effects were described as mean differences between the drug and placebo arms with corresponding 95% confidence intervals (CIs) and were pooled using random‐effects models. Potential publication bias was tested using funnel plots and Eggers regression test for funnel plot asymmetry. Screened were 511 records, of which 39 were included in the final synthesis with data from 3172 patients. A significant reduction in postoperative analgesic consumption was observed using preoperative administration of non‐steroidal anti‐inflammatory drugs (NSAIDs; 95% CI, −0.61 to −0.14; 31 comparisons), chiefly by the COX‐2 inhibitors class (95% CI, −0.95 to −0.33; 13 comparisons). Significant reduction was also observed for gabapentin (95% CI, −1.60 to −0.38; 6 comparisons). No significant effects were observed using opioids, propionic acids or oxicam derivatives.

Associations between autonomic dysfunction and pain in chemotherapy‐induced polyneuropathy

Autonomic neuropathy, a relatively common complication of several chemotherapy agents, can affect the vagus nerve and its pain inhibitory capacity, thus increasing sensitivity to pain. This study aimed to evaluate the relationships between autonomic parasympathetic function and the perception of (1) spontaneous pain; (2) experimental non‐painful sensations; and (3) experimental painful sensations in chemotherapy‐induced neuropathy patients.

Relationship between Personality Traits and Endogenous Analgesia: The Role of Harm Avoidance

Whether psychological factors such as anxiety and pain catastrophizing levels influence the expression of endogenous analgesia in general and, more specifically, the conditioned pain modulation (CPM) response is still under debate. It may be assumed that other psychological characteristics also play a role in the CPM response. The neurotransmitters serotonin, dopamine, and norepinephrine are involved both in CPM, as well as personality traits such as harm avoidance (HA), novelty seeking (NS), and reward dependence (RD), which can be obtained by the Tridimensional Personality Questionnaire (TPQ). However, the associations between these traits (HA, NS, and RD) with endogenous analgesia revealed by CPM have not yet been explored.

Efficient conditioned pain modulation despite pain persistence in painful diabetic neuropathy

Introduction: Alleviation of pain, by either medical or surgical therapy, is accompanied by transition from less efficient, or pro-nociceptive, to efficient conditioned pain modulation (CPM). Spontaneous decrease or resolution of pain with disease progression is reported for some patients with painful diabetic neuropathy (PDN). Objectives: To explore whether CPM changes similarly in parallel to spontaneous resolution of pain in PDN patients. Methods: In this cross-sectional study, thirty-three patients with PDN underwent psychophysical assessment of pain modulation on the forearm, remote from the clinical pain. Results: Pain duration was not correlated with neuropathic pain intensity, yet, it correlated with CPM efficiency; patients with longer pain duration had same pain level, but more efficient CPM than those with short-pain duration (&rgr; = −0.417; P = 0.025, Spearman correlation). Patients with pain more than 2 years (median split) expressed efficient CPM that was not different from that of healthy controls. These patients also had lower temporal summation of pain than the short-pain duration patients group (P < 0.05). The 2 patient groups did not differ in clinical pain characteristics or use of analgesics. Conclusion: Pro-nociception, expressed by less efficient CPM and high temporal summation that usually accompanies clinical painful conditions, seems to “normalize” with chronicity of the pain syndrome. This is despite continuing pain, suggesting that pro-nociceptivity in pain syndromes is multifactorial. Because the pain modulation profile affects success of therapy, this suggests that different drugs might express different efficacy pending on duration of the pain in patients with PDN.