QST of the face and forearm included warmth detection threshold (WDT), cold detection threshold (CDT), and heat pain thresholds (HPT), ratings of suprathreshold heat, and pressure pain thresholds (PPT), and was performed twice: once in the morning and once in the afternoon. Compared to healthy participants, BMS patients had higher pain sensitivity to phasic heat stimuli at most temperatures  on the forearm, but no differences in pain thresholds (HPT and PPT) regardless of time of day or body area tested. BMS patients had higher WDT , and lower CDT  of the forearm and lower WDT of the face . The differences in forearm WDT  and CDT  were most pronounced in the morning. In summary, BMS type I patients had increased pain sensitivity on the forearm, but no differences in pain thresholds on the face or forearm. Patients also showed altered thermal sensitivity, which depended on body area tested , and was more pronounced in the morning plausibly due to hypervigilance.Burning mouth syndrome (BMS) is a chronic orofacial pain condition that mainly affects postmenopausal women. BMS type I patients report little to no spontaneous pain in the morning and increases in pain through the day, peaking in the afternoon. Quantitative sensory testing (QST) findings from BMS type 1 patients are inconsistent as they fail to capture this temporal variation. We examined how QST in BMS type 1 ( Burning Mouth Syndrome (BMS) is a chronic orofacial pain condition that mainly affects post-menopausal women . The mosSomatosensory functions in people affected by BMS can be determined psychophysically using quantitative sensory testing (QST) . PreviouThese conflicting extra-trigeminal QST findings could be due to the cyclical nature of spontaneous pain in BMS . TherefoIn the current study, we examined psychophysical responses to thermal and pressure stimuli on the face and forearm in the morning and afternoon in BMS type I patients and healthy participants to address how time of day affects somatosensory responses in BMS type I. We also collected pain diaries from BMS patients across 8 days to illustrate the cyclical nature of pain in this BMS sample. We hypothesized that compared to healthy participants BMS patients have higher pain sensitivity, specific to the orofacial regions, during the afternoon.All research procedures were granted approval by the Institutional Review Board of the University of Maryland, Baltimore. After thorough explanation of the study, informed consent was obtained from all willing participants according to the Declaration of Helsinki.BMS participants were asked to complete a 2-day experimental session comprised of 3 days of pain diaries followed by test day 1, and test day 2 culminating with 3 more days of pain diaries. We required visit 2 to be within 9 days after visit 1. An option of a 1-day experimental session was offered in order to reduce scheduling conflicts and increase enrollment. The 1-day experimental session comprised of 3 days of pain diaries followed by test day 1 and culminating with 4 more days of pain diaries. Healthy participants from the current study also completed either a 2-day or a 1-day experimental session but they did not complete pain diaries.This study took place between the years 2014 and 2018, at the time BMS was a diagnosis of exclusion, i.e., once all possible physical causes of chronic oral mucosal pain/burning sensation are ruled out, patients could be assigned to the Type 1 or Type 2 category. Dental and oral health examinations were performed at the Oral Medicine Program at the University of Maryland School of Dentistry (led by TFM). BMS patients who presented with possible BMS were given a thorough medical history review and oral examination to rule out a specific disease  or medical cause  for the pain. A careful review was made looking for hormonal, allergic, salivary gland dysfunction, chronic low-grade trauma and/or psychiatric abnormalities as possible etiologies. Next an oral swab/brush culture was taken to rule out a fungal cause. Blood work request included: CBC with Differential, comprehensive metabolic panel, including fasting glucose, HbA1C, and TSH levels; along with iron, ferritin, folate, vitamin B1, B2, B6, B12, C, magnesium, and zinc levels; plus, testing for HSV 1 and 2 and herpes zoster titers; Lyme’s disease antibody; and H. Pylori antibodies; and finally, Sjogren syndrome panel ANA, anti-SSA/SSB. Additionally, because of our exclusion criteria, potential participants underwent thorough assessment to ensure no other orofacial co-morbidities were present  and medical records from their general providers were assessed to ensure no other chronic pain  or other types of co-morbidities  were present. However, to increase recruitment, we later expanded our inclusion criteria to include BMS participants with co-morbid pain conditions as dictated by a Health History Assessment collected during their participation. We list the results from this assessment in the Results section under Demographics.Lastly, patients were given a food diary to fill out for 7 days. Patients that were women ages 40–85, peri or postmenopausal, with a presumptive diagnosis of BMS , and a consistent circadian pattern of pain, where spontaneous burning pain is absent or minimal in the morning, and moderate to severe in the late afternoon (type 1 patients) were recruited into the study.BMS patients were recruited following diagnosis at the Oral Medicine Program at the University of Maryland School of Dentistry (led by TFM), where complete dental and oral health examinations were performed. A working diagnosis of BMS was based on a chief complaint of pain or burning in the oral mucosa and/or tongue and exclusion of other known causes of oral burning−like pain. If BMS patients were taking topical medications or in the transition of weaning off a systemic medication, to start a new one, we asked them to come in when they had completely weaned off of the medications and would test them prior to their transition into a new medication regimen. As mentioned above, to increase recruitment, we expanded our inclusion criteria to include BMS participants with co-morbid pain conditions.Additionally, healthy participants were recruited through campus−wide flyer advertisement and were free of any chronic pain conditions, psychiatric illness, local oral or systemic disease, and salivary dysfunction as dictated by their doctor’s report of medical history.Exclusion criteria for all studies: participants unable or refusing to sign consent for any part of the testing; daily regimen of opiates; excessive alcohol use as measured on the AUDIT  was enrolled in the current protocol with the 18 BMS patients; healthy participant group 2 (n = 10) was obtained from deidentified data from a previous study from our laboratory with identical methods for some of the QST procedures; and healthy participant group 3 (n = 12) was obtained from deidentified data from a concurrently run study in our laboratory with identical methods for some of the QST procedures.The healthy control group consisted of pooled data from three separate studies: healthy participant group 1  or an afternoon (PM) QST session on the first day and on the second day participants were assigned the opposite time of day (AM/PM) for QST testing. For example, if a participant was given afternoon QST on the first day, they would have QST in the morning of the second day. For participants who could not commit to two testing days we offered a 1-day experimental session, where we randomized whether a participant would experience a morning or an afternoon QST session.After participants signed the consent form, BMS patients were given an 8-day paper diary to track their oral burning pain intensity and unpleasantness. For the 2-day visit, they completed the diaries for 3 consecutive days prior to the laboratory visit, during the 2-day visit, and for 3 consecutive days after the visit. For the 1-day visit, they completed the diaries for 3 consecutive days prior to the laboratory visit, during the 1-day visit, and for 4 consecutive days after the visit. Participants were asked to rate their burning pain intensity on a scale of 0–10, with 0 meaning “none” and 10 meaning “as bad as you can imagine” and unpleasantness on a scale of 0–10, with 0 meaning “not bothersome” and 10 meaning “extremely bothersome,” at five different time-points: wakeup, 10 a.m., 2 p.m., 6 p.m. and bedtime each day.Thermal heat and cold stimuli were delivered to the forearm and face via a 27 mm diameter Medoc Pathway CHEPS Peltier thermode with a heating rate of 70°C/s and a cooling rate of 40°C/s . Four thermal tests where administered: three tests on the forearm  and one test on the face (temperature threshold testing). The thermode was repositioned along the forearm and cheek after each stimulus to avoid temporal summation.Participants received a warmth detection threshold (WDT) test, where the temperature increased from a baseline temperature of 32°C at a rate of 1°C/s until mouse click. Then, they received a cool detection threshold (CDT) test, where the temperature decreased from 32°C at a rate of 1°C/s until mouse click. In both WDT and CDT, participants were asked to click the mouse when they first detected a change in temperature. We then tested heat pain threshold (HPT), where temperature increased from 32°C at a rate of 1.5°C/s until mouse click. Participants were asked to press the mouse as soon as the temperature first became painful. WDT, CDT, and HPT were each performed three times and were calculated as the average temperature across the three trials. Subsequently, we created a WDT Total comparison comprised of the AM and PM six WDT exposures (three in the AM and three in the PM) averaged together for each group . We created a WDT AM comparison the three AM WDT exposures averaged for each group . The same procedure was followed for the PM comparison. Additionally, we created a WDT AM vs. PM comparison using the three WDT AM averages and the three WDT PM averages for each group . All of this was repeated for the CDT and HPT tests.Following the forearm temperature threshold testing procedures, participants received WDT, CDT, and HPT tests with temperature stimuli presented three times for each test as explained above; however, this time the thermode was placed on the left cheek. The temperature increased  or decreased (CDT) from a baseline temperature of 32°C at a rate of 1°C/s until mouse click when they first detected a change in temperature  and as soon as the temperature first became painful (HPT). WDT, CDT, and HPT were each performed three times and were calculated as the average temperature across the three trials. Subsequently, we created a WDT Total comparison comprised of the AM and PM six WDT exposures (three in the AM and three in the PM) averaged together for each group . We created a WDT AM comparison the three AM WDT exposures averaged for each group . The same procedure was followed for the PM comparison. Additionally, we created a WDT AM vs. PM comparison using the three WDT AM averages and the three WDT PM averages for each group . All of this was repeated for the CDT and HPT tests.Subsequently, a “levels” test was administered to the forearm where participants received a series of heat stimuli delivered in ascending order of target temperatures: 35°, 35°, 39°, 41°, 43°, 45°, 47°, and 49°C. We varied the ramp rates to each target temperature in order to maintain the same ramp time of 1.6 s with each heat stimulus, from the baseline temperature of 32°C. Target temperatures were sustained for 6 s, so the total heat stimulus duration including ramps was 9.2 s. A 20 s inter-stimulus interval between target temperatures allowed the participant to input their rating for the presented target temperature. Participants rated pain intensity on a numerical rating scale (NRS) of 0 (no pain) to 10 (extremely intense pain) and pain unpleasantness on an NRS of 0 (not bothersome) to 10 (extremely bothersome pain).Subsequently, we averaged the first pain intensity and unpleasantness ratings of the first two temperature exposures (35° and 35°C) to obtain a single value for 35°C and leaving us with 7 total temperature exposures in the morning and afternoon . Next, we created a pain intensity Total comparison comprised of the AM and PM pain intensity ratings averaged together to obtain a single value per temperature  per group  . The same procedure was followed to create a pain unpleasantness Total comparison per group . We also created an AM comparison, the 7 temperature stimulations in the AM are averaged together to get a single value per temperature  per group . The same procedure was followed to create a PM comparison per group . We also created an AM vs. PM comparison, were the 7 temperature stimulations in the AM are averaged together to get a single value per temperature  and the 7 temperature stimulations in the PM are averaged together to get a single value per temperature  per group . Additionally, the same procedure was followed to create an AM, PM, and AM vs. PM comparison pain unpleasantness rating per group .2 rubber probe tip diameter . Participants received pressure stimuli at four locations of the body: thumbnails (center of nail plate of the thumbnail avoiding the nailbed), elbows , temporalis muscle , and masseter muscle . Pressure was applied to the left thumbnail, elbow, temporalis, and masseter muscles  and then right thumbnail, elbow, temporalis, and masseter muscles . Participants were asked to raise a hand when the pressure first became painful and the pressure at that instant was recorded in kilograms.Bilateral pressure pain thresholds (PPT) were obtained using a Wagner Force Dial tm FDK 10/FDN Series Push Pull Force Gage pressure algometer with a 1 cmSubsequently, we created a PPT Total comparison of the masseter comprised of the AM and PM 12 pressure exposures (left and right masseter) averaged together for each group . We created a PPT AM comparison of the masseter the six AM pressure exposures (left and right masseter) averaged for each group . The same procedure was followed for the PM comparison of the masseter. Additionally, we created a PPT AM vs. PM comparison of the masseter using the six PPT AM averages and six PPT PM averages for each group . The same comparison groups created for the masseter results were followed for the temporalis, elbow, and thumbnail results.U-test between groups  of the average of both time points (AM and PM). For these analyses, all participants in the BMS and healthy groups were included, whether they had data from AM alone, PM alone, or both AM and PM, in which case an average was taken. (2) AM comparison: Mann-Whitney U-test between group analyses of data taken from each subject at the AM time point. (3) PM comparison: Mann-Whitney U-test between group analyses of data taken from each subject at the PM time point. (4) AM vs. PM comparison: Wilcoxon signed-rank test within group analyses of AM and PM time points within BMS and healthy groups. We also performed an area under the curve (AUC) with respect to ground analysis of pain intensity and unpleasantness ratings for the levels test. AUC was calculated according to the literature following the same grouping as listed above  Toted above . Becausepost hoc test for multiple comparisons. No diaries were collected from healthy participants as ratings of burning mouth pain and unpleasantness were presumably zero and therefore no comparisons were made for healthy participants.Mean, median, and range of BMS pain intensity ratings were reported for each of the 8 days. A Friedman test was used to compare average pain intensity for 5 time points in a day across 8 days, followed by a Dunn’s U-test. The same procedure was followed for the CDT Total comparison and HPT Total comparison of the face.As explained above, participants were presented with three trials within the WDT, CDT, and HPT tests. Therefore, to analyze the WDT Total comparison of the face, all participants in the BMS and healthy groups were included regardless of whether they had data from AM alone, PM alone, or both AM and PM, in which case an average was taken. We averaged the trials within WDT of each group  to perform Mann-Whitney U-test of the data taken from each subject at the AM time point. To assess the between group  differences in the afternoon (PM comparison), we performed a Mann-Whitney U-test of the data taken from each subject at the PM time point. To assess the within group  differences in the morning compared to the afternoon (AM vs. PM comparison), we performed a Wilcoxon signed-rank test of the AM and PM time points within BMS and healthy groups. These three group comparisons  were followed by a Bonferroni post hoc test for multiple comparisons with a corrected threshold of p = 0.0167. The same procedure was followed for the face CDT AM, PM, AM vs. PM comparison and the HPT AM, PM, AM vs. PM comparison.To assess the between group  differences in the morning (AM comparison), we performed a Mann-Whitney The same analyses procedure was followed for all WDT, CDT, and HPT forearm comparisons.U-test. The same procedure for the pain intensity Total comparison was followed for each subsequent temperature 39°, 41°, 43°, 45°, 47°, and 49°C. Additionally, this analysis procedure was followed to create a levels pain unpleasantness Total comparison per group  for 35°, 39°, 41°, 43°, 45°, 47°, and 49°C.Because of the small sample size in each group non-parametric tests were performed. Additionally, for both intensity and unpleasantness analyses separate models needed to be run for each temperature due to the variation in sample sizes within and between groups; as well as missing data at 45°, 47°, and 49°C between comparison groups in the unpleasantness analyses see . To analU-test of the data taken from the average pain intensity rating obtained in the morning. To assess the between group  differences in the afternoon (PM comparison) at 35°C, we performed a Mann-Whitney U-test of the data taken from the average pain intensity rating obtained in the afternoon. To assess the within group  differences in the morning compared to the afternoon (AM vs. PM comparison) at 35°C, we performed a Wilcoxon signed-rank test of the averaged AM pain intensity and the averaged PM pain intensity within BMS and healthy groups. These three group comparisons  at 35°C were followed by a Bonferroni post hoc test for multiple comparisons with a corrected threshold of p = 0.0167. The same procedure for the pain intensity AM, PM, AM vs. PM comparison was followed for each subsequent temperature 39°, 41°, 43°, 45°, 47°, and 49°C followed by a Bonferroni post hoc correction for multiple comparisons with a corrected threshold of p = 0.0167. Additionally, this analysis procedure was followed for the levels pain unpleasantness AM, PM, AM vs. PM comparison 35°, 39°, 41°, 43°, 45°, 47°, and 49°C followed by a Bonferroni post hoc correction for multiple comparisons with a corrected threshold of p = 0.0167.To assess the between group  differences in the morning (AM comparison) at 35°C, we performed a Mann-Whitney Given repeated exposure to temperatures and correlation between multiple intensity ratings from the levels tests we also performed an area under the curve (AUC) with respect to ground analysis of pain intensity for the levels test. AUC was calculated according to the literature following the same grouping as listed above . AdditioU-test. The same analyses procedure was followed for the PPT Total comparison of the temporalis, elbow, and thumbnail.As explained above, participants were presented with pressure a total of 6 times  and extremities (thumbnail and elbow). To analyze the PPT Total comparison of the masseter, the AM and PM 12 pressure exposures (left and right masseter) were averaged together for each group  regardless of whether they had data from AM alone, PM alone, or both AM and PM, in which case an average was taken. We then performed a Mann-Whitney U-test of the average of the six AM pressure exposures (left and right masseter) for each group . To assess the between group  PPT differences in the afternoon (PM comparison) of the masseter, we performed a Mann-Whitney U-test of the average of the six PM pressure exposures (left and right masseter) for each group . To assess the within group  PPT differences in the morning compared to the afternoon (AM vs. PM comparison) of the masseter, we performed a Wilcoxon signed-rank test using the six PPT AM averages and six PPT PM averages within BMS and healthy groups. These three group comparisons  were followed by a Bonferroni post hoc test for multiple comparisons with a corrected threshold of p = 0.0167. The same analyses procedures were followed for the PPT AM, PM, and AM vs. PM comparison of the temporalis, elbow, and thumbnail.To assess the between group  PPT differences in the morning (AM comparison) of the masseter, we performed a Mann-Whitney All participants were peri- or post-menopausal women. BMS participants had an age range of 47–74 years . Seventy-seven percent of BMS participants were Caucasian, six percent African American, six percent Asian, and eleven percent mixed race. Healthy participants had an age range of 43–73 years . Seventy-nine percent of healthy participants were Caucasian, seventeen percent African American, and four percent Asian.n = 6), irritable bowel syndrome (n = 4), headaches/migraines (n = 2), temporomandibular disorder (n = 2), foot neuropathy (n = 1), fibromyalgia (n = 1).Additionally, 10 out of the 18 BMS participants had co-morbid pain conditions. The presence of co-morbidities were as follows: arthritis  , 3.6 at 6 p.m.  and bedtime  compared to wake time. In addition, there were no significant differences in pain intensity ratings across each individual time point and the 8 days of diary recordings; for example, there was no significant difference in pain rating of wake time across the 8 days, no significant difference at 9 a.m. across 8 days, and so on.Pain intensity ratings of BMS patients were significantly higher as the day progressed from wake to bedtime (F 0.0001) . Post hop = 0.0494)  . There w 0.0494) .p = 0.0172) (p = 0.0113). There were no differences in the PM comparison or in the AM vs. PM comparison  . In the mparison .Face: BMS patients had no significant differences in CDT compared to healthy participants in the Total comparison . There wp = 0.0021) (p = 0.0096). There were no significant differences in the PM comparison, or AM vs. PM comparison within or between groups  . In the n groups .Face: BMS patients had no significant difference in HPT compared to healthy participants in the Total comparison . There wForearm: BMS patients had no significant difference in HPT compared to healthy participants in the Total comparison . In the p = 0.0006), 39°C by 1.583 pain ratings , 41°C by 1.417 pain ratings , 43°C by 3 pain ratings , 45°C by 2 pain ratings  (p = 0.0112) in the Total comparison. There were no differences in the AUC for pain intensity or unpleasantness Total comparison.In the Total comparison, BMS participants had significantly higher pain intensity at 35°C by 2.583 pain ratings  . In addiThere were no significant differences in pain intensity ratings in the AM comparison, PM comparison, nor in the AM vs. PM comparison. There were also no differences in AUC for pain intensity or pain unpleasantness in the AM comparison, PM comparison, or AM vs. PM comparison .In the Total comparison, BMS patients had no significant differences in PPTs of the masseter, temporalis, thumbnail, and elbow compared to healthy participants . There wIn this study, we investigated whether sensory sensitivity of the orofacial region and the forearm was affected by time of day and thus the presence of ongoing pain in BMS type I patients compared to healthy participants. Our hypothesis that compared to healthy participants, BMS type I patients have higher pain sensitivity, specific to the orofacial regions and in the afternoon, was not supported. Our main findings showed that time of day has a significant effect on the spontaneous orofacial pain as quantified by pain diaries. Overall, compared to healthy participants, BMS patients had higher pain sensitivity to phasic heat stimuli (“levels” test) at most temperatures, higher WDT, and lower CDT of the forearm and lower WDT of the face. However, there were no time-dependent differences in experimental thermal pain or pressure pain to the orofacial region. Instead, we found a significant time of day effect for the experimental thermal exposure to the forearm, with BMS patients displaying less sensitivity than controls to both cold and warm temperature detection at only the morning session. This is the first study to compare morning to afternoon QST pain measures in BMS patients compared to healthy participants.BMS type I is characterized as a burning sensation that is not present upon waking, but which develops in the late morning and progresses during the waking hours, with the greatest intensity of discomfort in the evening . Based oWe did not find time of day differences between BMS patients and healthy participants in orofacial thresholds assessed by morning and afternoon comparisons of WDT, CDT, HPT, nor masseter muscle or temporalis muscle PPT. Even though the lack of differences could simply be due to our low sample size, We also found no time-of-day differences in the extremities assessed by thumbnail and elbow PPT comparisons between BMS and healthy participants. Similar to our findings Central sensitization has been suggested as a potential mechanism for the presence of pain in other body regions of BMS patients . We founWe found some unexpected outcomes in BMS patients. HPTs tested on the face and forearm in BMS patients did not differ from those in healthy participants. Prior literature on HPTs shows conflicting results, including higher, lower, and non-differing HPTs compared to healthy participants in the orofacial region this while showing no differences in the extremities . It was The findings in the present study should be interpreted in light of some limitations. First, sample size was relatively small. Despite our efforts, due to difficulties recruiting healthy participants, we relied on using healthy controls from three separate studies which despite similarities in testing methods can be source of potential biases. Additionally, while we had initially planned to exclude BMS patients with other pain conditions, we modified our inclusion criteria to patients with co-morbid conditions to be able to reach our enrollment target. Given that 55% of our BMS patient sample had comorbid pain conditions, further examination of the effects of overlapping pains is warranted. Note that the presence of one or more other chronic pain conditions occurs in most patients with chronic pain, so our sample of BMS is not out of line with this data . Second,In conclusion, warm and cold processing is impaired in BMS type I patients, which could suggest hypervigilance toward clinically relevant pain of the orofacial area that results in reduced sensitivity to innocuous stimuli applied to distal body areas. Despite clear increase in spontaneous pain, we saw limited time-of-day dependent effects on QST measures. Subsequent studies should consider potential mechanisms underlying individual differences in BMS type I patients and investigate the impact of pain and other sensory sensitivities in brain signaling in order to further understand BMS symptomatology.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Institutional Review Board of the University of Maryland, Baltimore. The patients/participants provided their written informed consent to participate in this study.TM and DS conceived of and designed the experiment. SY prepared the study protocols and data collection methods. MK provided ongoing technical support. SB advised on non-parametric statistical analyses. SB, JD, DS, and TM all contributed to manuscript preparation. JP performed all data collection, data preprocessing, analysis, and writing of the manuscript. All authors contributed to the article and approved the submitted version.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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We report the results of this treatment evaluating pain relief and HRQOL improvement in this disorder.Postherpetic neuralgia (PHN) is the most common and bearable complication of herpes zoster (HZ). This pain may have negative impact on the patient's all aspects of daily life and health‐related quality of life (HRQOL). Despite numerous advances in treatment, many patients remain resistant to the current therapy options. It is the first time subcutaneous injection of methylprednisolone acetate and lidocaine has been used to treat A total of 43 patients with refractory PHN was enrolled in the observational study. All patients received daily subcutaneous injection of methylprednisolone acetate and lidocaine for 10 consecutive days. The severity of pain was assessed by using Visual Analog Scale (VAS), and 36‐Item Short Form Survey (SF‐36) was applied to evaluate HRQOL. Assessment of the pain and HRQOL was carried out at baseline and posttreatment at 4 weeks as well as 6 and 12 months.P < .001), and all subjects showed significant improvement in all eight domains of HRQOL. No major adverse events associated with the subcutaneous injection were observed.At baseline, all patients experienced severe PHN with average VAS scores of 8.44 ± 0.85 . At 4 weeks, 6 months, and 12 months after treatment, the pain had significantly decreased (Our results indicate that subcutaneous injection of methylprednisolone acetate and lidocaine can be an effective and safe treatment for PHN. During the period from May 2016 to October 2018, a total of 46 patients with refractory PHN were screened at the time of pretreatment examination and 43 patients were enrolled in the entire study (up to 12 months after treatment). All of them gave the written informed consent to participate in the study. The work was approved by Ethics Committee of Military Hospital 103 (code: 140/2016/IRB‐MH103).We defined refractory PHN as constant aching or intense burning pain, a paroxysmal and lancinating pain with allodynia and/or hyperalgesia that was in the restriction of dermatome involved to original herpes zoster,2.2All eligible patients received a combination of methylprednisolone acetate (5‐10 mg) and lidocaine 2% (6‐12 mL), depending on the severity and area of pain. The affected site was divided into a chessboard form with 0.3 to 1.0 mL subcutaneously injected at each point to cover the entire pain area Figure .The injection was once daily administered with a 25 G needle for 10 consecutive days. The injection points can be changed if pain at the previous injected point increases or a large hemorrhage occurred.The severity of pain was assessed by using VAS. It consists of a straight horizontal line of 100 mm length. The ends are defined as the extreme limits of the pain “no pain at all” on the left end (0 cm) and “as bad as it could be” on the right end of the scale (100 mm). The VAS was frequently used for measurement of pain in recent years.2.3At the time of pretreatment (baseline), the demographic data of the study population  were collected. In addition, VAS scores and scores for each of the eight items on the SF‐36 scale were also counted. At the time of completion of treatment, only VAS scores were calculated and recorded. At follow‐up 4 weeks, 6 months, and 12 months after treatment: scores of VAS and the eight concepts on the SF‐36 scale were again counted and collected.2.3.1P < .05 was considered statistically significant. The data were analyzed on SPSS software (version 22.0) for Windows operating system (SPSS Inc. IBM Company)  and improvement of HRQOL (SF‐36 score) over time. ) Figure .3During the 18‐month enrollment period, a total of 46 PHN patients were screened and 43 patients recruited in the study. Three of them were excluded for declining to participate in the study, and 43 subjects completed the 12‐month follow‐up. The clinical and demographic characteristics of the subjects before the start of the research are presented in Table P < .001). Further analysis of the data, all patients had an excellent pain relief during the 12‐month follow‐up. At the end of the study, 17/43 (39.5%) individuals had no pain anymore, and none of them reported recurrent pain at all posttreatment assessment.Figure P < .001). Four weeks after treatment, all patients had only mild pain and this outcome was maintained across a period of 12 months.Table The HRQOL, as measured by SF‐36, showed statistically significant improvement in all eight domains from baseline at any follow‐up evaluation Figure .3.1Local adverse effect reactions such as small subcutaneous bleeding Figure  and pain4PHN is the most common and troublesome chronic complication associated with HZ.Currently, in Vietnam, conventional regimens including anticonvulsants , tricyclic antidepressants (amitriptyline and nortriptyline), topical agents (5% lidocaine patch), and tramadol (in combination with acetaminophen) are available and acceptable for treatment patients with PHN. All patients who prior to being recruited into our research had been tried for treatment with the abovementioned drugs in other hospitals, but they showed a treatment failure. Their pain was still not well controlled and remained severe. In our study, the mean score of pain severity according to VAS before intervention was 8.44 ± 0.85 . Although opioids and intrathecal methylprednisolone are recommended according to American and European guideline  for therapy of this condition,refractory PHN.In the present study, the administration of subcutaneous injection of methylprednisolone in combination with lidocaine for 10 consecutive days had shown an excellent effect on pain reduction (measured by a VAS) and improvement of the quality of life  of 43 patients with In terms of pain‐relieving effect, we found that within initial 2 to 3 days of the intervention, pain‐relieving efficacy could not be observed, even increasing pain occurred at the injection points. Analgesic improvement with the regimen started 4 to 5 days during intervention, desired results were reached at the end of the procedure (on the 10th day of treatment course), and analgesic effect lasted throughout the 12 months of follow‐up. At the end of the study, although 26/43 (61.5%) of patients remained mild pain and pain completely disappeared in only 17/43 (38.5%) of individuals, all of them indicated satisfaction with the efficacy of this pain treatment. Only one 74‐year‐old female patient with HZ at lower thoracic (D9‐D12) area, 12 months after intervention, reported intermittent mild intra‐abdominal pain with VAS‐score of 3 (before treatment VAS‐score of 9), but the cutaneous symptoms cleared completely with this treatment. Therefore, the patient did not require any further intervention.It has been known that neural and perineural inflammation, peripheral sensitization of primary afferent sensory nerve fibers, and central sensitization are thought to be responsible for PHN.refractory PHN. In the literature, we found a small number of studies with other options to manage this condition. In a work conducted by Kotani and colleagues in 2000, that using the intrathecal methylprednisolone for therapy, PHN‐patient who was resistant to conventional regimens and showed a good and excellent result.The mixture of corticosteroids and local anesthetics has been broadly used to treat numerous disorders with neuropathic pain, including treatment and prevention of HZ and PHN,4.1The subcutaneous injection of methylprednisolone in combination with lidocaine is an invasive intervention, thereby technique and medication‐associated complications can occur during or after procedure. Local complications such as abscesses, cutaneous atrophy, and scarring have been reported in previous investigations,4.2A major limitation in this research was the lack of a control group for comparison. However, as earlier described, prior to enrolling, all available conventional medications for PHN management had been prescribed for the patients, but they all showed no response or tolerance. Therefore, we did not establish control groups as patients were treated with the above drugs. Ideally, the standard control group in our study should have been treated with subcutaneous injection of saline solution alone (placebo), but it would have been impossible because of different reasons as mentioned in previous studies.4.3Despite the abovementioned limitations, the method described in our study offers many advantages. Firstly, it is highly effective and safe. The excellent results reach 100% and exceed the initial expectations while the major complications are not seen, and all side effects are mild and reversible. Secondly, the intervention presents as a simple procedure because it only requires a syringe and a needle as an equipment that is easily available at any hospital or clinic. Additionally, any physician can implement this treatment method. Lastly, this treatment can be applied to the treatment of HZ at any site of the body. This point is superior to other interventions such as intrathecal or epidural injection; paravertebral block, which cannot be applied for PHN involving the trigeminal nerve.In conclusion, the results indicate that subcutaneous injection of methylprednisolone acetate and lidocaine can be an effective and safe treatment for refractory PHN.The authors declare no potential conflict of interest.Conceptualization: Duc Thuan Nguyen, Thanh Chung Dang, and Quang An NguyenData Curation: Duc Thuan Nguyen, Thanh Chung Dang, and Quang An NguyenFormal Analysis: Trung Duc Le, Thi Dung Hoang, Thi Ngoc Truong Tran, Ta Hai Ninh Duong, Van Tuan Nguyen, Van Quan Le, Tien Ung Hoang, Minh Tuan Duong, Dinh Son Nhu, and Viet Nga PhanInvestigation: Trung Duc Le, Thi Dung Hoang, Thi Ngoc Truong Tran, Ta Hai Ninh Duong, Van Tuan Nguyen, Van Quan Le, Tien Ung Hoang, Minh Tuan Duong, Dinh Son Nhu, and Viet Nga PhanMethodology: Duc Thuan Nguyen, Thanh Chung Dang, and Quang An NguyenResources: Trung Duc Le, Thi Dung Hoang, Thi Ngoc Truong Tran, Ta Hai Ninh Duong, Van Tuan Nguyen, Van Quan Le, Tien Ung Hoang, Minh Tuan Duong, Dinh Son Nhu, and Viet Nga Phan.Supervision: Duc Thuan Nguyen, Thanh Chung Dang, and Quang An NguyenWriting—Original Draft Preparation: Duc Thuan Nguyen, Thanh Chung Dang, and Quang An Nguyen.Writing—Review and Editing: Duc Thuan Nguyen, Thanh Chung Dang, and Quang An NguyenAll authors have read and approved the final version of the manuscript.Corresponding author, Duc Thuan Nguyen, had full access to all the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.Author Duc Thuan Nguyen (lead author) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained.In our study, there are no funding sources or financial supports. Therefore, there is no conflict of interest.FIGURE S1 The affected skin was divided into a chessboard for injection Click here for additional data file.FIGURE S2 Subcutaneous hemorrhage after injection Click here for additional data file.TABLE S1 Mean score of quality of life of study population before and after treatmentClick here for additional data file.


The increased awareness of discrepancies between self-reporting outcome measurements and objective outcome measurements within the field of neuromodulation has accelerated the search towards more objective measurements. The aim of this study was to evaluate whether an electronic nose can differentiate between chronic pain patients in whom Spinal Cord Stimulation (SCS) was activated versus deactivated. Twenty-seven patients with Failed Back Surgery Syndrome (FBSS) participated in this prospective pilot study. Volatile organic compounds in exhaled breath were measured with electronic nose technology (Aeonose™) during SCS on and off states. Random forest was used with a leave-10%-out cross-validation method to determine accuracy of discriminating between SCS on and off states. Our random forest showed an accuracy of 0.56, with an area under the curve of 0.62, a sensitivity of 62% (95% CI: 41–79%) and a specificity of 50% (95% CI: 30–70%). Pain intensity scores were significantly different between both SCS states. Our findings indicate that we cannot discriminate between SCS off and on states based on exhaled breath with the Aeonose™ in patients with FBSS. In clinical practice, these findings imply that with a noninvasive electronic nose, exhaled breath cannot be used as an additional marker of the effect of neuromodulation. One of the treatment options for a variety of chronic pain conditions is Spinal cord stimulation (SCS), a minimally invasive neuromodulation technique . SCS is One of the latest non-invasive technologies that has gained attention during the last decade is the use of electronic noses to measure exhaled breath and more specifically volatile organic compounds (VOCs), which could be used a more objective tool to evaluate the effects of output mechanisms of pain and neuromodulation. Electronic noses are preferred above gas chromatography or mass spectrometry since the latter are complex, costly and time-consuming , compareSince exhaled breath contains hundreds of different VOCs, each individual has a unique volatile chemical breath print . ElectroIn this study, patients with FBSS who received treatment with SCS at the department of Neurosurgery of Universitair Ziekenhuis Brussel were invited to participate. Every six months, according to routine clinical care at this center (and regulated by reimbursement rules), all patients have a standard clinical visit regarding their treatment progress. Those patients who were scheduled for a 6-month SCS follow-up visit, were invited to take part. Only patients with a minimum age of 18 years were allowed to participate. Patients were not allowed to take part in the study if they were previously diagnosed with major psychiatric problems, previously received a diagnosis of cancer or if they have an underlying respiratory disease.The study protocol was approved by the central ethics committee of Universitair Ziekenhuis Brussel (B.U.N. 1432020000074) on 27 May 2020. The study was registered on clinicaltrials.gov (NCT04469738) on 14 July 2020. All patients provided written informed consent before participation. The study was conducted according to the revised Declaration of Helsinki (1998).This is a pilot study with an experimental design, consisting of a single outpatient visit. All patients who took part in this study were instructed to switch off SCS 12 h before their study visit . During All patients were asked to confirm that they switched off SCS 12 h before the study visit. This statement was controlled by evaluating whether SCS was effectively switched off  when patients presented themselves for the study visit. No specific instructions regarding medication use where provided, so patients could continue with their current medication on the day of the measurements.The Aeonose™  is a handheld, battery-powered electronic nose which enables to analyse volatile organic compounds. When breathing through the device, exhaled breath is guided over three small hotplate metal-oxide sensors, which behave as semi-conductors at higher temperatures . The metPatients were instructed to inhale and exhale through a disposable mouthpiece of the Aeonose™ for 5 consecutive minutes. To ensure all air circulation went through the Aeonose™, patients received a nose clamp (to exclude nose breathing) and were instructed to enclose their lips over the mouthpiece at all times. Additionally, to eliminate exogenous influences on breath patterns, the mouthpiece contained a carbon filter to ensure the air was filtered and a HEPA filter to prevent contamination of the internal tubing of the device . To furtThe Visual Analogue Scale (VAS) was used to assess current pain intensity for low back pain and leg pain separately. Therefore, a 10 cm line was provided to all patients in paper format, representing a continuum between no pain and maximal pain. Pain intensity is expressed in mm on a scale from 0 to 100. Patients completed this questionnaire twice; once when SCS was switched off for 12 h and once when SCS was reactivated for 30 min. The VAS pain score is a reliable and valid tool that is sensitive to change ,29,30,31The Medication Quantification Scale III (MQS) was used to quantify medication use . For eacDue to the lack of previous studies in this population, an exact sample size calculation for this pilot study was deemed unfeasible. For a standard proof-of-concept study with an electronic nose, 25 patients are required ,34. Therp-values of 0.05 or less were considered statistically significant. Descriptive statistics are provided as mean (± SD) or as median (first and third quartile). A simple regression model was built with pain intensity scores as outcome variable and the on and off state of SCS and pain location (low back or leg) as explanatory variables. An automatic step function was applied to withheld relevant predictors.All descriptive analyses were performed in R Studio version 1.4.1106 . Data analysis of exhaled-breath patterns was performed by Aethena, a proprietary software program  which performs data compression, data classification and data reporting based on the raw data. The goal was to build a classifier to discriminate between both SCS groups (activated or deactivated). First, feature extraction was performed for data compression. Then, generated vectors were normalized and entered into a random forest . Finally, leave-10%-out cross-validation was applied to determine the performance of the created model.2. Twelve females (46%) and 14 males (54%) were included. The median duration that patients were implanted with SCS was 5.5 (Q1–Q3:2–8) years. The median score on the MQS was 9.15 (Q1–Q3:6.22–16.65). Patient characteristics are provided in In total, 27 patients were included in this study. All experiments were conducted between 12 December 2020 and 27 March 2021. One patient had a vagal syncope during the experimental measurement when SCS was switched off, wherefore the experiment was immediately terminated for this patient. Data of this patient were not included in the analysis, leading to a final dataset of 26 patients. Patients had a mean age of 56 (SD: 10) years and a median BMI of 27 (Q1–Q3:26–30) kg/mp < 0.001) on pain intensity. Pain location (low back or leg) was not withheld in the final model . Pain intensity scores were significantly different between both SCS states with median values of 65 (Q1–Q3:36–78.50) and 56 (Q1–Q3:34–72.25) during SCS off states and 30.50 (Q1–Q3:7.50–48.25) and 14.50 (Q1–Q3:3.25–43) during SCS on states for low back and leg pain, respectively. A simple regression model for pain intensity scores revealed a significant effect of SCS condition , specificity as true negatives/, positive predictive value as true positives/ and negative predictive value as true negatives/. Abbreviations. NPV: negative predictive value, PPV: positive predictive value, SCS: spinal cord stimulation, sens: sensitivity, spec: specificity.In this study we evaluated whether an electronic nose, by means of exhaled volatile organic compounds analysis, can discriminate between SCS on (activated for 30 min) and SCS off (deactivated for 12 h) states in patients with FBSS. Modern electronic nose technology is not focusing on individual compounds but creates a pathology-dependent signature, reflecting overall exhaled volatile organic compound content. For several pathologies, a specific nose  is developed that is able to diagnose certain diseases compared to a group without the disease, for example noses to diagnose tuberculosis , breast One of the potential explanations of this negative trial can be found in the lack of knowledge about wash-in periods of SCS in general and more specifically on the respiratory system. Up till now, the exact wash-in period of SCS is not yet unravelled, wherefore a time period of 30 min  was This is the first study exploring the use of an electronic nose in the context of neuromodulation. A literature review concluded that in order to better understand the complete mechanisms of action of SCS, it is necessary to carry out properly controlled experiments with objective outcome measures . SeveralIn this study, several limitations should be taken into account. We first need to acknowledge that patients were not instructed to omit the use of analgesics due to ethical reasons which could have influenced the results. It is suggested that medication could influence the concentration of volatile metabolites . A studyOur findings indicated that discriminating between SCS off and on states in patients with FBSS was not possible with exhaled breath, measured with Aeonose™.


This study investigated quantifiable measures of cutaneous innervation and algesic keratinocyte biomarkers to determine correlations with clinical measures of patient pain perception, with the intent to better discriminate between diabetic patients with painful diabetic peripheral neuropathy (PDPN) compared to patients with low-pain diabetic peripheral neuropathy (lpDPN) or healthy control subjects. A secondary objective was to determine if topical treatment with a 5% lidocaine patch resulted in correlative changes among the quantifiable biomarkers and clinical measures of pain perception, indicative of potential PDPN pain relief. This open-label proof-of-principle clinical research study consisted of a pre-treatment skin biopsy, a 4-week topical 5% lidocaine patch treatment regimen for all patients and controls, and a post-treatment skin biopsy. Clinical measures of pain and functional interference were used to monitor patient symptoms and response for correlation with quantitative skin biopsy biomarkers of innervation (PGP9.5 and CGRP), and epidermal keratinocyte biomarkers . Importantly, comparable significant losses of epidermal neural innervation  and dermal innervation were observed among PDPN and lpDPN patients compared with control subjects, indicating that innervation loss alone may not be the driver of pain in diabetic neuropathy. In pre-treatment biopsies, keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling were all significantly increased among PDPN patients compared with control subjects. Importantly, no keratinocyte biomarkers were significantly increased among the lpDPN group compared with control. In post-treatment biopsies, the keratinocyte Nav1.6, Nav1.7, and CGRP immunolabeling intensities were no longer different between control, lpDPN, or PDPN cohorts, indicating that lidocaine treatment modified the PDPN-related keratinocyte increases. Analysis of the PDPN responder population demonstrated that increased pretreatment keratinocyte biomarker immunolabeling for Nav1.6, Nav1.7, and CGRP correlated with positive outcomes to topical lidocaine treatment. Epidermal keratinocytes modulate the signaling of IENF, and several analgesic and algesic signaling systems have been identified. These results further implicate epidermal signaling mechanisms as modulators of neuropathic pain conditions, highlight a novel potential mode of action for topical treatments, and demonstrate the utility of comprehensive skin biopsy evaluation to identify novel biomarkers in clinical pain studies. Diabetes continues to be an increasing epidemic as treatment for sequela associated with the disease remain limited –4. CurreDiscovered in the late 1980's, a human pan-neuronal enzyme, designated PGP9.5 (PGP), was used to develop an antibody biomarker . PGP immA predominant hypothesis for this paradox is the “irritable nociceptor” which posits that the remaining C-fibers have undergone a structural and/or neurochemical pathological change that renders them hypersensitive to noxious or even non-noxious stimuli , 26–28. PGP immunodetection of IENF has become the accepted diagnostic of SFN in chronic pain, however PGP has no known direct effect on neuronal signaling as a mechanistic biomarker and does not consistently validate subjective patient perceptions of chronic pain intensity , 47–53. Our first objective was to use CMA on skin biopsies in an open-label proof-of-principle clinical trial to determine if mechanistically-relevant pain biomarkers had quantitative correlation to subjective pain perception among diabetic patients ranging from high to low level neuropathy pain as compared to normal subjects. Based on the evidence for Nav involvement in chronic pain, our second objective used topical 5% lidocaine patch applications to test whether any of the patients received clinical benefit that correlated with the quantifiable biomarkers measured with CMA from pre-treatment and post-treatment skin biopsies. The skin biopsy CMA focused on quantifying biomarkers among two components: the C-fiber innervation and the epidermal keratinocytes. Expanding on prior quantification of PGP for IENF in diabetic patients, our analysis distinguished between two major functionally different types of C-fiber – peptidergic and non-peptidergic – that might be differentially affected as a potential marker of chronic pain , 47, 48.Recent optogenetic evidence has now confirmed prior immunolabeling studies implicating epidermal keratinocytes in modulating the sensitivity of C-fibers through an expression and release of a mixed variety of neurotransmitters involved in algesic, analgesic, and pruritic mechanisms , 71–82. All clinical research portions of this study were conducted under IRB approval from Albany Medical College (2008–2324) and all clinical procedures were carried out at Albany Medical Center, Albany, NY, USA. Each subject was informed of the entire study process and consented to all testing parameters, procedures, and use of biopsy material for research purposes. The open-label clinical research study was registered with ClinicalTrials.gov (identifier number: NCT01086150) as a means to increase enrollment.The study was designed to enroll 40 patients  and 10 age- and gender-matched control subjects. All enrolled patients met the Toronto criteria for confirmed clinical diabetic sensorimotor polyneuropathy . The finFollowing the patient clinical assessments, all study subjects (controls and patients) had a 3 mm glabrous skin punch biopsy collected from the lateral margin of one foot, about half-way between the heel and base of the fifth toe, where QST testing was performed. The lateral foot site was chosen because it is a more prevalent and intense pain location reported by diabetic patients as compared to the more proximal location 5 cm above the lateral malleolus that has become a standard biopsy site used for SFN diagnosis in most human chronic pain afflictions, including PDPN. Moreover, the lateral foot has a greater variety and concentration of peripheral innervation, including large-caliber myelinated non-painful tactile varieties of innervation that are also impacted by diabetes, making this location optimal for QST testing. Finally, the lateral foot has a higher concentration of microvascular arbors and neurovascular innervation. While not included in this report, the myelinated innervation and neurovascular components within the same biopsies will be the subject of future studies. All study subjects were subsequently monitored for 7 days following biopsy collection and patient groups kept daily diary NRS records of pain and sleep disturbance prior to beginning topical treatment .After the 1-week pre-treatment period, all study subjects returned to the clinic, healthy control subjects were screened for any difficulties from biopsy collection or changes in pain status, of which none were reported. Of the initial 40 diabetic subjects enrolled and biopsied at baseline, 33 continued onto the study drug phase. One patient was removed for increased glucose levels, and 6 withdrew for various undisclosed reasons. None of the withdrawals were associated with negative consequences of pre-treatment biopsy collection, there were no reports of negative consequences following the pre- or post-treatment biopsies, and all patients were not in a stage of disease with any tissue healing issues or loss of tissue integrity. The patient groups completed a VAS measure, and after which the patients and healthy subjects initiated applications of a 5% lidocaine patch  directly to the area of foot pain for those with PDPN (including the biopsy site location) or over the lateral dorsum (including the biopsy site) of the foot for those with lpDPN and controls, using a maximum of 4 patches per day (2 every 12 h) over a 4-week topical treatment protocol. Following completion of the 4-week treatment period, repeat neurological examination, QST, VAS, BPI, NPS, NIS-LL, and NSS were performed/administered to the patient groups, and all study subjects had a post-treatment skin biopsy collected at a site 1 cm proximal to the initial biopsy site see . PatientStandard demographic  and clinical data , and quantitative sensory testing (QST) were collected from all study subjects, and subjective clinical measures  were obtained from the PDPN and lpDPN patients to assess pain and functional symptoms at pre-treatment and after the 4-week topical treatment protocol. Daily pain and sleep disturbance diaries  were maintained during the 1-week pre-treatment period and during the 4-week patch treatment period see .Quantitative Sensory Testing was performed at the lateral foot using standardized methods with values for cold and warm detection and heat pain thresholds used for determination of small fiber functionality .The Visual Analog Score (VAS) is a simple measure of subjective pain rated on scale of 0–100 (or 0–10) with terms of no pain (0) through worst pain imaginable (100 or 10), presented here as a simple 100 mm line for patients to mark at the distance that corresponds to the level of their perceived pain.Numerical Rating Score  were used for the daily diary pain measures, as no pain (0) through worst pain (The Brief Pain Inventory (BPI) records the subjective pain experience during the previous 24 hr , as well as the level to which pain interfered with normal routines (daily life interference index). Pain severity and pain interference are rated from 0 (no pain/interference) to 10 (incapacitating pain/interference). The BPI is a self-administered single page questionnaire addressing how the patient perceives the pain and the degree that the pain caused interference with normal daily activity, mood, work, interpersonal relations, sleep, and overall quality of life. Reports demonstrate strong internal consistency and reliability for the BPI in patients with chronic pain and diabetic neuropathy , 86.The Neuropathic Pain Scale measures the following 10 aspects of pain, each on a scale of 0–10 : intensity, unpleasantness, hot, cold, sharp, dull, itchy, skin sensation (sensitivity), surface pain, and deep pain. The NPS Composite Score (NPS 10) is the sum of all 10 NPS descriptors . Although the NPS can be used to further render multidimensional aspects of neuropathic pain into several different composite scores , we used the full composite NPS10 scores to evaluate responsiveness.Sensation . The components of the sensory examination, except for joint position, are assessed on the dorsal surface at the base of the right and left great toenails. Joint position is assessed by moving the terminal phalanx of the right and left great toes. Sensory assessment is scored as 0 , 1 (decreased), or 2 (absent). Four assessments are performed bilaterally creating a maximum possible score of 16. Reflexes. Reflex assessment is scored as 0 , 1 (decreased), or 2 (absent), with adjustments made for the patient age . Two assessments are performed bilaterally creating a maximum possible score of 8. Muscle weakness. Muscle weakness is scored as 0 , 1 (25% weak), 2 (50% weak), 3 (75% weak), 3.25 (move against gravity), 3.5 , 3.75 , or 4 . Eight assessments are performed bilaterally with a maximum possible score of 64.The Neuropathy Impairment Score is a composite clinical scoring system used to measure the functional impairment of peripheral neuropathy, and the NIS-LL is a lower limbs specific subset of the NIS used to evaluate the location which most often presents the earliest symptom onset in PDN . The NISNeuropathy Symptom Score (NSS) is a clinical scoring scale that measures the positive and negative symptoms associated with neuropathy. The questionnaire asks the patient 31 questions based on 3 general symptom groups, 1) muscle weakness in various muscle groups or while performing daily tasks, 2) sensory disturbances such as difficulty with identifying objects in the mouth or hand or burning/numbing sensations at any location, and 3) autonomic symptoms such as fainting or abnormal appetite, sweating or eye sensitivity. The score is the sum of all “yes” responses (0–31), with a higher number indicating an increased degree of neuropathy.All biopsies were processed, immunolabeled, and evaluated following standard INTiDYN ChemoMorphometric Analysis (ITD-CMA™) protocols using routine published methodologies , 88, 89.Following primary antibody incubations, slides were rinsed in excess PBS and then incubated with appropriate species secondary antibodies conjugated with either Cy3 (red fluorescence) or Alexa488 (green fluorescence) diluted 1:500 in PBS-T at room temperature for 2 hrs. The DNA binding protein DAPI  was also included in the secondary antibody mix to stain cell nuclei (blue fluorescence). After secondary antibody labeling, slides were rinsed in excess PBS and mounted under coverslips with 90% glycerin in PBS with 0.05% sodium azide, and stored at −20°C until analysis.n = 15 measures per biopsy analyzed using the freely available ImageJ software (v1.51).Epifluorescent 20x microscopy image montages of PGP immunolabeling from each biopsy were captured and used to quantify the cutaneous innervation with Neurolucida software  mapping routines, including epidermal, subepidermal, and upper dermal compartments. For epidermal keratinocyte assessments, Nav1.6, Nav1.7, and CGRP epifluorescence microscopy images were obtained with a Hamamatsu ER DVC high-speed camera and linear focus encoder which was also operated with the Neurolucida software package. At least 5 non-edge and non-overlapping fields from 3 separate sections for each biomarker assessment were captured at identical camera settings and average pixel intensity (PI) values of T-test, or ANOVA with Tukey-Kramer post-hoc testing) and those without normality were compared by non-parametric methods , as shown  prior to implementation of treatment, a MANOVA was used  were analyzed across the three cohort groups  using Microsoft Excel v2010) with Analyze-it  add-in functions. Collected data sets that passed the Anderson-Darling normality test were analyzed for between-group comparisons by parametric methods . There were 11 control, 12 lpDPN, and 21 PDPN group subjects. Correlative results indicated that gender across the groups was not significantly different, χ2[2] = 1.05, p = 0.59. One subject identified as a person of color, and all others identified as Caucasian. Ages between groups were statistically significant, F = 5.22, p < 0.01. Follow up analysis adjusting for multiple tests indicated that the control group (M = 46.18) was significantly younger than the lpDPN group (M = 58.58). No differences were found between the age of diabetes onset, diabetes duration, or neuropathy duration between the lpDPN and PDPN patient groups. No significant differences were found between groups on BMI, F = 2.52, p = 0.09. Significant differences were seen between groups on HbA1c, F = 23.66, p < 0.01. Follow up analyses, correcting for multiple tests, indicated that the control group was significantly lower than both the lpDPN and PDPN groups, but no significant difference was found between the lpDPN and PDPN groups. Significant differences were noted on systolic BP, F = 3.95, p < 0.05, and follow up analyses, correcting for multiple tests, found the PDPN group was significantly higher than the control group. No significant differences were found between groups on the diastolic BP measure. Additional correlational analysis demonstrated that neuropathy duration, previous use of anti-cancer, anti-coagulant, anti-depressant, NSAID, or sleeping aid drugs, or previous/current comorbid allergy/immune, asthma, migraine, psychiatric, or thyroid disorders were not correlated with any pre-treatment biopsy measures. In contrast, weight, BMI, systolic BP, HbA1c, previous use of anti-hypertensives, gabapentin, or narcotics, or previous/current comorbid gastrointestinal, hypertension, or musculoskeletal disorders had at least one significant correlation (p < 0.05). These additional correlative results will be followed-up in future studies.Composite pain scores  demonstrp < 0.05 by paired Student's t-test) following topical treatment  = 3.76, p < 0.001, and follow up ANOVA of individual outcome variables indicated that all variables showed significant differences. To follow up, a Bonferroni adjustment was made when evaluating differences between groups on all outcome variables.To evaluate the impact of topical 5% lidocaine on cutaneous innervation, skin biopsies were immunolabeled using anti-PGP, a neuron-enriched marker well-characterized to label all cutaneous innervation . DetaileThe results indicate that all biopsy PGP innervation markers  were able to significantly differentiate between the control and PDPN groups, and three of the four PGP measures  were also able to significantly differentiate between the control and lpDPN groups . No innevia Nav channels, likely has effects on the CGRP-positive peptidergic axons within the dermis that mediate vasogenic inflammatory responses, co-express TrpV1, and likely play a role in pain perceptions  = 1.06, p = 0.41. These results indicate that while there were pre-treatment differences between groups across the keratinocyte biomarkers, after the course of treatment and adjusting for pre-existing differences on those measures, the markers no longer showed significant differences across groups after the treatment.To investigate keratinocyte immunofluorescent labeling pixel intensity (PI) levels for the presumptive algesic neurosignaling molecules Nav1.6, Nav1.7, and CGRP, PI from identically captured images were analyzed. Representative images of Nav1.6, Nav1.7, and CGRP immunolabeling used for analysis are shown in n = 14) of the participants being classified as non-responders (NON) and 58% (n = 19) as responders (RESPONDER). Subsequently, to determine what extent pre-treatment variables could predict effective response to topical lidocaine, logistic regression models were performed. The first logistic model utilized the pre-treatment keratinocyte biomarker Nav1.6 to predict responder status. The regression model was significant, χ2[1] = 8.67, p < 0.05, and R2 = 0.31. The model correctly classified 26 of 33 total participants (79%). Sensitivity was 84% and specificity was 72%. These results suggest that pre-treatment keratinocyte Nav1.6 expression was a statistically significant predictor of responder status. A second logistic model used the pre-treatment keratinocyte biomarkers Nav1.7 and CGRP as independent measures to predict responder status. The regression model was significant, χ2[1] = 12.50, p < 0.05, and R2 = 0.42. The model correctly classified 28 of 33 participants (85%). Sensitivity was 90% and specificity was 79%. These results suggest that the pre-treatment keratinocyte biomarkers Nav1.7 and CGRP were also statistically significant predictors of responder status. A third logistic model was used to evaluate the clinical measures  as predictors of responder status. This model was not statistically significant, χ2[1] = 6.50, p = 0.27, and R2 = 0.25, indicating that these measures do not appear to have predictive value.The lpDPN and PDPN cohorts were evaluated for response to topical lidocaine treatment based upon a 30% reduction in VAS scores. This analysis resulted in 42%  endings, have inhibitory and excitatory neurosignaling capabilities that may involve Nav subunit and/or CGRP expression , 79, 81.Our assessments of IENF density of PGP labeling confirmed prior reports of a consistent and significant paradoxical reduction  among the PDPN patients as compared to that in normal subjects, but there was no significant correlation between the severity of IENF reduction and patient perceptions of pain severity , 48, 51.Also seen in other chronically painful peripheral neuropathies, electrophysiological evidence of increased sensitivity and spontaneous activity among the remaining innervation is the basis for the irritable nociceptor hypothesis of spontaneous hyperactivity. This prevailing theory for the seemingly paradoxical loss of nociceptors is based on electrophysiological evidence that chronic neuropathic pain may be mediated by a hypersensitivity of the remaining innervation. Importantly, comparable losses among both lpDPN and PDPN indicate that reduced innervation is not itself a precipitator of chronic pain among diabetic patients. There are different reasons that reductions in presumed C-fiber nociceptors occurs among a variety of chronic pain afflictions, of which some are obvious such as after nerve traumas or infections such as acute herpes zoster that may be consistent triggers for pathological chronic pain mechanisms. The loss of innervation in lpDPN patients may be due to any of the numerous diabetic pathophysiologic mechanisms, including hyperglycemia, chronic inflammation, and ROS generation that are detrimental to vulnerable C-fibers, yet without inducing pain , 66–70.in vitro, which is a direct activator of small fiber axons  subjects that had resolved with severe PHN  shows a response that mimics the drug treated group, thereby eliminating any statistical differences. This study utilized an open-label design and all patients and control subjects received drug treatment. There was not a true placebo group for this study. Therefore, the positive  clinical responses of the responder subgroup of the PDPN cohort are presumed to be pharmacologic in nature , although the chance for a placebo effect related to subjective pain symptoms, in the absence of pharmacology, remains a possibility.This current study was an open-label proof of principle study that was not designed to assess efficacy of the lidocaine patch in PDPN, Altogether, the results indicate that cutaneous innervation loss  does not fully explain the pain phenotype in diabetic neuropathy. That efficacious topical treatment associated with keratinocyte Nav1.6 and Nav1.7 channels and CGRP immunolabeling, and specifically that epidermal keratinocyte biomarker levels correlated with pain reduction, implicates these mechanisms as potential contributors to the pain phenotype. Continued clinical research with comprehensive skin biopsy analysis will continue to uncover novel biomarkers and drug targets for chronic neuropathic pain, including keratinocyte/neuron interactions, which may be treated through rationally designed topical therapies.The original contributions presented in the study are included in the article/supplementary materials, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by Albany Medical College. The patients/participants provided their written informed consent to participate in this study.PA, JW, CA, and FR were involved in all aspects of the study. GH was involved in morphologic data collection, analysis, and interpretation. GH, ER, MD, MC, and JB were involved in clinical and morphologic data collection, analysis, and writing. All authors contributed to the article and approved the submitted version.Funding for this clinical pain research project was provided, in part, through an investigator-initiated grant mechanism from Endo Pharmaceuticals (awarded to CA), by the Center for Neuropharmacology and Neuroscience at Albany Medical College, and by Integrated Tissue Dynamics, LLC (INTiDYN). All authors conceived, planned, performed, analyzed/interpreted the data, and documented the findings without input from Endo Pharmaceuticals.GH, ER, and MD are employed by INTiDYN. JB was a paid consultant of INTiDYN. PA and FR are owners of INTiDYN. INTiDYN remains a private company with no stock or options conflicts. The remaining 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Hashimoto thyroiditis (HT) may lead to muscle weakness due to hypothyroid dysfunction. However, clinical experience treating patients with HT suggests that neuromuscular symptoms may develop in these patients despite long-standing euthyroidism.In 24 euthyroid patients with HT and 25 healthy controls, physical fatigability was assessed using the arm movement test (AMT) and 6-min walk test (6MWT). Fatigability was based on calculation of linear trend (LT) reflecting dynamic performance within subsequent constant time intervals. Perception of physical fatigue and muscle pain was analyzed using fatigue (FSMC) and pain questionnaires. Obtained results were correlated with clinical, neurophysiological and lab findings.p = 0.002). Neither pain score nor physical fatigue score showed a correlation with LT in 6MWT nor did mood, or anti-TPO antibody titer.HT patients showed a negative LT in 6MWT significantly differing from stable performance in controls. LT in AMT did not differ between HT and controls. FSMC scores and pain perception revealed significantly higher levels in HT patients than in controls. Physical FSMC score was primarily influenced by pain perception (standardized regression coefficient, beta = 0.633, A significant physical fatigability could be shown in euthyroid HT patients despite missing obvious neuromuscular deficits in routine testing. Further, elevated pain and fatigue perception in HT patients seem to contribute to nonspecific muscle complaints in these patients. A possible pathogenic role of thyroid autoimmunity in hidden neuromuscular involvement may be suggested. It is well known that neuromuscular symptoms can be associated with thyroid dysfunction. Here, muscle weakness is observed more in hypothyroidism than in hyperthyroidism, exhibiting clinical features that suggest functional myopathy . HashimoProspective data on neuromuscular involvement in HT patients are rare. The aim of this study therefore was to investigate the prevalence of neuromuscular symptoms and to assess objective motor fatigability in euthyroid HT patients beyond electrophysiological findings, muscle pain, and subjective fatigue.M = 36.1, SD = 13.5) were prospectively included in the study  aged 21 to 69 years  and 25 healthy controls  aged 23–64 years  was used to quantify maximal strength (in pounds) in isometric contraction of the hand (determined in 3 runs).After inclusion in the study, all patients were carefully clinically examined. In all patients, rheumatic disease was excluded according to the American Rheumatic Association criteria . SensoryIn addition, nerve conduction velocities (NCV) of sural and tibial nerves, including F-waves, were measured. A NCV of at least 40 m/s and amplitudes of at least 5 mV  and 5 µV  were deemed as normal. An electromyography (EMG) of vastus, tibial, and paravertebral muscles of 10th thoracal level was performed.In a sitting position, subjects were asked to hold a standardized item weighing 500 g  with the arm horizontally outstretched and to move it repeatedly between 2 points, forming a horizontal quarter circle as rapidly as possible. Within 90 s of testing, the number of correct bottle placements (taps) was assessed in 6 subintervals (15 s each). The mean number of taps per subinterval was indicated as individual motor performance level in AMT. RNS of accessory nerve was performed directly within 1 min before and after finishing the test to unmask any neuromuscular transmission defect .Performance of 6MWT followed a standard protocol . ParticiAdditionally, HT patients and control subjects completed the following validated questionnaires:Fatigue Scale for Motor and Cognitive Function (FSMC) . This 20Pittsburgh Sleep Quality Index (PSQI), an 18-item assessment of subjective sleep quality during the preceding 4 weeks .Center for Epidemiological Studies Depression Scale-Short Form (CES-D-SF) , an assePSQI and CES-D were applied to unmask confounder effects of sleep disturbances on physical performance and perception of fatigue which could be ruled out in regression analysis.Brief pain inventory (BPI) was used to assess pain in both groups . The paiAMT and 6MWT were run after the clinical neurological examination. Before and after completing the tests, participants assessed their current, perceived physical and cognitive performance level using a 10-point Visual Analog Scale (VAS) ranging from one (very low) to 10 (very high).Linear trend (LT) was calculated to measure physical fatigability as the dynamic in AMT and 6MWT performance, using the subsequently recorded number of taps (bottle placements in AMT) and distance achieved (6MWT) within fixed 15-s and 60-s time intervals, respectively , 15, 25.The LT for the 6MWT and AMT was calculated according to the formula below , 15. TheThus, LT was applied to reflect the degree of deviation from a constant course of performance. An LT of 0 describes a stable performance; an LT < 0 indicates a decline in performance and is a correlate of physical fatigability. The LT is independent of the absolute level of performance in accordance with the formula.t test for unpaired samples was run to compare results of HT patients and the control group in the physical testing parameters and the questionnaire scores , which could only be demonstrated neurophysiologically in 2 of the 24 patients. EMG revealed increased insertional activity in 3 of the 24 patients and positive sharp waves in 2 of the 24 patients. Muscle action potential analysis and recruitment pattern did not reveal any abnormalities consistent with myopathy. All clinical and neurophysiological findings are summarized in Table Creatine kinase (CK), myoglobin, and thyroid hormone  levels were normal.All HT patients were negative for ab against titin, muscle specific tyrosine kinase (MuSK) receptor, low-density lipoprotein receptor-related protein 4 (LRP4), aquaporin, glutamic acid decarboxylase (GAD), voltage-gated potassium channels, acetylcholine receptor (AChr) ab, and antinuclear ab.There was no difference between groups in dynamometer grip and motor performance levels in both AMT and 6MWT Table . The mear = 0.69, p < 0.001) but not in AMT. This means that cumulative walking distances were longer in patients with positive LT. An influence of mood (CES-D-SF) and sleep quality (PSQI) as well as pain, ab titer, and Body Mass Index (BMI) on LT could be excluded in regression analysis.In 6MWT, LT in HT patients was negative and significantly differed from the control group, indicating a gradual decrease in walking performance as an objective parameter of fatigability Table , Fig. 2.p < 0.001) and CES-D-SF assessment (p < 0.05)  (5) Table .Self-assessment of the FSMC scores revealed significantly higher fatigue levels in HT patients than in controls as well as increased pain perception Table . Based op = 0.002), whereas an effect of all other correlating factors  could be ruled out in regression analysis.In regression analysis, the physical FSMC score was primarily influenced by pain perception  and PSQI  and the pain interference score also correlated with BMI  and FSMC cumulative score .Pain severity scores moderately correlated with BMI  suggests that common neuromuscular symptoms develop in these patients despite long-standing euthyroidism . In our In the early course of thyroid diseases, sensorimotor axonal neuropathy has been reported in 40% of patients with hypothyroidism and 20% with hyperthyroidism , whereasIn addition, the presence of myopathy has been suspected in HT according to previous case series that included histological data , 26, 28.In our patients, there were no myogenic changes in EMG, but in 5/24 either positive sharp waves or increased insertional activity was found, which might be indicative for some mild myopathy  of myasthenia gravis (MG) patients, including in 4.4% with Graves’ disease, 9% with HT, and 13.4% with antithyroid ab only . MG coexFatigability can be determined by applying the LT method as we previously showed in MG patients . Based op = 0.001)[Consistent with data in MG patients, HT patients with a higher motor walking level showed a reduced fatigability in 6MWT . However = 0.001). This is = 0.001).Based on regression analysis, neither disease duration nor ab titre, pain scores, BMI, mood, or sleep quality scores nor subjective fatigue perception (FSMC) affected objective fatigability. Therefore, we suggest that fatigability in 6MWT seems to be a suitable independent and objective parameter of neuromuscular involvement in HT. The cause of fatigability is not well understood yet. We argue that it might be explained by coexisting hidden autoimmune inflammatory mechanisms and metabolic dysfunction, especially in proximal muscle groups, which contribute to neuromuscular involvement in Hashimoto patients.Patients with HT often report profound fatigue, but also poor sleep quality and both muscle and joint tenderness. However, these symptoms sometimes consistently persist despite a euthyroid status while receiving hormone substitution , 19, 27.In our study, pain perception seems to moderately correlate with BMI and PSQI scores but not with objective fatigability (LT), anti-TPO ab titer, or mood. Mood and sleep quality in HT patients were significantly deteriorated in comparison to controls. However, an influence of mood and sleep on objective physical fatigability measurements or on physical FSMC was not found.In our patients, pain perception did strongly correlate with physical FSMC score in regression analysis (beta = 0.633**). This emphasizes the well-known impact of musculoskeletal pain on the biopsychosocial perspective, including its downstream effects on contextual factors, such as sleep interruption, fatigue, depressed mood, activity limitations, and participation restrictions . This shIn our study, a significant physical fatigability could be shown in euthyroid HT patients. Fatigability may develop despite normal clinical, neurophysiological, and laboratory criteria. Furthermore, pain and fatigue were significantly elevated in HT patients and correlated with each other. Our findings strengthen the theory of a possible pathogenic role of thyroid autoimmunity in hidden neuromuscular involvement and nonspecific muscle complaints in these patients. Therefore, conducting LT testing in 6MWT to evaluate walking fatigability might constitute a valuable additional diagnostic tool. Increased attention to pain and fatigue assessment may help to manage symptoms better in HT patients.


Recurrent hemarthrosis that begin in childhood lead to progressive joint deterioration. Patients with haemophilia have chronic pain, functional disability and a reduced perception of health-related quality of life.To analyse the perceived quality of life of adult patients with haemophilic arthropathy and its relationship with pain, joint condition, kinesiophobia and catastrophism.36-Item Short Form Health Survey), perceived usual and maximum pain , joint condition , kinesiophobia  and catastrophism  were assessed. Sociodemographic, clinical and therapeutic variables and drug consumption for pain control were collected. Descriptive statistics used means and standard deviations. The correlation of quality of life with the dependent variables was calculated with the Pearson correlation test. The differences in quality of life as a function of the binomial variables were calculated with Student’s t-test for independent samples.Eighty-three adult patients with haemophilia were included in this multicentre, cross-sectional, descriptive study. Perceived quality of life (p < .05) with all items of quality of life questionnaire. Kinesiophobia correlated (p < .05) with all items of quality of life except to role-emotional . Habitual and maximal joint pain correlated with all items except to role-emotional  and mental component score . Catastrophism and weekly drug intake were inversely correlated with quality of life. Age was positively correlated with perceived quality of life. There were differences in quality of life as a function of the severity of haemophilia and the intake of drugs for pain control.Physical component of quality of life perceived by patients with hemophilia is lower than Spanish population (30.51 VS 48.85). Regarding the mental component, patients with hemophilia showed higher values (56.07 VS 49.97). Catastrophism correlated (The perceived quality of life of adult patients with haemophilia is worse than that of the Spanish population. Pain, kinesiophobia, catastrophism, haemophilia severity and the intake of pain-control medication influence the quality of life of these patients. This study identifies the clinical and therapeutic factors that affect the quality of life of adult patients with degenerative haemophilic arthropathy.The perceived quality of life of adult patients with joint damage and the factors that influence the quality of life of adult patients with haemophilic arthropathy were observed.A total of 83 patients with a rare disease and an advanced degree of joint damage were recruited from across the country. Different psychosocial, clinical and therapeutic variables common to all patients with haemophilia were assessed.Pain, kinesiophobia, catastrophism and weekly drug intake are the variables that most influence quality of life. A quality-of-life-based approach should be a fundamental aspect in the treatment of these patients.The severity of haemophilia depends on the clotting factor in functional plasma and is categorized as mild 5–40 % FVIII), moderate 1–5 %) and severe (< 1 %) –5 % and . Prophyl0 % FVIIIThe characteristic clinical manifestation of haemophilia is the development of musculoskeletal haemorrhages, mainly joint bleeding. In 70–80 % of cases, hemarthrosis is located in the knees, elbows and ankles . The lowArthropathy causes changes in joint condition; decreased range of motion; proprioceptive, biomechanical and gait disturbances; and atrophy of the periarticular musculature . As a coQuality of life includes individuals’ perception regarding their position in life within the context and values of the culture in which they live and in relation to their goals, expectations, standards and concerns . PatientProphylaxis versus on demand treatment in adults with severe hemophilia and arthropathy decrease bleeding, pain, and better joint health, activity, satisfaction, and perception of quality of life  Based onThe main objective of this study was to assess the current perceived quality of life in a population of adult patients with haemophilia in different regions of Spain. The secondary objectives were (i) to analyse the correlation of perceived quality of life with the patients’ perceived pain, joint condition, kinesiophobia, catastrophism and coping strategies; (ii) to assess the relationship of quality of life with age and clinical variables ; and (iii) to identify possible modifiable aspects to improve the quality of life of these patients.This was a multicentre, cross-sectional, descriptive study. Data were collected at the national level from March 2018 to October 2019, with the purpose of collecting information on the health status and perceived quality of life of patients with haemophilic arthropathy. The data were collected through face-to-face personal interviews and physical assessments.Patients were recruited from nine patient associations throughout Spain . Patients who were interested in participating in the study and who met the selection criteria contacted the researchers through their respective associations.Haemophilia Joint Health Score (HJHS)) [The inclusion criteria for the study were as follows: patients with haemophilia A or B; patients with a diagnosis of haemophilic arthropathy (more than 3 points on the  (HJHS)) ; and patA record of relevant clinical and sociodemographic data was prepared, and the following questionnaires were used:36-Item Short Form Health Survey (SF-36) scale [Perceived quality of life was measured with the 6) scale . This seJoint condition was measured with the HJHS . This scPerceived pain was measured with a visual analogue scale. The patients were asked about their maximum pain and usual pain in the week prior to the study. This scale has a range of 0 to 10 points (from no pain to maximum perceived pain).Pain Catastrophizing Scale [Catastrophism was assessed with the ng Scale . This scTampa Scale of Kinesiophobia (TSK-11) was used to assess patients’ fear of moving or engaging in physical activity [The activity . We usedactivity  of this activity . The minactivity .Data analysis was performed with the statistical package SPSS Statistics version 25 . Descriptive statistics were calculated using central tendency (mean) and dispersion (standard deviation). The correlation between perceived quality of life and the dependent variables was determined using the Pearson correlation test. Using a one-way ANOVA test, differences in perceived quality of life were analysed as a function of haemophilia severity, treatment type and the development of inhibitors. All results were considered significant at a level < 0.05.www.clinicaltrials.gov (id. NCT03499522).The study was approved by the Ethics Committee of the Virgen de la Arrixaca University Hospital (id. 2020-2-9-HCUVA). The patients signed written informed consent documents before beginning the study assessments. The study was registered with the International Registry of Clinical Trials Eighty-three patients were recruited for this study. The mean age was 43.87 years DT: 10.10), with a mean height of 1.79 m (DT: 0.07), with a mean weight of 85.93 kg (DT: 13.09) and a mean body mass index of 26.62 kg/m2 (DT: 3.48). The majority of the patients had a diagnosis of haemophilia A (83.1 %), received prophylactic treatment (28.9 %) and had a severe phenotype of the disease (85.5 %). 51 patients (61.44) were coinfected with both HIV and HCV. Regarding the consumption of drugs for pain control, the majority of the subjects (69.9 %) used pain medications, with a mean frequency of 4.13 (SD: 2.99) days per week. The most commonly used drugs were celecoxib (32.8 %), NSAIDs (27.6 %), etoricoxib (17.2 %), etoricoxib and celecoxib (8.6 %), celecoxib and NSAIDs (8.6 %) and paracetamol (5.2 %). . The use of drugs for pain control was negatively correlated with all domains (p < .001) except for the total mental health score . Kinesiophobia was negatively correlated with all domains of quality of life (p < .05) except for emotional role .Catastrophism was negatively correlated with all domains of perceived quality of life (p < .05) with most of the domains of quality of life except emotional role  and total perceived mental health . The usual pain perceived by the patients was negatively correlated (p < .05) with all domains except the emotional role and the total perceived mental health.The maximum perceived pain was negatively correlated  and the total mental health score . Elbow joint deterioration presented an inverse correlation with social functioning  and mental health . The degree of ankle arthropathy was negatively correlated with the total perceived mental health .The overall joint condition was negatively correlated only with mental health , general health , vitality , social functioning  and total perceived physical health .  except total perceived mental health . Patients with severe haemophilia indicated worse perceived quality of life (p < .05) in all domains assessed except in total perceived mental health . Patients without inhibitors showed better physical functioning , physical role  and total perceived physical health  than those who had not developed antibodies , we observed that the severity of haemophilia influences the patient’s mental health (t (37.28) = 4.14; r = .56). The intake of drugs for pain influences physical role (t (80.65) = 7.39; r = .63), body pain (t (81) = 6.56; r = .58), vitality (t (75.94) = 5.90; r = .56) and total perceived physical health (t (64.08) = 7.13; r = .66). The type of treatment and the development of inhibitors minimally influenced perceived quality of life (r < .30). . This difference, despite the development of joint sequelae characteristic of adult patients with haemophilia, may be due to patients’ ability to adapt over the years. The stabilization process, the absence of acute processes with the onset of advanced degenerative damage and compensatory measures to overcome physical limitations could lead to better mental perceived mental health among patients with haemophilia.Forsyth et al.  indicateThe patients included in our study had high values for kinesiophobia. This finding coincides with observations for patients with haemophilia that have been reported in previous studies , 35. HigHolstein et al.  reportedThe inverse relationship between joint condition and quality of life has been described by Davari et al. . The conForsyth et al.  indicateThis study aims to increase scientific knowledge regarding the psychosocial variables of patients with haemophilia. These variables influence patients’ experiences of pain, catastrophism and kinesiophobia. Similarly, the clinical situation and psychosocial variables influence the quality of life perceived by these patients.The absence of a relationship between the patients’ joint condition and their perceived quality of life should be a reason to investigate the efficacy of interventions aimed at improving quality of life. Therapies and interventions aimed at improving pain, catastrophism or kinesiophobia, such as motor imagery or movement visualization, could be useful alternatives in the management of these patients.This study has several limitations. The first is that all subjects were recruited in Spain; consequently, these data should be extrapolated taken with caution because in subjective matters such as the perception of quality of life or pain, sociocultural components have a great influence. Therefore, it would be desirable to conduct similar studies in other countries to see if the results are comparable. Second, in this study, only patients with haemophilia A and B were recruited. Therefore, these results cannot be extrapolated to patients with other coagulopathies. Finally, this cross-sectional study only indicates the situation of the population at a given time. Future measurements with the same sample should generate a more reliable view of the patients’ situation, their perceptions over time and the evolution of the disease.The quality of life perceived by patients with haemophilia is lower than that reported by the Spanish population and by patients in other European countries. Pain, kinesiophobia and catastrophism are the main psychosocial variables that are related to a worse quality of life. Clinical variables, such as haemophilia severity and the use of drugs for pain control, are also related to a worse quality of life.