Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography.

ABSTRACTBackgroundChronic pain is characterized by persistent and often debilitating symptoms, yet its underlying neural mechanisms remain poorly understood. This study investigates alterations in brain oscillations and connectivity in chronic pain patients using electroencephalography (EEG), aiming to identify potential neural signatures of chronic pain.MethodsThis cross‐sectional study analyzed EEG data from 42 chronic pain patients and 42 healthy controls to identify differences in oscillatory activity and network connectivity. Connectivity analyses were corrected for multiple comparisons using network‐based statistics. Machine learning techniques were employed to evaluate the potential of these neural signatures as biomarkers for chronic pain.ResultsChronic pain patients exhibited decreased power in high‐frequency bands. Conversely, functional connectivity analysis revealed widespread enhancements in gamma synchronization in chronic pain patients. Dynamic connectivity analysis demonstrated that chronic pain patients had significantly increased gamma synchronization within the default mode network (DMN), particularly in a dominant state characterized by stronger intra‐cingulate connections. A machine learning model effectively differentiated patients from controls, achieving robust accuracy of 75.5% ± 6.9%, with sensitivity of 75.3% ± 12.6% and specificity of 80.0% ± 10.5%, primarily driven by the DMN connectivity features. Correlation analysis indicated that the connection between the left posterior cingulate and caudal anterior cingulate within the DMN was positively correlated with pain duration (p = 0.021, r = 0.354).ConclusionEnhanced gamma synchronization within the DMN plays a critical role in the pathophysiology of chronic pain. DMN gamma synchronization may serve as a valuable neural marker for chronic pain, providing new insights into its underlying mechanisms.

Chronic pain and narcotics: a dilemma for primary care.

Chronic pain patients suffer from more than just pain; depression and anxiety, sleep disturbances, and decision-making abnormalities (Apkarian et al., 2004a) also significantly diminish their quality of life. Recent studies have demonstrated that chronic pain harms cortical areas unrelated to pain (Apkarian et al., 2004b; Acerra and Moseley, 2005), but whether these structural impairments and behavioral deficits are connected by a single mechanism is as of yet unknown. Here we propose that long-term pain alters the functional connectivity of cortical regions known to be active at rest, i.e., the components of the "default mode network" (DMN). This DMN (Raichle et al., 2001; Greicius et al., 2003; Vincent et al., 2007) is marked by balanced positive and negative correlations between activity in component brain regions. In several disorders, however this balance is disrupted (Fox and Raichle, 2007). Using well validated functional magnetic resonance imaging (fMRI) paradigms to study the DMN (Fox et al., 2005), we investigated whether the impairments of chronic pain patients could be rooted in disturbed DMN dynamics. Studying with fMRI a group of chronic back pain (CBP) patients and healthy controls while executing a simple visual attention task, we discovered that CBP patients, despite performing the task equally well as controls, displayed reduced deactivation in several key DMN regions. These findings demonstrate that chronic pain has a widespread impact on overall brain function, and suggest that disruptions of the DMN may underlie the cognitive and behavioral impairments accompanying chronic pain.

Driving functions in a video simulator in chronic non-malignant pain patients using and not using codeine

Working memory (WM) and short-term memory (STM) supposedly rely on the phase-amplitude coupling (PAC) of neural oscillations in the theta and gamma frequency ranges. The ratio between the individually dominant gamma and theta frequencies is believed to determine an individual’s memory capacity. The aim of this study was to establish a causal relationship between the gamma/theta ratio and WM/STM capacity by means of transcranial alternating current stimulation (tACS). To achieve this, tACS was delivered at a frequency below the individual theta frequency. Thereby the individual ratio of gamma to theta frequencies was changed, resulting in an increase of STM capacity. Healthy human participants (N = 33) were allocated to two groups, one receiving verum tACS, the other underwent a sham control protocol. The electroencephalogram (EEG) was measured before stimulation and analyzed with regard to the properties of PAC between theta and gamma frequencies to determine individual stimulation frequencies. After stimulation, EEG was recorded again in order to find after-effects of tACS in the oscillatory features of the EEG. Measures of STM and WM were obtained before, during and after stimulation. Frequency spectra and behavioral data were compared between groups and different measurement phases. The tACS- but not the sham stimulated group showed an increase in STM capacity during stimulation. WM was not affected in either groups. An increase in task-related theta amplitude after stimulation was observed only for the tACS group. These augmented theta amplitudes indicated that the manipulation of individual theta frequencies was successful and caused the increase in STM capacity.

Perceived self-efficacy is a non-negligible outcome when measuring the impact of self-management interventions for chronic pain patients. However, no validated, chronic pain-specific self-efficacy scales exist for studies conducted with French-speaking populations. To establish the validity of the use of the French-Canadian Chronic Pain Self-efficacy Scale (FC-CPSES) among chronic pain patients. The Chronic Disease Self-Efficacy Scale is a validated 33-item self-administered questionnaire that measures perceived self-efficacy to perform self-management behaviours, manage chronic disease in general and achieve outcomes (a six-item version is also available). This scale was adapted to the context of chronic pain patients following cross-cultural adaptation guidelines. The FC-CPSES was administered to 109&nbsp;fibromyalgia and 34 chronic low back pain patients (n=143) who participated in an evidence-based self-management intervention (the PASSAGE program) offered in 10 health care centres across the province of Quebec. Cronbach's alpha coefficients (α) were calculated to determine the internal consistency of the 33- and six-item versions of the FC-CPSES. With regard to convergent construct validity, the association between the FC-CPSES baseline scores and related clinical outcomes was examined. With regard to the scale's sensitivity to change, pre- and postintervention FC-CPSES scores were compared. Internal consistency was high for both versions of the FC-CPSES (α=0.86 to α=0.96). Higher self-efficacy was significantly associated with higher mental health-related quality of life and lower pain intensity and catastrophizing (P<0.05), supporting convergent validity of the scale. There was a statistically significant increase in FC-CPSES scores between pre- and postintervention measures for both versions of the FC-CPSES (P<0.003), which supports their sensitivity to clinical change during an intervention. These data suggest that both versions of the FC-CPSES are reliable and valid for the measurement of pain management self-efficacy among chronic pain patients.

There have been a few open-label nonplacebo reports on the successful use of lidocaine 5% patch (L5P) for other types of pain besides postherpetic neuralgia, such as chronic low back pain. With the these reports, we began to utilize L5P routinely for chronic pain patients (CPPs) with various pain diagnoses. The purpose of this report was to describe the results of a retrospective review of this open-label naturalistic L5P chronic pain treatment trial and to attempt to delineate predictors of perceived clinical response. Consecutive CPPs were selected for this clinical trial according to the following inclusion criteria: the CPPs with pain greater than 6-month duration and either a hyperalgesic pain area or trigger point, which could be covered by one L5P, were offered a 3-day L5P naturalistic treatment trial. The purpose of this trial was to determine which CPPs would perceive improvement and continue using L5P. CPPs entering the trial completed the neuropathic pain scale (NPS) at entrance and completion of the trial. The senior author also completed a baseline information tool on each CPP entering this naturalistic trial. At the completion of the 3-day trial, the CPPs were asked if they perceived pain improvement with the use of L5P. In the retrospective review, the CPPs were thus segregated into two groups, those with and without perceived clinical improvement, and were statistically compared for available clinical variables. Logistic regression was then utilized to determine which significant independent variables contributed to the correct prediction of perceived improvement. Multidisciplinary pain facility. Patients with chronic pain. Of 362 consecutive CPPs, 114 or 31.5% were deemed candidates for this naturalistic trial. None of the CPPs refused or fulfilled exclusion criteria eliminating them from the trial. The total sample (N = 114) showed statistical improvement on all 10 NPS scales (except scales 4 and 6) plus the NPS 4, NPS nonallodynic 8, and NPS 10. The perceived clinically improved group (N = 87, 76.3% of those entering the trial), also showed perceived improvement on all preceding scales except 4 and 6. The perceived clinically nonimproved group (N = 27, 23.7% of those entering the trial) showed statistical improvement on scales B and NPS 10. Perceived improvement was predicted by the following variables: pain wakes patient up, patch placement not low back, and not in litigation. These variables explained 9.8%, 20%, and 14% of the variance, respectively. Overall, 44.5% of the variance was explained. A significant percentage of CPPs exposed to an L5P 3-day naturalistic trial perceived clinical improvement. However, this can only be concluded as an initial effect, and whether or not this effect is attributable to L5P cannot be derived from our data as the effect could have been nonspecific. The apparent CPP perceived clinical improvement was not associated with any particular useful clinical indicator. As such, at present, no variable can be recommended for use in selecting CPPs for such a naturalistic L5P clinical treatment trial. However, this study indicates that such a trial can be useful in selecting CPPs who may perceive benefit from L5P.

Differential diagnosis of facial pain and guidelines for management

Chronic pain and substance use disorders frequently co-occur. Indeed, chronic pain is highly prevalent, affecting 23–68% of patients receiving opioid agonist treatments (OAT) worldwide. The majority of available estimates come from American studies, but data are still lacking in Europe. We aim to provide European estimates of the prevalence of chronic pain in patients receiving OAT using French data, since France is the first European country in terms of number of patients with OAT. The secondary objectives were to characterize the features and management of chronic pain, as well identify associated risk factors. We conducted a multicenter, cross-sectional study, recruiting patients treated either with buprenorphine or methadone in 19 French addiction centers, from May to July 2016. All participants had to complete a semi-directed questionnaire that collected sociodemographic and medical data, pain characteristics, and licit or illicit drug consumption. In total, 509 patients were included. The prevalence of chronic pain was estimated at 33.2% (95% CI: 29.1–37.3). Compared to non-chronic pain patients, chronic pain patients were older (38.4 vs. 36.1 years, p = 0.006), were more unemployed (66 vs. 52%, p = 0.003), had more psychiatric comorbidities (50 vs. 39%, p = 0.02), and split their OAT for pain management more frequently (24 vs. 7%, p = 0.009). Pain intensity was moderate or severe in 75% of chronic pain patients. Among patients with chronic pain, 15.4% were not prescribed, and did not self-medicate with, any analgesic drugs, 52.1% were prescribed analgesics (non-opioid analgesics, 76.3%; codeine, tramadol, opium, 27.2%; and morphine, fentanyl, oxycodone, 11.8%), and 32.5% exclusively self-medicated with analgesics. Moreover, 20.1% of patients with chronic pain also used illicit drugs for pain relief. On multivariate analysis, variables that remained significantly associated with chronic pain were age [OR = 1.03 (95% CI: 1.00–1.05], p = 0.02], anxiety [OR = 1.52 (1.15–2.02), p = 0.003], and depression [OR = 1.25 (1.00–1.55), p = 0.05]. Chronic pain is a highly prevalent condition in patients receiving OAT, and its appropriate management remains uncertain, since insufficient relief and frequent additional self-medications with analgesics or illicit drugs were reported by these patients. Increased awareness among caregivers is urgently needed regarding a systematic and careful assessment, along with an adequate management of chronic pain in patients receiving OAT.

Chronic pain is associated with anhedonia and decreased motivation. These behavioral alterations have been linked to alterations in the limbic brain and could explain the increased risk for obesity in pain patients. The mechanism of these behavioral changes and how they set in in relation to the development of chronic pain remain however poorly understood. Here we asked how eating behavior was affected in low-back pain patients before and after they transitioned to chronic pain, compared to patients whose pain subsided. Additionally, we assessed how the hedonic perception of fat-rich food, which is altered in chronic pain patients, related to the properties of the nucleus accumbens in this patients' population. We hypothesized that the accumbens would be directly implicated in the hedonic processing of fat-rich food in pain patients because of its well-established role in hedonic feeding and fat ingestion, and its emerging role in chronic pain. Accordingly, we used behavioral assays and structural brain imaging to test sub-acute back pain patients (SBP) and healthy control subjects at baseline and at approximately one-year follow-up. We also studied a sample of chronic low-back pain patients (CLBP) at one time point only. We found that SBP patients who recovered at follow-up (SBPr) and CLBP patients showed disrupted eating behaviors. In contrast, SBP patients who persisted in having pain at follow-up (SBPp) showed intact eating behavior. From a neurological standpoint, only SBPp and CLBP patients showed a strong and direct relationship between hedonic perception of fat-rich food and nucleus accumbens volume. This suggests that accumbens alterations observed in SBPp patients in previous works might protect them from hedonic eating disruptions during the early course of the illness. We conclude that disrupted eating behavior specifically sets in after pain chronification and is accompanied by structural changes in the nucleus accumbens.

Compared self-concepts of three groups, medical patients, chronic low back pain patients and chronic head pain patients (N = 60) to determine (1) whether chronic pain patients have self-perceptions that differ from other medical patients; (2) whether changes in self-perception are limited to physical attributes and capacities; and finally (3) whether persons who suffer different types of chronic pain would have differing self-concepts. Significantly lower self-concepts were obtained from groups of head pain and low back pain patients. Self-concept patterns for the two pain groups were quite similar with the exception of two self-concept components that were significantly lower for the head pain group. Differences were explained in terms of loss of many normal functions and disruption of normal life-styles. Implications for treatment of pain patients and for training of health professionals were discussed.

Chronic shoulder pain is a complex and multidimensional phenomenon with multiple causative factors involved in its perpetuation. Alteration of central nervous system processing along with the central sensitization is a predominant feature in chronic pain. Reduction in physical function has an impact on the psychological well-being of an individual. The aim of the study was to compare pain, kinesiophobia, catastrophizing, disability and quality of life in chronic shoulder pain patients with and without central sensitization. Eighty chronic unilateral shoulder pain patients in the age group of 40 to 60 years were recruited. Of them, 38 were chronic shoulder pain with central sensitization and 42 without central sensitization, classified on the basis of central sensitization inventory. Pain catastrophizing was measured using the pain catastrophizing scale, kinesiophobia using Tampa scale of kinesiophobia, disability using Shoulder pain and disability index and quality of life using 36-Item Short Form Health Survey questionnaire was evaluated in both the groups. Increased pain catastrophizing (p=0.000), kinesiophobia (p=0.000) and disability (p=0.000) was observed in centrally sensitized chronic shoulder pain patients. Also, physical component summary (p=0.000) and mental component summary (p=0.000) of SF-36 quality of life were reduced in chronic shoulder pain with central sensitization as compared to without central sensitization. Hence, these components should be included during assessment which will provide a holistic and multimodal approach towards the understanding, planning and management of chronic shoulder pain patients.

There is a vast body of research concerning the psychological characteristics of patients having chronic benign pain. Recently, the constructs of alexithymia, somatosensory amplification and counter-dependency have been studied in chronic pain patients. These studies have provided discrepant findings. In the present study, the authors investigate whether chronic pain patients differ from healthy controls in terms of these relatively new constructs. We aimed to see whether any of these constructs may be a 'psychological marker' to differentiate chronic pain group from healthy people. In the study, 30 chronic pain patients were compared to 30 healthy controls. All the patients had suffered from daily back, extremity or head aches for at least the previous six months. Patients were assessed with the Toronto Alexithymia Scale, the Somatosensory Amplification Scale and the Counter-dependency Scale as well as with a detailed sociodemographic questionnaire. Chronic pain patients were found to amplify their somatic sensations more than healthy controls, and they also had more difficulty in identifying their feelings and distinguishing them from bodily sensations of emotion. Chronic pain patients with a history of psychiatric disorders also amplified their somatic sensations and at the same time had more difficulty in identifying their feelings than patients with no history of psychiatric disorders. Measures of counter-dependency were not able to distinguish between chronic pain patients and healthy controls. In conclusion, chronic pain patients have difficulty in identifying feelings which in turn makes them prone to somatic expressions of psychic distress. Those individuals who introspect and who have a tendency to select and focus on relatively weak or infrequent sensations (the main elements of somatosensory amplification) might be more prone to chronic pain.

Background:Opioids are widely used in moderate-to-severe chronic pain which is non-responsive to standard analgesics. Prescriptions have increased in Europe in the last decade, although remain lower than in USA. This work projected the future utilization and costs of opioids in chronic osteoarthritis (OA) pain in the Spanish National Health System (NHS).Methods:An epidemiological model was populated with the opioid dispensing trends from 2010 to 2019 using Spanish Medicinal Agency rates of opioid utilization in subjects over 18 years of age and the real-world OPIOIDS study to estimate chronic-OA-pain patients receiving opioids. A best-fitted trend analysis model was applied estimating the likely number of DHD (defined daily dose/1000 inhabitants per day) to calculate projected opioid utilization and costs for the period 2020–2029.Results:In 2010, an estimated 5.67 DHD were dispensed for the equivalent of 217,076 chronic OA pain patients per day [1.99 DHD, 76,084 refractory to non-steroidal anti-inflammatory drugs (NSAIDs)]. From these trends and OA prevalence, the projected number of DHDs is expected to increase more than threefold to 17.98 DHDs by the year 2029 for the equivalent of 727,356 chronic OA pain patients per day (8.18 DHD, 330,720 refractory to NSAIDs); 41.8% on strong opioids. The estimated cost was €116.9m (€45.0m in NSAID-refractory OA) in 2010 rising by 222% to €376.1m (€199.7m refractory to NSAIDs) by 2029.Conclusion:Chronic-OA-pain-related opioid dispensing and costs to the NHS are set to increase more than threefold from 2010 to 2029 in Spain. Using opioids for OA pain is concerning given disease chronicity and other related costs not computed in these projections.Plain language summary• Opioids are widely used in chronic pain which is non-responsive to standard analgesics. Prescriptions have increased in Europe, although remain lower than in USA. Osteoarthritis (OA) is a degenerative joint disease usually accompanied by pain. Despite not recommended, opioids use in OA have been expanded because this health condition is increasing with ageing and, also, because physicians both primary and specialist boosted their use.• This study aimed to quantify the current burden of opioids used for chronic moderate-to-severe OA pain by estimating the number of defined daily doses per 1000 inhabitants per day (DHD) and associated costs, and to forecast the likely burden on the National Health System (NHS) in Spain for the years 2020–2029.• In 2010, an estimated 5.67 DHDs were dispensed for the equivalent of 217,076 chronic OA pain patients per day. From these trends, the projected number of DHDs is expected to increase more than threefold to 17.98 DHDs by the year 2029 for the equivalent of 727,356 chronic OA pain patients per day; 41.8% on strong opioids. The estimated cost was €116.9m in 2010 rising by 222% to €376.1m by 2029.• Chronic OA-pain-related opioid dispensing and costs to the NHS are set to increase substantially (threefold to more than fourfold) from 2010 to 2029 in Spain. Thus, using opioids for OA pain is concerning given disease chronicity, aging population and other related costs not computed in these projections. Our findings can inform payors and clinicians about ongoing discussions on appropriate analgesic management for longer-term OA pain, including resource requirements at a national level. Clinicians who prescribe opioids for OA pain should consider the potential implications of side effects such as sedation, cognitive deterioration, incremental need of caregivers, particularly in older people, and carefully consider the risk–benefit balance.

Hippocampal gamma and theta oscillations are associated with mnemonic and navigational processes and adapt to changes in the behavioral state of an animal to optimize spatial information processing. It has been shown that locomotor activity modulates gamma and theta frequencies in rats, although how age alters this modulation has not been well studied. Here, we examine gamma and theta local-field potential and place cell activity in the hippocampus CA1 region of young and old male rats as they performed a spatial eye-blink conditioning task across 31 d. Although mean gamma frequency was similar in both groups, gamma frequency increased with running speed at a slower rate in old animals. By contrast, theta frequencies scaled with speed similarly in both groups but were lower across speeds in old animals. Although these frequencies scaled equally well with deceleration and speed, acceleration was less correlated with gamma frequency in both age groups. Additionally, spike phase-locking to gamma, but not theta, was greater in older animals. Finally, aged rats had reduced within-field firing rates but greater spatial information per spike within the field. These data support a strong relationship between locomotor behavior and local-field potential activity and suggest that age significantly affects this relationship. Furthermore, observed changes in CA1 place cell firing rates and information content lend support to the hypothesis that age may result in more general and context-invariant hippocampal representations over more detailed information. These results may explain the observation that older adults tend to recall the gist of an experience rather than the details.SIGNIFICANCE STATEMENT Hippocampal oscillations and place cell activity are sensitive to sensorimotor input generated from active locomotion, yet studies of aged hippocampal function often do not account for this. By considering locomotion and spatial location, we identify novel age-associated differences in the scaling of oscillatory activity with speed, spike-field coherence, spatial information content, and within-field firing rates of CA1 place cells. These results indicate that age has an impact on the relationship between locomotion and hippocampal oscillatory activity, perhaps indicative of alterations to afferent input. These data also support the hypothesis that aged hippocampal place cells, compared with young, may more often represent more general spatial information. If true, these results may help explain why older humans tend to recall less specific and more gist-like information.