Patients with complex regional pain syndrome (CRPS) report cognitive difficulties, affecting the ability to represent, perceive and use their affected limb.  Complex regional pain syndrome (CRPS) is a chronic disorder associated with sensory, motor, autonomic and trophic symptoms such as pain, temperature change, skin color change, swelling and limited movement in usually one limb. CRPS often follows a minor or mild trauma to a limb . The patStudies have shown that CRPS patients also tend to have more difficulties in perceiving somatosensory stimuli applied to the affected part of the body . For insheightened attention for bodily sensations : (1) patients with CRPS type I of one of the upper limbs, (2) patients with unilateral wrist pain and (3) patients with unilateral shoulder pain. Participants from all groups were included when they were native Dutch speaking and had experienced unilateral upper limb pain for longer than 3 months. They were excluded when they also reported pain at the opposite side of the body with respect to their affected limb, nerve injury , ongoing limb trauma or recent (<3 weeks) surgery of the painful limb. At entry, all participants were tested with the same battery of tests to either confirm (in case of CRPS patients), or rule out (in case of wrist and shoulder pain patients) the diagnosis of CRPS according to the Budapest criteria see . All patParticipants completed an ad hoc questionnaire assessing socio-demographic characteristics, the Pain Grading Scale PGS;  and a Hahttp://hdl.handle.net/1854/LU-7179946), but these results were not used for the purpose of this study and are therefore not further discussed.After each experimental block, a series of self-report items assessed (i) the intensity of the vibrotactile stimuli on each hand ; (ii) to what extent they were able to concentrate during the task ; (iii) to what extent they experienced the task as fatiguing . At the end of the experiment, additional items assessed to what extent participants (iv) directed their attention to the vibrotactile stimuli; (v) made an effort to complete the task; (vi) experienced fear/tension during the task and (vii) found the task meaningful . Participants also completed a set of self-report questionnaires , attached to the sensory territory of the superficial radial nerve of each hand . The actuators were driven by self-developed software and a controlling device that converted electrical signals (Watt) into oscillating movements of the actuators against the skin. The intensity of the vibrotactile stimuli were determined individually and matched between both hands by means of a double random staircase procedure, based on the staircase procedure of In the first phase of the study, participants completed the socio-demographic questionnaire, the Pain Grading Scale and the Hand Dominance Questionnaire (~10 min). In the second phase, participants were seated and the diagnostic screening (interview + testing) for CRPS took place (~20 min). In the third phase of the study (~90 min) during which the TOJ task was performed, the experimenter attached the actuators to the hands and gave the participants instructions about the staircase procedure. Following this, the headphones were turned on and the staircase procedure was initiated. Responses were inserted manually on a keyboard by the experimenter. As soon as the staircase procedure was finished, headphones were temporarily removed.left” versus “right”) in order to practice response mapping. In the second practice block , pairs of tactile stimuli were administered one to either hand and separated by the three largest stimulus onset asynchronies (SOA’s) used during the experiment, that is, ±200, ±90 or ±55 ms  (left first” versus “right first”). The third practice block  was identical to the second but was made up of 18 trials and participants were asked to cross their hands over the body midline . When instructions were not completely understood, or if performance was suboptimal, practice blocks were repeated until performance was satisfactory. In addition, participants could only proceed from the third practice block to the first experimental block when a minimal performance of 75% was achieved on trials with the highest SOA (±200 ms).During the TOJ task, participants were instructed to fixate their gaze on a red LED in front of them, to place their chin in the chin wrest and to keep their hands still on the table throughout the task. After receiving these instructions, headphones were turned back on. The TOJ task started with three practice blocks of increasing difficulty. In the first practice block , participants were administered only one tactile stimulus in each trial  and were asked to locate the stimulus (“d first) . Particileft hand” versus “right hand”), regardless of arm position. The experimenter inserted these responses manually on a keyboard . Participants were asked to maintain a steady pace in responding and to be as accurately as possible. After each experimental block, participants filled in the post-block items and temperature was reassessed on the back of both hands.During the experiment proper, 4 blocks of 60 trials each were presented to the participants. Each trial was made up of a pair of tactile stimuli one administered to the left and one on the right hand, according to five possible SOAs ranging from 10 to 200 ms , 2015. Tz-score. The best-fitting straight line was computed for each participant and for both postures (crossed versus uncrossed arm position) and the derived slope and intercept were used to calculate the point of subjective simultaneity (PSS) and the just noticeable difference (JND).Based on the procedure of The PSS refers to the point at which a participant reports the two tactile stimuli (on the left and right hand) as occurring first equally often. This point can be interpreted as the SOA value that corresponds to a 0.5 proportion of left hand/right hand first responses . The PSSThe JND indicates the interval between both tactile stimuli (on the left and right hand) needed to achieve a 75% correct performance and as such, provides a standardized measure of the sensitivity of participants’ temporal perception. It is calculated by dividing 0.675 by the slope of the best-fitting straight line  and corrPSS values and their corresponding JND values were excluded from the analyses, if one of following criteria was not met: (1) The absolute value of the PSS values had to be smaller than twice the largest SOA ; (2) the performance (% correct answers) of the participants for the largest SOA  had to be above 60%  in both postures (hands uncrossed versus crossed). Extremely large PSS values and low performance indicate that participants were not able to perform the task correctly even at large SOAs, where the task performance is expected to be nearly perfect. The difference in missing values between the uncrossed and the crossed position was compared using a chi-squared test for equality of proportions.Hand (left versus right hand) as within-subjects’ factor and Group  as between-subjects’ factor1Note that data on the self-reported intensity of the tactile stimulation was missing for one shoulder pain patient.. The same analysis was used to compare the average intensity of the tactile stimulation, as delivered by the apparatus, in Watt (W). The mean scores on the other self-report measures (see “Self-Report Measures”) were compared between the three patient groups with a one-way ANOVA.To investigate the equivalence of the average self-reported intensity for the left compared to the right hand, a repeated measures ANOVA was conducted with t-tests were performed. For each patient group we tested if the PSS values in the crossed and uncrossed posture differed significantly from 0 ms. Next, in order to compare the PSS values across the different postures, results were analyzed using linear mixed effect models in R  across patient groups  on the PSS values. Posture and group as well as their interaction effect were entered to the model as fixed factors and a random subject-based intercept was added to the model. This model was not simplified as it included only the main variables of interest. Second, a model was fitted for each patient group separately to explore the potential influence of individual difference variables: pain intensity at the moment of testing (0–10), pain duration (in months), affected side (left or right) and temperature difference  and posture were included in the model. We attempted to simplify the model to obtain the most parsimonious model that fitted the data. To achieve this, we systematically restricted the full model based on Akaike’s Information Criterion (AIC) (posture (uncrossed versus crossed hands) across patient groups  on the JND values.To investigate whether there was a prioritization of stimuli on either the affected limb or the unaffected limb, one-sample ence see  between on (AIC) . A variaWe did not a priori include or exclude participants based on their JND value. However, sensitivity analyses were performed for both the PSS and JND to check whether excluding participants with JND values larger than the largest SOA  changed the results profoundly. Moreover, sensitivity analyses were performed excluding three patients who did not fulfill the research criteria of CRPS (see section “Participants” and p < 0.05. The regression coefficients (β) and their associated confidence intervals were reported as a measure of the effect size. Raw data and R scripts are available at https://osf.io/x82wk/?view_only=7abac8c2449b4bfdb843d9a0cdce6ef0.The final models were fitted with REML estimation. The ANOVA table was inspected to test hypotheses about main and interaction effects. Kenward–Roger approximations to the degrees of freedom were used to adjust for small sample sizes . The sigAn overview of patient characteristics is presented in M = 51.31, SD = 11.72, range = 23–68 years; 3 men, 2 ambidextrous at the moment of testing; average pain duration: M = 10.29 months, SD = 9.93) took part in this study . The experiment was discontinued for one participant who was unable to perform the task adequately, and another had to be excluded due to contralateral upper limb pain at the time of the experiment. Three more participants did not meet the research criteria for the diagnosis of CRPS at the time of the experiment. Analyses were first performed including these participants. Next, a sensitivity analysis was performed, excluding these participants . See http://hdl.handle.net/1854/LU-7179946 for a more detailed overview of recruitment and inclusion.CRPS patients were initially diagnosed by their medical doctor. At the beginning of the research session the Budapest criteria were assessed by the researcher see . The preM = 39.69, SD = 12.38, range = 24–59 years; 4 male; 5 left handed, 2 ambidextrous; 9 left side painful; average pain duration: M = 24.38 months, SD = 28.25) participated . Participants could still be excluded after the study when they reported contralateral upper body pain at the time of the experiment or when the diagnostic screening resulted in a diagnosis of CRPS. However, none of the participants had to be excluded (see http://hdl.handle.net/1854/LU-7179946).Patients with unilateral ulnar wrist pain  were invM = 52.15, SD = 7.58, range = 40–64 years; 9 male; 1 left handed, 5 ambidextrous; average pain duration: M = 21.39, SD = 16.50) took part . Two participants who were unable to perform the task adequately, were excluded. Three additional participants were excluded due to contralateral upper body pain at the time of the experiment. In sum, 15 participants  were included for further analysis (see http://hdl.handle.net/1854/LU-7179946).Patients with unilateral shoulder pain, due to frozen shoulder syndrome  or rotatM = 2.61, SD = 2.64; right hand: M = 3.00, SD = 2.45) and did not differ significantly between both hands  = 3.23, p = 0.08) across all patient groups  = 1.88, p = 0.17). Participants reported directing their attention to a large extent to the vibrotactile stimuli . They reported that they were able to concentrate well during the task  and that they found the task only mildly fatiguing . Participants made a large effort to complete the task , reported finding the task meaningful  and reported little fear/tension during the task . There were no significant differences between the three patient groups.The results of the PGS are illustrated in M = 0.094, SD = 0.023; right: M = 0.093, SD = 0.045; F  = 0.02, p = 0.905) for none of the three patient groups  = 1.51, p = 0.233). There were also no differences in intensity of the tactile stimuli between the affected and the unaffected hand  = 0.62, p = 0.435) for none of the three patient groups  = 0.37, p = 0.691).The mean intensity (in Watt) of the tactile stimuli, derived from the staircase procedure, was not significantly different between the left and the right hand .In the crossed hands posture, 10 PSS values (22%) were excluded from the analyses: two values because they did not meet criterion 1, four values did not meet criterion 2, and finally three values were excluded because they did not meet both criteria. These values belonged to three CRPS patients (21%), three shoulder pain patients (20%) and four wrist pain patients (25%). No values were excluded in the uncrossed hands posture. A chi-squared test indicated that the proportion missing values was significantly larger for the crossed than for the uncrossed posture , t (13) = −0.04, p = 0.97; Shoulder: M = −10.33 (95% CI [−31.42 to 10.76]), t (14) = −1.05, p = 0.31; Wrist: M = −1.45 (95% CI [−21.06 to 18.15]), t (15) = −0.16, p = 0.88) and the crossed (CRPS: M = −32.92 (95% CI [−78.89 to 13.06]), t (10) = −1.60, p = 0.14; Shoulder: M = −7.05 (95% CI [−49.79 to 35.69]), t (11) = −0.36, p = 0.72; Wrist: M = −33.23  = −1.77, p = 0.10) posture.PSS values for each patient group and each posture are displayed in group and posture revealed no significant effects  = 0.14, p = 0.87; posture: F  = 2.22, p = 0.14; group × posture: F  = 0.92, p = 0.41), indicating that the PSS values did not differ significantly between the three groups and between the two postures.The model investigating the main and interaction effect of F < 1.59, all p > 0.24).None of the variables  improved the fit of the model. None of the variables had a significant effect on the PSS values  = 5.44, p = 0.03, β = −37.69, CI [−67.40 to −7.98]) was significant. Higher temperatures for the affected versus the unaffected limb are associated with more positive PSS values in the uncrossed posture, but more negative PSS values in the crossed posture (t-test showed that for this patient group the affected hand had a significantly higher temperature than the unaffected hand (Δ = 0.06 (95% CI [0.008–0.12]), t (29) = 2.35, p = 0.03)2t (27) = 0.93, p = 0.36; wrist pain patients: Δ = 0.53,  = 1.28, p = 0.21).Note that for the other two patient groups this difference was not significant .The final model included the main effect of  posture . Interestemperature difference and pain duration. In this model the main effect of temperature difference was significant  = 8.51, β = 12.25, CI [4.48–20.03]), indicating that higher temperatures for the affected versus the unaffected limb are associated with more positive PSS values and thus a stronger prioritization of the unaffected limb  = 4.39, p = 0.06, β = −0.74, CI [−1.44 to −0.05]), but there was a trend suggesting that longer symptom duration might be associated with more negative PSS values  = 11.48, p = 0.002, β = 156.17, CI [66.13–246.21]), indicating that participants had more difficulty with the task when their hands were crossed. The main effect of group  = 1.64, p = 0.20) and the interaction effect between group and posture  = 0.74, p = 0.48) were not significant.JND values for each patient group and each posture are displayed in Five patients had a JND <−200  and were excluded from the analyses. The JND of the other patients ranged from −198.07 to −43.48.group and posture still revealed no significant effects  = 0.28, p = 0.75; posture: F  = 1.25, p = 0.27; group × posture: F  = 0.76, p = 0.48). For all patient groups, the models controlling for individual difference variables were refitted. For the CRPS patients, the final model included the main effect of pain intensity, affected side, posture and temperature difference and the interaction effect between posture and temperature difference. There was a significant effect of affected side  = 7.40, p = 0.03, β = −78.07, CI [−133.44 to −22.71]), indicating that patients with CRPS affecting the left side had significantly more positive PSS values than patients with CRPS affecting the right side of their body. The interaction effect between posture and temperature difference was marginally significant  = 4.40, p = 0.05, β = 16.52, CI [2.06–30.98]). Higher temperatures for the affected versus the unaffected hand were associated with more positive PSS values. This association was stronger in the crossed versus the uncrossed posture. None of the other effects were significant . For the shoulder patients, the final model included the main effects of pain duration, posture and temperature difference and the interaction effects between temperature difference and posture and between pain duration and posture. The interaction effect between posture and temperature difference was significant  = 5.38, p = 0.04, β = −34.64, CI [−61.39 to −7.89]), indicating that lower temperatures for the affected versus the unaffected limb are associated with more positive PSS values in the crossed posture and more negative PSS values in the uncrossed posture. Finally, the interaction effect between pain duration and posture was also significant  = 9.62, p = 0.02, β = 4.40, CI [1.68–7.12]), indicating that longer pain duration was associated with more positive PSS values in the crossed posture, while there was no clear association in the uncrossed posture. None of the other effects were significant . For the wrist pain patients, the final model included the main effects of temperature difference and pain duration. The main effect of temperature difference was significant  = 8.62, p = 0.008, β = 14.05, CI [5.32–22.79]), with lower temperature for the affected limb versus the unaffected limb associated with more negative PSS values. The main effect of pain duration was not significant  = 4.13, p = 0.07, β = −0.76, CI [−1.49 to −0.03]), but there was a trend suggesting that longer pain duration was associated with more negative PSS values.For the PSS values, the model investigating the main and interaction effect of group and posture still revealed a significant main effect of posture  = 28.30, β = −65.66, CI [−89.73 to −41.60]), indicating that JND values were more negative in the crossed than in the uncrossed posture. The main effect of group  = 0.26, p = 0.77) and the interaction effect of group and posture  = 0.09, p = 0.91) were not significant.For the JND values, the model investigating the main and interaction effect of Three CRPS patients did not fulfill the research criteria of CRPS (see “Participants”) during the diagnostic screening procedure. Keep in mind that these were initially diagnosed by a clinician. Analyses were performed again excluding these participants.posture, pain duration, pain intensity and the interaction between posture and pain duration and posture and pain intensity. None of the main or interaction effects reached significance .The final model included the fixed effect of The goal of this study was to replicate and extend the findings of In general, the results of this study did not support a bias to tactile stimuli in patients with CRPS. First, the mean PSS values were not significantly different from zero, suggesting the absence of a consistent bias at the advantage of one of the two stimulated body parts, neither the affected nor the unaffected hand. This is in contrast with the results of previous studies . Also, fIt has to be noted that there are some differences in design or patient characteristics between the present and previous studies  that mayConversely to the PSS values, we did observe significant results on the JND index. The JND, standing for Just Noticeable Difference, is a measure of the slope of the psychometric functions fitting participants’ performances. It reflects the sensitivity of the task and the ability of the participants to perform it . In the N = 14 for the uncrossed posture and N = 11 for the crossed posture) was comparable to the sample used by N = 10) and N = 13).This study has some limitations. First, a small sample of patients was tested in each group and an a-priori sample size calculation based on the study of Second, for several patients the task was too difficult in the crossed posture as evidenced by extremely large PSS values and consequently we were not able to use some of the data for the crossed posture. This could have artificially reduced the effect of posture. Sensitivity analyses showed that excluding these participants from the analyses did not drastically alter the results. Future studies might choose to use data-adaptive methods  in whichFinally, we did not submit an a-priori locked protocol for this study. Current guidelines within the pain field recommend to preregister the research plan before data collection . It shouThe results of this study did not support the hypotheses about the existence of systematic and specific cognitive biases affecting the ability of CRPS patients to process their affected hand. However, variability of the patients’ data was large, suggesting that other factors, such as duration of symptoms and temperature differences between the affected and unaffected limb, might play a role in the development of cognitive deficits in CRPS. This could also be the case in non-CRPS chronic pain patients, as skin temperature seemed to influence tactile TOJ in these patients. Additional studies are needed that take these variables into account by, for example, comparing biases in CRPS (and non-CRPS) patients in an acute versus a chronic pain state.10.7717/peerj.8819/supp-1Supplemental Information 1Click here for additional data file.


Bifidobacterium longum (B. longum) ES1 is a probiotic strain capable of modulating microbiome composition, anti-inflammatory activity and intestinal barrier function. We investigated the use of B. Longum ES1 in the treatment of patients with diarrhoea-predominant irritable bowel syndrome (IBS-D). Sixteen patients were treated for 8 or 12 weeks with B. Longum ES1 (1 × 109 CFU/day). Serum zonulin and cytokines were measured at baseline (T0) and at the end of therapy (T1). Clinical response to therapy was assessed by IBS Severity Scoring System. Interleukin (IL)-6, IL-8, IL-12p70 and tumor necrosis factor (TNF) α levels decreased from T0 to T1, irrespective of treatment duration (p < 0.05), while zonulin levels diminished only in patients treated for 12 weeks (p = 0.036). Clinical response was observed in 5/16 patients (31%): 4/8 (50%) treated for 12 weeks and 1/8 (13%) treated for 8 weeks. Abdominal pain improved only in patients treated for 12 weeks , while stool consistency improved regardless of therapy duration (p < 0.001). In conclusion, the results of this pilot study showed, in IBS-D patients treated for 12 weeks with B. longum ES1, a reduction in the levels of pro-inflammatory cytokines, and intestinal permeability as well as an improvement in gastrointestinal symptoms, but further studies including a placebo-control group are necessary to prove a causal link. Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder affecting approximately 15–25% of the population, with higher prevalence in the female gender . The losZonulin is a 47-kDa protein involved in the regulation of tight junctions (TJs), the primary determinants of paracellular permeability . Serum zMany studies have reported the presence of moderate immuno-inflammatory activity in both large and small intestine of patients with IBS . AccordiEmerging literature data support a pathophysiological role of microbiome in IBS. The dysbiosis observed in subjects with IBS is characterized by reduced biodiversity, an increase in Bacteroides and Clostridia, and a reduction in Bifidobacteria ,15. TherBifidobacterium longum (B. longum) ES1 [The rationale for the use of gum) ES1  in patiegum) ES1 , exert agum) ES1 , and resgum) ES1 ,23.Several meta-analyses have reported on the effectiveness and safety of probiotics in patients with IBS, especially for products containing Bifidobacteria and Lactobacilli. However, there was significant inter-study heterogeneity, warranting cautious interpretation of the findings. The heterogeneity mainly regarded differences in subgroup analyses of probiotics type, combination and dose, IBS subtype, symptomatic assessment scores and treatment duration ,25. FinaB. longum ES1 treatment in a homogeneous group of patients with IBS-D, by evaluating clinical response, through the use of validated questionnaires for IBS, and serological response, by the determination of serum levels of inflammatory cytokines and zonulin, in order to analyse potential effects on immune modulation and restoration of the intestinal barrier, respectively, and (2) to evaluate differences in response depending on the treatment duration. The results of this pilot study will allow us to define the optimal duration of probiotic therapy and to calculate the necessary sample size to conduct a subsequent randomized, double-blind, placebo-controlled clinical trial.The aim of this pilot study was (1) to assess the use of We carried out a prospective study at the Gastroenterology Unit of “A.O.U. Città della Salute e della Scienza di Torino” hospital, Italy from April 2019 to October 2019.9 colony-forming unit (CFU) of B. longum ES1 away from meals. Inclusion criteria were: age between 16 and 65 years old, diagnosis of IBS-D according to the Rome IV criteria and Bristol stool scale [2, willingness to sign the informed consent to participate to the study. Exclusion criteria were: history of GI surgery, diagnosis of IBD or CD, thyroid diseases, diverticular disease, small intestine bacterial overgrowth (SIBO), colorectal cancer, other clinically relevant diseases, treatment with drugs that alter intestinal function , treatment with antibiotics (any previous antibiotic therapy should have been discontinued at least 4 weeks before the start of probiotic therapy) and other pre/probiotics (other pre/probiotics therapy should have been discontinued at least 2 weeks before starting therapy), pregnancy/breastfeeding.Patients affected by IBS-D were recruited and treated with a strain-specific probiotic therapy for 8 or 12 weeks. Probiotic therapy consisted of daily administration of 1 × 10ol scale , body maClinical history, data on physical examination, recent biochemical examinations and signed informed consent were collected. Disease severity was assessed at baseline with the Functional Bowel Disorder Severity Index (FBDSI) questionnaire . At baseAll patients underwent baseline venous sampling (T0) and after 8 or 12 weeks of therapy (T1); serum was collected in polypropylene 2 mL tubes labelled with the study participant identification code and stored at −80 °C until analysis.The study followed the principles of the Declaration of Helsinki and was approved by the local ethics committee  .® Zonulin ELISA Kit, Immunodiagnostik AG, Bensheim, Germany) according to the manufacturer’s instructions. Concentrations were calculated using a four-parameter algorithm, and the results were given in ng/mL, as previously reported [® Multiplex Immunoassay  on a Luminex® 200 system . Individual standard curves were generated for each cytokine; the results are given in pg/mL [Serum zonulin was assessed by competitive enzyme-linked immunosorbent assay (ELISA) .Continuous variables were expressed as median and 95% confidence interval (CI) or as mean ± standard deviation (SD). The normality of data distribution was tested by D’Agostino-Pearson test. The comparison between quantitative variables was carried out using the Student n = 10/16, 38%). Patients mainly had normal weight (BMI < 25 kg/m2) and all of them consumed a Mediterranean diet [Sixteen patients aged between 16 and 59 years were enrolled. Basal characteristics of the included cohort are reported in ean diet . No dietsr = 0.658, 95% CI 0.241–0.870, p = 0.006) and an inverse correlation between IBS-SSS and overall IBS-QoL score . Age positively correlated with serum zonulin levels  and negatively correlated with FBDSI . A significant positive correlation was also observed between abdominal pain intensity and TNFα levels . Only a slight positive trend was observed regarding the correlation between serum zonulin and BMI , between serum zonulin and IL-6 values  and between IL-8 and TNFα values . No other significant correlations were observed between serum zonulin or cytokines levels and other demographic and clinical characteristics of the study population ; indeed, a trend towards IBS-SSS score reduction from T0 to T1 was found only in patients treated for 12 weeks . An improvement ≥30% of the abdominal pain intensity was found in 5/16 (31%) patients, all of them treated for 12 weeks ; consistently, patients treated for 12 weeks showed a significant reduction in the intensity of abdominal pain compared to those treated for 8 weeks . Conversely, no significant improvement in bloating was reported (p = 0.340), independent of therapy duration. An overall IBS-QoL score increase of ≥14 points was obtained only in 1/16 (6%), who was treated for 12 weeks. Stool consistency improved regardless of the duration of therapy (p < 0.001). Nine out of 16 (56%) patients normalized stool consistency : 5/8 (63%) were treated for 12 weeks, whereas 4/8 (50%) were treated for 8 weeks (p = 0.626). None of the patients reported adverse events during or after treatment.The clinical response to probiotic therapy, in terms of IBS-SSS score decrease of ≥50 points, was observed in 5/16 patients (31%), of whom 4/8 (50%) were treated for 12 weeks and 1/8 (13%) was treated for 8 weeks (p = 0.036)  .B. longum ES1 for 12 weeks versus 8 weeks.In this pilot study, we found an improvement in overall symptoms of IBS and an improvement in the immune-inflammatory state and integrity of intestinal barrier. These aspects were especially significant in patients treated with Bifidobacterium infantis M-63, breve M-16V, and longum BB536 in patients with IBS decreased abdominal pain frequency and improved QoL in a significantly higher proportion of patients, when compared with placebo [B. longum NCC3001) improved psychiatric comorbidities and increased quality of life in patients with IBS [B. longum ES1. However, compared to previous studies, we did not observe an amelioration in the quality of life of our population. Likely, the probiotic mixture or specific strain beneficial for each patient remains to be determined.Accumulating evidence suggests that commensal bacteria may play a role in IBS and that specific probiotic therapy is able to improve GI symptoms in such patients . Indeed, placebo . Moreovewith IBS . ConsistB. longum ES1 led to a significant reduction in cytokine levels from baseline to the end of therapy, contributing to the clinical improvement observed in our population. Taken together, these results confirm both the low-grade inflammation described in patients with IBS [B. longum ES1 and, overall, support probiotic therapy as a valid treatment option in patients with IBS.Human and animal studies support the concept that a low-grade inflammation may perturb GI reflexes and activate the visceral sensory system contributing to the altered GI physiology and hypersensitivity underlying IBS ,44. Morewith IBS  and the B. longum BB536 and Lactobacillus rhamnosus HN001 with vitamin B6, compared to placebo, significantly improved GI symptoms and restored intestinal permeability in patients with IBS, as deduced by the improved percentage of sucralose recovery [Finally, in the intricate puzzle of IBS pathophysiology, it has been shown that altered intestinal permeability plays an essential role, particularly in its diarrhoea-predominant variant. Indeed, several case-control studies showed that intestinal permeability measured by multi-sugar absorption test increased in patients with IBS-D compared to healthy controls ,51. Morerecovery . Taking recovery  and highrecovery . In the B. longum ES1 treatment in our population. We observed a significant improvement of inflammatory status and stool consistency, irrespective of the treatment duration. None of the clinical outcomes allow any inference on the effect on IBS natural history in view of duration of therapy, nature of IBS symptoms (waxing and waning), and marginal differences. Since this was a pilot study, its aim was to evaluate whether our hypothesis could be sufficiently supported to justify a detailed investigation. Such data are promising and set the basis for controlled clinical trials with broader case studies.The main limitations of the current study are the limited sample size and the lack of a placebo-treated control group, to provide definitive conclusions on the real efficacy of In conclusion, our preliminary results showed a reduction in the levels of pro-inflammatory cytokines in the overall study cohort and possibly an improvement in intestinal permeability and gastrointestinal symptoms in a subgroup of patients with IBS-D. Further randomized, double-blind, placebo-controlled studies are fundamental to validating the results of this pilot study on larger groups of patients with IBS-D.


Background: Virtual reality (VR) applied to patients with neck pain is a promising intervention to produce positive effects when used alone or combined with exercise. Therefore, the objective of this manuscript is to compare the effects of VR versus exercise treatment on pain intensity, conditioned pain modulation (CPM), temporal summation (TS) and functional and somatosensory outcomes in patients with non-specific chronic neck pain (NS-CNP). Methods: A single-blinded, randomized clinical trial was carried out. A total sample of 44 patients with NS-CNP was randomized into a VR treatment group or neck exercises group. The intervention consisted of two treatment sessions per week, for four weeks and eight sessions. Four measurement moments  were considered. Pain intensity, CPM, TS, functional and somatosensory outcomes were measured. Results: Statistically significant differences were revealed for time factor  and group*time interaction for kinesiophobia  showing post-hoc differences in favor of the VR group at 3 months . Significant effects were shown for time factor (p < 0.05) but not for the group*time interaction (p > 0.05) for pain intensity, rotation range of motion (ROM), Neck Disability Index, pain catastrophizing, fear-avoidance beliefs, left side pressure pain threshold (PPT) and anxiety. Statistically significant differences were not found for time factor (p > 0.05) and neither in group*time interaction (p > 0.05) for CPM, TS, right side PPT, flexo-extension and lateral-flexion ROM. Conclusions: Kinesiophobia was the only outcome that showed differences between VR and exercise at 3 months. Nevertheless, pain intensity, CPM, TS, ROM, neck disability, pain catastrophizing, fear-avoidance beliefs, PPT and anxiety did not show differences between both interventions. Between 50% and 85% of the general population experience neck pain at some point in their lives and every person who experiences neck pain is likely to experience it again 1–5 years later  showed tThere is a strong relationship between cervical disability and neck pain ,6. WithiIn addition, psychological factors, such as fear of movement, anxiety or depression, are also associated with chronic neck pain ,13. ThesMoreover, alterations of pain processing have been investigated in patients with neck pain, showing local and distant mechanical hyperalgesia . RegardiRegarding the management of neck pain and its related alterations, attentional distraction—defined as shifting the attention away from the pain—is a commonly used strategy. In this context, virtual reality (VR) is defined as a computing system used to create an artificial world in which users have the impression of being able to navigate and manipulate objects in it ,20. VR tThe hypoalgesic effects of distraction by VR have been mainly investigated during experimentally induced pain in healthy subjects or during acute procedural pain. In rehabilitation sciences, some clinical trials have previously evaluated the effectiveness of VR on individuals with neck pain ,23. Two Although other studies have failed to demonstrate a hypoalgesic effect of distraction, the majority of studies have shown that distraction does reduce pain, most of them in acute conditions . A meta-Therefore, the main objective of this study is to compare the effects of VR versus exercise on pain intensity as well as conditioned pain modulation (CPM) and temporal summation (TS) in patients with non-specific chronic neck pain (NS-CNP). Secondly, we aim to evaluate the effects of VR versus exercise on functional and psychological variables in patients with NS-CNP.A randomized single-blind controlled trial was conducted in conformity with the Consolidated Standards of Reporting Trials (CONSORT)  requiremFrom January 2020 to March 2020, 44 individuals with NS-CNP were recruited from Rey Juan Carlos University, CEU San Pablo University, and the Community of Madrid through social networks, posters, brochures and emails. The inclusion criteria were: (a) non-specific chronic neck pain; (b) age 18 to 65 years. The exclusion criteria were the following: (a) pregnancy; (b) specific neck pain caused by metastasis, neoplasia, infectious or inflammatory disorders, bone fractures or traumatic precedents with neck injuries; (c) positive neurological signs or evidence of spinal compression ; (d) cervical osteoarthritis; (e) spondyloarthritis; (f) neck pain associated with vertigo (vestibular involvement); (g) neck pain associated with whiplash injuries; (h) previous cervical surgeries; (i) headaches prior to the onset of neck pain and without cervical origin; and (e) inability to provide informed consent. All participants received an explanation of the study procedures, which were planned according to the ethical standards of the Declaration of Helsinki . WrittenTwo trained physical therapists were assigned to provide the treatments and collect the data from each subject, including pain related measurements and psychological variables. A different researcher conducted the statistical analysis and other assessors assisted in writing and reviewing the document. Only the person in charge of the statistical analysis was blinded. Neither the therapists or the patients were blinded due to the nature of the proposed experiment.The VR Vox Play glasses were used with an HMD clamping system (weight 330 g) to which a Smartphone (LG Q6) was attached . Two VR The subjects started with the free mobile application “Fulldive VR” in which only lateral flexion movements are necessary. The patient was immersed in an environment that simulated the living room of a house and at the same time they could visualize a gallery of previously selected photos. Then, they had to change the images in the viewfinder by tilting their neck bilaterally, as well as naming the photos that were displayed. New images were added each week to introduce a novel factor to the patient and to keep them motivated by the exercise program. Once the patient felt comfortable with the system and adapted to the headset, then after one minute rest, the difficulty of the exercise program was increased with the free mobile application “VR Ocean Aquarium 3D” where flexion, extension and rotation movements were added. The patient was immersed in a virtual environment that simulated an ocean, moving forward and observing different marine animals by making the neck movements. The patient named the animals they were visualizing. In addition, the application presented auditory and sensory stimuli by integrating the sound of the sea.In the first sessions, the patients were instructed to perform a previous cranio-cervical flexion before starting any movement. Then, the therapist controlled the contraction of the superficial musculature with their hands. Gradually, the aid of the physiotherapist was removed so that the participants could integrate deep muscle contraction and the correct cranio-cervical posture innately. For these patients to carry out the same work as the control group, the physiotherapist counted and controlled in each exercise the number of movements the patient performed, in order to not exceed the dose proposed: 3 series of 10 repetitions of each exercise with 30 s rest between exercises.This group performed three series of 10 repetitions of every exercise, with a 30 s rest between exercises. The researcher provided the necessary verbal corrections for the proper execution of the exercises, using the same verbal commands for all participants . FlexionThis scale created by Scott Huskinsson in 1976  was used2 tipped-diameter algometer  applied at a rate of 40 kPa/s [CPM is a psychophysical experimental measure of the endogenous pain inhibitory pathway. The CPM test consists of the evaluation of a painful test stimulus followed by a second evaluation at the same time as a distant, painful conditioning stimulus . The test stimulus was a pressure pain threshold (PPT) measured using a 1 cm40 kPa/s . CPM was then induced by combining the protocol described by Cathcart et al. and an inflated occlusion cuff around the subject’s arm, contralateral to the most affected trapezius, until the patient felt a painful intensity (conditioning stimulus) of 6/10. The occlusion cuff was inflated at a rate of 20 mm Hg/s and held for 30 s. After another 30 s, the pressure was made on the distal phalanx of the first finger on the opposite hand until the patient noticed a painful sensation. The cuff pressure was then increased or decreased until the intensity of the pain was rated 3/10.This method has been shown to have good reliability and validity for examining the temporal sum and CPM .TS consisted of the application of a series of short noxious stimuli which typically results in a continuously increasing perception of pain along with the series. This represents features of central sensitization of pain pathways, equivalent to the wind-up physiological phenomenon . The proInitially, a PPT used as a test stimulus was measured locally and distally. Then, the TS was triggered by 10 consecutive pressures on the PPT at the pressure determined at each location. For each pulse, the pressure was gradually increased at a rate of 2 kg/s at the determined PPT and held for 1 s before being released . The intensity of the 1st, 5th and 10th pulse pain was assessed using a numerical rating scale (0 being no pain and 10 being worst possible pain). A 5 min rest period was programmed afterward .To assess the active cervical range of movement (CROM) the CROM device  was used, which is composed of two goniometers that allow measuring the range of motion in the different planes of movement . Each moThis device has been verified to be reliable for measuring cervical ROM  compared to the universal, gravitational goniometer or visual estimation. In addition, it has a lower cost than other more technological systems to take cervical measurements such as the 3D Space System or radiographic measurements .Neck Disability Index is a modification of the Oswestry Disability Index and is the most widely used scale for cervical dysfunction and pain. In addition, it is a one-dimensional measure that is used to determine the level of disability that the patient perceives due to neck pain ,43. It iThe Pain Catastrophizing Scale assesses the degree of negative thoughts and feelings about patients’ pain. It consists of 13 items valued from 0 (never) to 4 . The possible range is 0–52 points, with lower scores indicating less catastrophism levels . It is aThe Pain-related fear of movement was assessed using the 11-item Spanish Version of the Tampa Scale of Kinesiophobia . The finThe fear-avoidance beliefs questionnaire (FABQ) was developed to measure levels of fear and avoidance beliefs about work and physical activity. The instrument consists of two subscales, a four-item physical activity subscale (FABQ-PA) and a seven-item work subscale (FABQ-W). Each item is scored from 0 to 6 and summed to produce the subscale score. Possible scores range from 0–28 to 0–42 for the FABQ-PA and FABQ-W, respectively . This sc2) attached to a pressure (force) gauge. The pressure was applied at a rate of 0.31 kg/s [The pain pressure threshold (PPT) is defined as the minimum pressure at which the pressure sensation changes to a pain sensation. The mechanical pressure algometer  employed in this study consisted of a round rubber disk  .Pain-related anxiety was measured with the 20 items version of the Pain Anxiety Symptoms Scale (PASS-20), described by McCracken and Dhingrain in 2002. It consists of 20 items that measure four components of pain anxiety: fear, escape/avoidance, cognitive anxiety and physiological anxiety. Patients score each of these items through a six-point Likert-type scale, in which 0 is never and 5 is always. Total score ranges from 0 to 100 with higher scores indicating greater anxiety about pain ,54. The Before entering the study and prior to the intervention, all participants granted their consent and were given a set of questionnaires which included self-reported psychometric forms to evaluate the psychological outcomes and sociodemographic data. Subsequently, the pre-intervention measurements were performed and depending on the group they belonged to according to the randomization, the participants performed the VR intervention or the neck exercises. The intervention consisted of two treatment sessions per week for 4 weeks, with eight sessions in total. This study showed a 3 months follow-up with evaluations at baseline, immediately, 1 month and 3 months after the intervention. The interventions and the CROM measurement were performed in the sitting position while the PPT, TS and CPM measurements were measured in the supine position. The Visual Analogue Scale (VAS) was selected as the primary measurement of our results in this study. The effect of the size for the VAS was estimated in medium (SE = 0.25). The correlation between repeated measures was assumed to be 0.5. Assuming the performance of four measurements , the sphericity correction was determined to be 0.5. With a statistical power of 0.80 and an alpha level of 0.05, a total sample size of 36 patients was estimated. Taking into account 15% of the losses, it was necessary to reach a total of 42 patients. The sample size was calculated using the program G*Power 3.1.7  . The randomization was performed using a computer-generated random sequence table with an unbalanced four-block design . One of the researchers that was not involved in the data collection or intervention of the subjects of the study generated and oversaw the randomization list. A number was randomly given to each of the subjects and with the software they were anonymously and randomly allocated in one of the two groups using the generated list, ensuring the blind allocation and including 22 participants in each group. Nonetheless, the subjects were conscious of whether or not they were wearing the VR headset therefore they knew if they belonged to the intervention or control group and could not be blinded. Qualified physiotherapists performed the assessments and interventions and a different researcher who was blinded to the allocation conducted the assessment of the outcomes.Data analysis was carried out using the version 25.0 of the SPSS statistical program . The Shapiro–Wilk test was applied to check the fit of the variables to a normal distribution. The results of the study were represented using descriptive statistics . For comparisons between groups, a simple analysis of variance (ANOVA) or mixed variance models (2 × 4) with post hoc Bonferroni tests for multiple comparisons were applied. For analysis of the variable temporal summation, we used non-parametric statistics because it presented an abnormal distribution. Descriptive statistics were used to summarize data, including means and SDs, medians and interquartile ranges (IQR) for continuous data. The Kruskal–Wallis test was used to compare the two groups to baseline data and across groups each time. The Friedman test was used to analyze the change from the intragroup results and the Wilcoxon signed-rank test was used for post hoc intragroup comparisons. p < 0.05 were considered statistically significant. Partial eta squared was calculated for the parametric variables, meanwhile rank correlation was calculated for the non-parametric on the primary and secondary outcome variables. The magnitude of the effect was classified as small (0.20 to 0.49), medium (0.50 to 0.79) or large (0.8) according to Cohen’s method [For the data analysis, a 95% confidence interval was used. All values that had a s method . AnalyseA total of 44 patients with NS-CNP with an average age of 29.7 ± 10.81 years, 21 males (47.7%) and 23 females (52.3%), were admitted after fulfilling the inclusion criteria from January to March 2020. p < 0.01; ηp2 = 0.44) but not for the group*time interaction  for pain intensity over the VAS. The post hoc analysis revealed significant within-group differences in all groups between baseline and post-treatment and 1 month and 3 month follow-up measures. There was a large effect size for the VR group post-treatment , 1 month follow-up  and 3 month follow-up . There was a large effect size for control group post-treatment , 1 month follow-up  and 3 months follow-up   .p = 0.33, ηp2 = 0.20) and neither in group*time interaction   .p < 0.05). The Wilcoxon test did not show significant differences when the baseline data were compared with the follow-up periods measured (p > 0.05). The Friedman test was not statistically significant (p > 0.05) for any group. All data can be observed in  for the rotation but not in the group*time interaction . There were no statistically significant effects for flex-extension and lateral flexion movements found in the time factor , nor for time*group interaction . The post hoc analysis was not significant for within-group differences in both groups between baseline and follow up measures for rotation motion  but not in the group*time interaction  in the neck disability index. p = 0.01, d = 0.99), 1 month follow-up  and 3 month follow-up . There was a large effect size for control group post-treatment , 1 month follow-up  and 3 months follow-up   .p < 0.01, ηp2 = 0.38) but not in the group*time interaction . The post hoc analysis revealed significant within-group differences in both groups between baseline and post-treatment, 1 month and 3 month follow-up measures, with a medium–large effect size for the VR group post-treatment , 1 month follow-up  and 3 month follow-up . There was a medium–large effect size for the control group post-treatment , 1 month follow-up  and 3 month follow-up . In this psychological variable, the ANOVA showed significant differences over time  and in the group*time interaction . The post hoc analysis revealed significant within-group differences in the VR group between baseline and follow-up at 3 months, with a medium effect size  The post hoc analysis revealed significant within-group differences only in the VR group between pre- and 1 month  and pre- and 3 months . The ANOVA revealed significant differences over time  but not in the group*time interaction . p < 0.01, d = 1.06) and with medium effect size for the control group   .p < 0.01, ηp2 = 0.15) but no statistically significant effects were found for right side PPT . No statistically significant differences were found for either measure in the group*time interaction . The post hoc analysis revealed significant within-group differences in the VR group between baseline and 1 month and 3 month measures, with a medium effect size for PPT in the left side  but not in the group*time interaction . The post hoc analysis revealed significant within-group differences in all groups between baseline and post-treatment, 1 month and 3 month follow-up-intervention measures, with a medium–large effect size for the VR group post-treatment , 1 month follow-up  and 3 month follow-up . There was a medium effect size for the control group post-treatment , 1 month follow-up  and 3 months follow-up . In this variable, the ANOVA showed significant differences over time  did not show statistically significant changes between groups at 3 months follow-up, meaning that VR can be as effective in modulating pain and decreasing perception to repetitive painful stimulation as evidence-based exercises for the neck. We found statistically significant changes in the TS for the intervention group at 1 month; however, there is little evidence and research that focuses on these variables related to chronic neck pain to compare our findings related to VR and chronic neck pain. Hayashi et al. in 2019 , found sRelated to pain intensity, a recent meta-analysis concluded that immersive VR has minimal carryover effect beyond the immediate post VR exposure , which cOur secondary variables showed that VR could increase the range of motion for the rotation and decrease the perception of disability. We found in a previous study that the observed actions are also effective in improving the CROM. This may be due to the fact that the visualization of images might cause increased activity of the corticospinal system  and prodThese results may be explained when a patient’s chronic neck pain is deeply engaged in an immersive VR experience, as it becomes difficult to perceive stimuli outside of the field of attention. This makes pain management possible by blocking sensory information via opioid analgesics or by creating a distraction ,70 afterThe psychosocial variables also showed significant changes for both groups, especially in the VR group. For the fear-avoidance beliefs, in 2019 Fowler et al.  indicateRegarding kinesiophobia, we found that it was the only variable to have significantly improved compared to the exercise group, especially at 3 months follow-up, and was considered as an effective tool for reducing fear of movement. Other studies have found that VR reduces kinesiophobia in patients with chronic spinal pain which was associated with an increase in function ,67,72. IAs far as the authors are concerned, this is the first randomized clinical trial that has studied the use of VR for NS-CNP and compared pain-related, motor and psychological outcomes compared to an exercise group in the short-term. Recent reviews have concluded that more research is needed regarding VR as a treatment of musculoskeletal disorders ,26,65. TAccording to the obtained results, VR could be an effective tool for reducing the pain-related fear of movement and as effective as exercise in decreasing pain intensity or modulating pain. Putting its applicability into practice will be useful for patients with limited mobility and fear of movement as a previous step for active exercise and therapy, improving those aspects and increasing their internal locus of control and self-efficacy during the initial phases when motion is more limited, or pain is very severe. Given the cost and its effectiveness, it is worthy to note that a VR headset should be implemented in clinics for the patients who may benefit from this intervention, using these contemporary tools as useful interventions in conjunction with traditional treatments, especially since the new technologies are gaining ground on daily life activities. Furthermore, it could present collateral benefits such as enhancing their adherence to treatment and autonomy to practice at home. The authors also encourage further research on this topic so the mechanisms of VR and its applicability will be better understood in order to obtain more benefits for patients.This study presents several limitations. There was no placebo group, so we could not compare the non-specific effects of this therapy, similarly, there was no group that received a passive treatment, meaning both of our groups underwent active interventions which may explain our minimum differences between groups. In addition, the patients could not be blinded since they were aware of wearing an immersive VR device. Another limitation is that our results show the effects on a short-term period (3 months) so it would be interesting to see the long-term effects of this therapy. Moreover, motion sickness produced by virtual reality headsets was not taken into account and measuring it could influence its effects on the subjects of study. Furthermore, it is unclear if using different types of VR (semi-immersive or non-immersive), more adapted games specifically focused on muscle endurance or gradually introducing different grades of difficulty to the patients would have led to different results.VR was not superior to exercise in improving pain intensity, CPM, ROM, neck disability, pain catastrophizing, fear-avoidance beliefs, PPT or anxiety in patients with NS-CNP. Kinesiophobia was the only variable that showed differences between VR and exercise at 3 months, with a decrease of almost 10 points in the VR group versus a decrease of less than 4 points in the exercise group. Therefore, immersive VR showed to be a more effective tool for reducing the pain-related fear of movement in NS-CNP.


First bite syndrome (FBS) is a condition in which the first bite of each meal causes parotid pain. Etiologies of FBS include prior surgery of the upper cervical region and, rarely, head and neck tumors. Idiopathic FBS rarely presents in patients without a history of surgery or evidence of an underlying tumor. Idiopathic FBS may be categorized into two subtypes: that in patients with diabetes and that in patients without diabetes. Idiopathic FBS in patients without diabetes may be overlooked or misdiagnosed because the condition has been described only in a few case reports. We aimed to identify the clinical and pain-related characteristics of idiopathic FBS in patients without diabetes.  We retrospectively analyzed the clinical data of five patients without diabetes who were diagnosed with idiopathic FBS in our department between January 2010 and December 2016.  Four of the five patients were female, and the overall median age was 52 years (range: 13–61). All patients immediately experienced parotid pain upon tasting food without chewing. Addition of an acidic solution to the ipsilateral posterior third of the tongue evoked parotid pain. The median degree of pain intensity and interference with eating due to pain was 9 (range: 3–10) and 9 (range: 5–10) on a numerical rating scale of 0–10, respectively. Idiopathic FBS was bilateral in two patients. Two patients had tenderness on mild pressure over the affected parotid region. Two patients presented with ipsilateral idiopathic Horner's syndrome.  Our findings indicate that the characteristics of idiopathic FBS in patients without diabetes are largely consistent with those previously reported in postoperative FBS, supporting the notion that idiopathic FBS is a subtype of FBS. Thus, it is necessary to consider idiopathic FBS during the evaluation of facial pain triggered at the beginning of a meal. First bite syndrome (FBS) is a relatively rare clinical condition in which the first bite of each meal causes severe pain or cramping that gradually subsides with subsequent mastication , 2. PatiThe etiology and pathogenesis of FBS remain to be elucidated. FBS mainly occurs after upper neck surgery; therefore, most studies have focused on the association between FBS development and operative procedures –6, 8, 9.FBS in the absence of prior surgical intervention is rare; therefore, it has mainly been described only in case reports. The reports suggest that FBS is associated with tumors, namely, malignant tumors arising from the parapharyngeal space , 12, parIn rare cases, FBS may be idiopathic , 19; theWe included all patients who were diagnosed with FBS in the Department of Oral and Maxillofacial Surgery at Tohoku University Hospital over a 6-year period between January 2010 and December 2016. The study was performed in accordance with the standards outlined in the Declaration of Helsinki and was approved by our Institutional Review Board (2016-3-25). Written, informed consent for participation in this study was not obtained from the patients due to the retrospective nature of the study. However, we made a public announcement on our institution's Internet homepage as requested by the Institutional Review Board. We diagnosed patients with idiopathic FBS if they met the following four criteria: (1) pain in the parotid region occurring on the first few bites of each meal, which improved with subsequent mastication; (2) no evidence of parotid gland, masticatory muscle, temporomandibular joint, or odontogenic/neurologic pathology as the cause of facial pain; (3) no history of surgery involving the upper neck region; and (4) no detectable tumors arising from the head or neck on magnetic resonance imaging (MRI) [Clinical data were obtained from the medical records, including the examination protocols and questionnaires utilized in our orofacial pain clinic. The following factors were analyzed: patient characteristics; clinical, laboratory, and imaging findings; and clinical course of idiopathic FBS. Patient characteristics included age, sex, medical history, duration of idiopathic FBS, and diagnosis and treatment before referral. The anatomical location/side of idiopathic FBS pain and the sites of pain on the face and neck upon palpation were recorded. Sensory abnormalities of the oral mucosa and facial skin on touching with a cotton swab were also recorded along with any autonomic symptoms.All imaging findings were reevaluated. These included panoramic radiography, 1.5-T MRI of the head and neck , 1.5-T MRI of the temporomandibular joints, and salivary gland scintigraphy  .We also reviewed the following: (1) whether the application of an acidic solution with a cotton swab to the tongue elicited parotid pain; (2) whether chewing a cotton swab or gauze triggered pain; (3) severity of pain and interference with eating over a 7-day period; and (4) the duration and quality of idiopathic FBS pain. Pain and interference with eating were rated using an 11-point numerical scale. For pain, the scale ranged from 0 (“no pain”) to 10 (“worst pain imaginable”); for interference with eating due to pain, the scale ranged from 0 (“does not interfere”) to 10 (“completely interferes”). Improvements in idiopathic FBS were documented when patients experienced a decrease in pain intensity following therapy.n = 11), temporal tumors (n = 1), or cervical cysts (n = 1). Of the remaining five patients, four were women, and the overall median age was 52 years (range: 13–61)  . All fiv: 13–61) . PatientIdiopathic FBS was bilateral in two patients and unilateral in three patients . The paiPatient 5 had developed right-sided Horner's syndrome a few years before the onset of idiopathic FBS; therefore, the patient was examined by an ophthalmologist, neurologist, and pulmonologist. MRI and computed tomography of the entire oculosympathetic chain revealed no pathologies in the head, neck, or chest region that might have caused Horner's syndrome. Patient 3 had miosis on the affected side and was diagnosed with idiopathic Horner's syndrome by a neurosurgeon at the previous hospital.Panoramic radiography was performed to rule out any odontogenic cause or other jaw-related pathologies, and the findings were unremarkable. Initial and follow-up MRI of the head and neck revealed no pathological abnormalities responsible for the parotid pain in any of the patients. MRI of the temporomandibular joints revealed mild anterior disk displacement with reduction in two patients (Patients 2 and 3) . DynamicLaboratory blood investigations were performed in all patients. Patient 2 had high titers of antinuclear antibodies and was referred to a rheumatologist who ruled out autoimmune diseases.The overall median degree of pain intensity and interference with eating due to pain was 9 (range: 3–10) and 9 (range: 5–10), respectively . ParotidAll patients were initially treated with neurotropin , an extract of inflamed cutaneous tissue derived from rabbits inoculated with the vaccinia virus. The median follow-up period in patients was 48 months (range: 3.7–60 months).Patient 1 was treated with neurotropin (12 NU/day) for 7 months, and the pain intensity of the first bite pain decreased from 10 to 2 on the numerical rating scale. She achieved near-complete resolution of the FBS pain after 6 months of cessation of neurotropin. This patient has been followed up for 32 months without obvious signs of recurrence. Patient 3 was treated with neurotropin (16 NU/day), and after 3 months, the intensity of the pain decreased from 9 to 3 on the numerical rating scale. However, she was lost to follow-up. Patients 2 and 5 were unresponsive to neurotropin (16 NU/day); pregabalin was also ineffective and induced drowsiness. Rubbing the affected parotid region before a meal and ingesting bland foods at the beginning of a meal partially alleviated the first bite pain; whenever these measures were not undertaken, the first bite pain worsened. Patient 4 received neurotropin (16 NU/day) for 3 weeks without effect and did not receive any further treatment because the parotid pain was tolerable. However, the pain gradually subsided over the ensuing 5 months.This study has documented parotid pain consistent with postoperative FBS in patients with no history of surgery, head and neck tumors, or diabetes. The cause of FBS in our study remained unknown; therefore, they are likely to be idiopathic. In our patients, gustatory stimuli reflexively evoked pain in the parotid region, and the trigger zone was located in the posterior one-third of the ipsilateral tongue. It is important to note that two patients also had ipsilateral Horner's syndrome.The patients in our study experienced sharp pain at the beginning of a meal, which resolved within 20 s but recurred at the next meal or when chewing was paused for several minutes. The first bite pain was intense enough to discourage chewing, and after its decline, 4/5 patients resumed eating painlessly. Unlike a previous study in which 6/9 patients with idiopathic parotid pain presented with severe postprandial pain , our patHowever, none of our patients had a history of surgery involving the upper neck region, or structural or functional abnormalities in the involved parotid glands on clinical examination or imaging that could cause severe pain. To the best of our knowledge, this is the first study to demonstrate the absence of functional parotid abnormalities in patients with FBS using salivary scintigraphy. Tumors in the head and neck rarely cause FBS –15, and Idiopathic FBS pain occurs immediately after tasting liquid or solid foods, particularly tart foods. The relationship between gustatory stimuli and reflex stimulation of the parotid gland was confirmed by the elicitation of parotid pain by the application of an acidic solution to the posterior third of the affected tongue. These findings highlight gustatory stimuli, and not chewing, as the FBS trigger and localize the trigger zone to the posterior third of the tongue. Although not required for the elicitation of pain, chewing worsens the pain. The glossopharyngeal nerve conveys taste sensations from the gustatory receptors on the posterior third of the tongue to the nucleus of the solitary tract. It also provides parasympathetic secretomotor innervation to the parotid gland through the neighboring auriculotemporal nerve , 22. BasThe pathogenesis by which the expulsion of saliva induces severe parotid pain in the absence of anatomical obstruction of the parotid duct remains unknown in the present study. The parotid gland is amply supplied with sensory fibers from the auriculotemporal nerve. Furthermore, parotid myoepithelial cells are dually innervated by the sympathetic and parasympathetic nerves, with both impulses stimulating myoepithelial cell contraction and consequent salivary flow , 22. In Netterville et al.  proposedThere was no clinical evidence of impaired sympathetic innervation of the parotid glands in the remaining three patients  in our study. However, cervical sympathetic denervation due to ligation of the external carotid artery or excision of the cervical ganglion does not always induce postoperative FBS . FurtherAlthough our cases involved pain characteristic of FBS, they were initially misdiagnosed as trigeminal neuralgia or temporomandibular disorders, which resulted in inappropriate clinical management. Importantly, idiopathic FBS should not be confused with trigeminal neuralgia as this can lead to unnecessary microvascular decompression. Unlike idiopathic FBS, trigeminal neuralgia is associated with brief, electric shock-like pain evoked by innocuous mechanical stimuli, such as light touching of the face, talking, chewing, and brushing , 29. NeuAlthough postoperative FBS pain may decrease in severity with time or disappear spontaneously –6, 9, noOur study has some limitations, such as the retrospective, single-center design and a small number of cases. Therefore, our findings may not be generalizable to all patients with idiopathic FBS. Despite these limitations, our study highlights the characteristics of idiopathic FBS. In the future, we need to accumulate evidence from more cases to confirm our findings and discover therapeutic interventions in patients with idiopathic FBS.We characterized the clinical and pain-related characteristics of idiopathic FBS in five patients without diabetes. Our findings indicate that these characteristics are largely consistent with those of postoperative FBS, thus supporting the notion that idiopathic FBS is a subtype of FBS. We emphasize the need to consider idiopathic FBS in the differential diagnosis of facial pain triggered at the beginning of a meal. The major clinical feature of idiopathic FBS pain that differentiates it from other types of facial pain is its reproduction with an acidic solution applied to the tongue.


Medial branch nerve block (MBB) and facet joint injections (FJIs) can be used to manage axial low back pain. Although there have been studies comparing the MBB and FJI effects, a few studies have compared the therapeutic effects of both interventions combined with each separate intervention. This study aimed to compare the pain relief effect of MBB, FJI, and combined treatment with MBB and FJI in patients with axial low back pain.  We conducted a retrospective review of patients with axial low back pain who had chart records of the Numeric Rating Scale (NRS) and Oswestry Disability Index (ODI) scores measured before treatment and within 6 weeks after treatment. The proportion of patients with successful responses (>30%) was calculated and is presented with Wald confidence intervals.  We included 66 patients . All the patient groups showed significant posttreatment improvements in the NRS  scores and the ODI  scores. Furthermore, there was no significant among-group difference in the ODI and NRS scores.  MBB, FJI, and combined treatment with MBB and FJI can reduce axial low back pain and improve secondary functional degradation. Although combined treatment with MBB and FJI required a longer intervention time, it did not have a pain relief effect superior to that of MBB or FJI alone. The prevalence of chronic spinal pain with various structural etiologies in the general population is around 66%; among them, 44%, 56%, and 15% of the patients present with cervical, lumbar, and thoracic pain, respectively . ChronicLumbar facet joint pain is caused by acute or chronic inflammation of a lumbar zygapophyseal joint and affects 15–45% of patients with chronic LBP [Furthermore, facet joint pain management can be achieved using facet joint procedures using therapeutic interventions, including fluoroscopically guided facet joint injection (FJI), medial branch block (MBB), or radiofrequency ablation –6. FacetThere have been numerous studies examining and comparing the individual effects of MBB and FJI on pain alleviation. However, only few studies have compared the effects of combined treatment with MBB and FJI with those of the individual interventions. We hypothesized that a patient's pain relief would be greater when the anti-inflammation or direct anesthesia of the facet joint capsule induced by FJI and the anesthetizing of the medial branches of the posterior primary rami caused by MBB occurred simultaneously. This study, therefore, aimed to compare the effects of FJI, MBB, and combined treatment with MBB and FJI in patients with axial LBP.In this retrospective study, we reviewed the records of patients who received FJI, MBB, or combined treatment with MBB and FJI for axial LBP between December 2016 and April 2020. This study was approved by the Institutional Review Board of our university hospital (CUH 2020-05-011).The inclusion criteria were patients with axial LBP who had chart records for the Numeric Rating Scale (NRS) and Oswestry Disability Index (ODI) scores before treatment and within 6 weeks after treatment.The exclusion criteria were patients who had NRS and ODI records obtained >6 weeks after treatment or those with missing records for pre- or posttreatment NRS or ODI scores.All interventions were performed under the control of a C-arm image intensifier  with the patient unsedated and in a prone position. The procedures were performed via an aseptic technique using a 6.0 cm-long 24G spinal needle.Initially, we identified the target level in the C-arm AP view and subsequently aligned the superior and inferior endplates of the target vertebral body. Next, the C-arm was moved into an oblique view on the same side as the treatment site while ensuring visibility of the Scotty dog sign and the junction between the transverse process (TP) and superior articular process (SAP) , 10. At First, we identified the target level in the C-arm AP view. Subsequently, the image intensifier was tilt-angled towards the same side as the injection site until the silhouette of the target facet joint space could be observed and the entry site to the joint was maximally visible; the angle here was generally 5–10° , 10. RadMBB and FJI were performed together at the injection target area using the aforementioned procedures. Dexamethasone 5 mg was mixed with 1% lidocaine where the lidocaine volume was adjusted depending on the injection site. We injected 1.5 cc and 1 cc of injectant into each medial branch innervating the target joint and each target facet joint, respectively .The primary outcome to measure the effectiveness of the intervention was the NRS score of chronic LBP. For the NRS assessment, the patients chose a number between 0 and 10 to represent their pain extent. A score of 0 indicates no pain whatsoever, while a score of 10 indicates the most severe pain imaginable . For thep < 0.05.All statistical analyses were performed using IBM SPSS statistics version 24.0. Regarding demographic characteristics, continuous variables are presented as the mean and standard deviation and underwent between-group comparisons. Categorical variables are presented as frequencies and percentages and analyzed using a Chi-square test. For within-group comparisons, a normality test was initially performed. Subsequently, a parametric paired t-test was used for normally distributed variables, while a nonparametric Wilcoxon signed-rank test was used for nonnormally distributed variables. Between-group comparisons were performed using parametric one-way analysis of variance and a nonparametric Kruskal–Wallis test for normally and nonnormally distributed variables, respectively. For the normality test, the Shapiro–Wilk statistic was used. The proportion of patients with successful responses (>30%) was measured and is presented with Wald confidence intervals. Statistical significance was set at There were 33, 17, and 16 patients in the MBB, FJI, and combined treatment with MBB and FJI groups, respectively. All three groups showed a significant postintervention decrease in the NRS score . The posSimilar to the NRS score, all three groups showed a significant postintervention decrease in the ODI . The meaIn the MBB group, one patient complained of mild dizziness. One patient each in the MBB and FJI groups complained of paresthesia in the calf area and were followed up as outpatients; however, they improved without any particular treatment. None of the other patients showed any major adverse effects.In this study, all patients with axial LBP who underwent MBB, FJI, or combined treatment with MBB and FJI showed significant posttreatment improvements in pain scores and pain-caused daily living restrictions, as measured using the ODI. However, there were no significant among-group differences.Fluoroscopy-guided FJI and MBB are useful diagnostic and therapeutic methods for LBP caused by facet joint pathology . In FJI,Although numerous studies have assessed the individual effects of MBB and FJI for axial chronic LBP and compared their effects, there have been very few studies comparing the MBB and FJI effects and the effects of combined treatment with MBB and FJI. This study aimed to compare the effects of the interventions individually and both combined in patients with axial LBP.We divided the patients into three groups according to the received intervention methods and analyzed the pre- and posttreatment ODI and NRS scores. There has been previous moderate evidence that MBB and FJI provide short- and long-term pain relief for facet joint pain, which is the major cause of axial LBP , 31. SimWe hypothesized that the patient's pain relief would be greater when the anti-inflammation or direct anesthesia of the facet joint capsule induced by FJI and the anesthetizing of the medial branches of the posterior primary rami caused by MBB occurred simultaneously. However, we found no significant differences in the therapeutic effects of MBB, FJI, and combined treatment with MBB and FJI. In addition, while combining the interventions that resulted in a longer treatment period, it did not lead to a superior pain-reducing effect than individual treatment.After MBB, one patient complained of a mild headache and dizziness, which improved without any particular treatment. These symptoms could have been caused by lidocaine used for local anesthesia. Although we used only a small quantity of 1% lidocaine, its entry into a blood vessel adjacent to the target area, including the radicular artery or radicular vein, increases its blood levels. This can result in CNS-related adverse reactions, including drowsiness or psychosis, as well as vasoconstrictor reactions, including elevated heart rate and blood pressure , 35. FurThis study has some limitations. First, since this was a retrospective study, we could not consistently control the time between the intervention and follow-up tests to examine the treatment effects. Nevertheless, there were no significant among-group differences in the age, pre-ODI, pre-NRS, and postintervention evaluation interval . Second,MBB, FJI, and combined treatment with MBB and FJI are all effective at reducing axial LBP, as well as at improving pain-induced secondary functional degradation. Although combined treatment with MBB and FJI requires a longer intervention time, it did not show an effect superior to that of MBB or FJI.


Objectives: While opioids temporarily alleviate pain, the overshoot of balancing pain drivers may increase pain, leading to opioid induced hyperalgesia (OIH). Our goal was to find out what chronic opioid treatment does to pain tolerance as measured by the cold pressor test (CPT), an objective measure of pain tolerance, and to find an alternative effective treatment for chronic pain and FM.Materials and Methods: The setting was an academic addiction medicine service that has an embedded pain service. Patients had routine clinical care starting with an evaluation that included assessment of medical and psychiatric conditions. Participants were 55 patients with OIH and 21 patients with fibromyalgia; all had at least two CPTs. Treatment included a single dose of buprenorphine for detoxification. In this open-label case series, patients were treated with low dose naltrexone (LDN), a pure opioid receptor antagonist that, we hypothesize, treats OIH and FM by restoring endogenous opioid tone.Results: Comparing initial and last CPT times, those with OIH more than quadrupled their pain tolerance, and those with FM doubled theirs. This improved pain tolerance for OIH and FM was statistically significant  and had a large effect size .Discussion: Results suggest that patients on chronic opioid therapy should have pain tolerance measured by CPT with detoxification and LDN provided to correct opioid induced hyperalgesia if found. FM may also be treated with LDN. The main limitation of the findings was lack of a randomized control group treated with placebo. The opioid epidemic has long entered the public consciousness. Three hundred eighty-three thousand and ninety-one deaths from overdose in the US during 2001 to 2017 has punctuated this awareness , and a mUnderstanding the deleterious effects from chronic exogenous opioid exposure on the endogenous opioid system informs the understanding of fibromyalgia (FM), a syndrome of chronic pain that is diffuse yet accentuated at multiple tender points along with other somatic and cognitive symptoms –18. The We conceptualize FM's alterations in the endogenous opioid system involving an autoimmune process . Mu-opioGiven these considerations of the endogenous opioid system in OIH and FM, we present a case series to demonstrate the effect of low dose naltrexone (LDN) on pain tolerance in OIH and FM. Naltrexone's antagonism at mu, kappa, delta, and orphanin FQ/nociceptin opioid receptors and at opioid growth factor receptor (OGFr) induces a variety of cellular responses at different doses , 24–38. A pain service is embedded in the Addiction Medicine Service at the State University of New York Upstate Medical University to evaluate pain complaints in patients with comorbid opioid use disorder. Patients are generally poor: 2/3 of our patients have Medicare or Medicaid insurance. Many are chronically ill with multiple medical and psychiatric diagnoses. Prospective patients are not required to have any diagnosis other than chronic pain prior to evaluation on the pain service. Many addicted patients also have chronic pain. Evaluators include medical, physician assistant and psychiatric nurse practitioner students, neurology, internal medicine and psychiatry residents, and pain medicine and addiction psychiatry fellows—along with senior staff physicians and nurse practitioners. Patients are asked to sign an IRB-approved form for their deidentified information to be used in case series reports. Treatment progress is monitored by joining subjective reports of pain with the cold pressor test (CPT), a validated, objective measure of chronic and experimental pain , with goWe reviewed all patients who presented for an initial intake between January 2017 and July 2019. There were 786 initial evaluations. Three hundred seventy six had an initial CPT. Seventy six were treated with LDN and had follow-up CPTs. Roughly half of all patients who present to the Addiction Medicine Service are evaluated at the embedded pain service. Of these patients, a smaller proportion have fibromyalgia rather than opioid use disorder, as reflected in the larger number of OIH patients in the study sample. Of the 76 patients treated with LDN and had follow-up CPTs, 55 were diagnosed with OIH, and 21 were diagnosed with FM.Because the evaluations are complex, and cognitive impairment is common, we require that every new patient bring a sober support person. The support person is present for the evaluation and discussion of diagnoses, proposed treatments, and whether to engage in treatment on the service. Support persons from a prior case series had average CPT of 113 seconds . In thatThe services have a holistic nature. We start with the chief complaint and history of present illness, then the psychiatric, medical, family and social histories. A comprehensive substance use history is taken on alcohol, cannabis, nicotine, cocaine, amphetamine, benzodiazepine and opioid use. A Hamilton Rating Scale for Depression, a Modified Mini-Mental State Examination and a FACES Pain Scale (FPS) are recorded.We use screens for common comorbid disorders. The Adult ADHD Self Report Scale for attention deficit hyperactivity disorder (ADHD) is given, followed by a DSM5 interview if ADHD is suspected. The Structured Clinical Interview for DSM5 (SCID2) checklist is used to screen for borderline personality disorder. While ADHD, borderline personality and depressive disorders are unusual in pain patients, they are present in about half of our opioid use disorder patients . A physiThe dose, frequency, and duration of opioid exposure, obtained in the substance history, are rendered as morphine years (MY). A “morphine year” had been described in a previous publication as daily use for a year at 60 morphine milligram equivalents (MME). We had found a positive correlation between MY and the prevalence of depression, ADHD, and borderline personality. MY were higher in younger patients because of the use of illicit opioids, as doses sold by street dealers are about 100 times greater than prescribers. We had found a negative correlation between CPT and MY, with more cumulative opioid use leading to lower CPT, suggesting that opioid exposure causes a steady decrease in pain tolerance .Exposure to opioids almost always caused short CPT. CPT was repeated on follow-up appointments to gauge changes in pain sensitivity. The test was stopped at 180 s for patients that had a high pain tolerance. Changes in pain sensitivity were used to reassess LDN treatment. Patients also reported their pain on initial evaluation via the FACES Pain Scale. On follow-up visits, patients reported if their pain was better, worse, or no change. Patients were diagnosed with OIH if they were experiencing significant pain while on opioids and had a CPT less than two-thirds of the healthy controls' average of 113 s .The patient arrives in early withdrawal with symptoms such as gut cramps, anxiety, and increased pain. 8 mg sublingual buprenorphine tablets are taken in front of staff until withdrawal symptoms remit; usually 24 or 32 mg are sufficient. The duration of the “detox” is about 15 min. Patients were sent home with clonidine, hyoscyamine, trazodone, olanzapine, and gabapentin for attenuated withdrawal symptoms. These symptoms and their treatments were explained on a written handout topped by the senior author's cell phone number. Directions were given to “call day or night if you need help” . In addition to pharmacotherapy, patients received psychotherapy daily for the first week and then twice a week until discharge. After buprenorphine administration, LDN was started at 0.1 mg twice a day and titrated with the following schedule:0.2 mg twice a day on day two0.3 mg twice a day on day three0.4 mg twice a day on day four0.5 mg twice a day on day five1.0 mg twice a day for days five and six2.0 mg twice a day for days 7 and 84.5 twice a day thereafterGiven the difficulty with finding pharmacies that will accommodate this varied dosing, we dissolve a 50 mg pill of naltrexone in 50 ml of water, and we show patients how to use an insulin syringe to draw up 0.1 mg increments. This titration occurred more slowly if there was a return of opioid withdrawal symptoms with increased dosing, understood as if the receptor system was slow to regenerate and therefore not tolerating the increasing doses of LDN. FM patients not currently on opioids started LDN as soon as their treatment plan was agreed upon.Stata 16 was utilized. The Wilcoxon signed-rank test was used to determine the statistical significance of the change in CPT. Ordinal least squares regression was used to determine if the relationship of change in CPT varied significantly with age, sex, days between first and last measurement, FPS, and MY. Non-parametric statistics were used because the data did not meet the normality assumption.Of the 363 patients who had an initial CPT, 76 returned for follow-up and continued treatment with LDN. This reflects the nature of our service; some patients will not return for treatment because:They believe that they should be treated with opioids despite short CPTs that are diagnostic of OIHSome expect pills to fix their pain exclusively and will not engage in active treatments that include the examination of a lack of self-care during an extended evaluation that requires appearing for further visitsSome seek a source of opioids and drop out when it becomes apparent that opioids are not part of the treatmentThe remaining 20% of patients were a highly motivated group, culled from an intake system that requires active engagement. The results from these 55 OIH and 21 FM patients are summarized in p < 0.0001). FM patients exhibited an increase in their pain tolerance of 16 s (p < 0.003). The effect sizes were substantial (r = 0.82 for OIH and r = 0.63 for FM). After their initial CPT, OIH patients averaged 3 months before they completed their last repeat CPT. FM patients averaged 7 weeks between their initial and final CPT. Only in OIH was there a statistically significant relationship between the change in CPT and the number of days between the first and last CPT measurement  and FM (14 s) when considering the control group from a prior case series had an initial pain tolerance of 113 s . The pat4 s and FPatients maintained on opioids for chronic pain presented with an average initial CPT of 24 s and FPS of 5.4/10, underscoring their diminished pain tolerance when compared to a prior control group's 113 s average . HoweverWhat accounts for the greater magnitude of response to LDN found in OIH compared to FM? While we propose that the endogenous opioid system is integral to the pathophysiology of both conditions, the mechanisms by which LDN may restore endogenous opioid tone remains largely a mystery, as varying doses and binding durations may produce different effects at each of the opioid receptor types , 34, 36.Alterations in the affective processing of pain in FM and OIH , 53 may Given these encouraging results, what are the implications for future research as well as the current status of the use of opioids in treating chronic pain? The brain rebels against chronic opioid treatment by the opponent process , 60, 61,This is a chart review study of the cold pressor test in a variety of patients presenting for addiction and/or pain treatment. The topic and the concept of the study are certainly of interest, but the methodology is challenging, as the CPT data were derived from charts and was not delivered in a standardized fashion . Ideally, one would need demographically matched groups of controls, patients with chronic pain not on opioids, patients with chronic pain on opioids without addiction, and patients with chronic pain who are on opioids who are addicted. Patients who had no history of opioid exposure were so unusual that we were not able to find enough subjects to construct such a control group.Since subjects were not randomized to experimental and control groups, the potential of a placebo effect could not be evaluated. However, it may be that placebo responses do not significantly affect cold pressor pain. Placebo effects are shown to be greater in clinical pain (such as low-back pain) rather than experimental pain (CPT) . Since oIt is possible that patients who were experiencing positive results from the treatment remained in treatment long enough to have a second CPT, while non-responders dropped out, skewing the reported results toward responders. Our titration schedule takes into account the sensitivity of the already diminished endogenous opioid system of our patients. Recent findings suggest a dose-response relationship to LDN among FM patients ; it is pBy constantly using patient feedback, we have been able to discover how to detoxify patients from opioids as an easy outpatient procedure, assess pain tolerance with the cold pressor test, and ameliorate opioid induced hyperalgesia with low dose naltrexone. These are all innovative procedures. The weakness of our report is the lack of randomized control groups.Routine use of CPT is helpful in diagnosing OIH. It helps patients see that using opioids for chronic pain treatment increases pain. Opioids have a high prevalence of risks, including death from accidental overdose, iatrogenic addiction, unrelatedness, falls, and constipation.FM mimics OIH; its symptoms are congruent possibly because it is an autoimmune disease that also reduces CNS pain-damping opioid tone . DetoxifThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.DJ wrote the first draft. All other authors contributed intellectually to the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Over 7% of the Western population suffer from intractable pain and despite pharmacotherapy, many patients’ pain is refractory . In addiFor those patients who do not respond to SCS and other forms of more “peripheral” neuromodulation, deep brain stimulation (DBS) and motor cortex stimulation (MCS) are alternatives. Farrell and colleagues  review tIn addition to studies looking at neuromodulation as a general treatment for refractory conditions, more work is needed into its use in specific pain syndromes. Roy et al.  summaris