P = .16, I2 = 87.3%). Subgroup analysis did show a significant effect size for patients compared to healthy controls with active disease (1.32) but not for quiescent disease (−0.02). These results suggest that reduced rectal pain thresholds to experimental stimulation are not seen in IBD populations except during active flares of the disease. Further research is required to understand the pathophysiology of chronic abdominal pain in quiescent IBD populations with and without chronic abdominal pain to identify appropriate management strategies.Abdominal pain is a key symptom of inflammatory bowel disease (IBD), particularly in active IBD, but also occurs in patients with quiescent disease suggesting that mechanisms other than active inflammation may be responsible. Putative hypothesis to explain chronic abdominal pain in patients with quiescent IBD includes crossover with irritable bowel syndrome where rectal hypersensitivity is common and has pathophysiological implications. In contrast, in IBD, the role of rectal hypersensitivity has not been established. We aimed to determine if rectal hypersensitivity was more common in IBD compared to a healthy control population. We searched MEDLINE and EMBASE databases (1970–2018). Prospective studies that measured pain/discomfort thresholds to mechanical rectal stimuli in IBD and healthy controls were included. Data were pooled for meta-analysis and effect sizes were calculated with 95% confidence intervals (CIs). Our search strategy identified 222 citations of which 8 met the inclusion criteria, covering 133 individuals with IBD (67 men), aged between 10 and 77 compared to 99 healthy controls (55 men), aged between 10 and 67. The prevalence of rectal hypersensitivity in IBD compared to healthy controls was similar with an effect size of 0.59 (95% CIs: −0.27 to 1.44,  Abdominal pain is a key feature of symptomatic flares of disease where there is significant inflammation. Therefore, one of the main treatment goals is to heal inflammation and achieve a symptom-free remission. However, chronic abdominal pain remains a prominent feature in a significant proportion of patients with quiescent disease.Inflammatory bowel disease (IBD) is characterized by chronic noninfectious inflammation of the GI tract, the 2 most common subtypes being ulcerative colitis (UC) and Crohn’s disease (CD). IBD affects 6.8 million individuals worldwide and its age-standardized prevalence rates are increasing over time putatively as a result of urbanization, increasingly hygienic environments, increased meat consumption, and a lower intake of dietary fiber.8 Factors that have been proposed to explain this overlap include psychosocial stress, genetics, altered microbiome, and aberrant epithelial immunology.9 This crossover though is poorly understood, and it is unclear whether IBD–IBS crossover is similar to the disease pattern of IBS or is a separate entity. When pain is present in quiescent IBD, the cause is incompletely understood, but it is considered that visceral hypersensitivity may exert an important effect.11Around 39% of patients with IBD have irritable bowel syndrome (IBS)-type symptoms, this has been termed IBD–IBS crossover. IBD–IBS crossover is typified by chronic visceral pain, which negatively impacts the quality of life, and is frequently referred to as a functional-organic overlap.12Visceral sensitivity is usually evaluated by measuring rectal sensitivity to mechanical , nutrient, chemical, thermal, or electrical stimuli, to discriminate between hyper, normo, and hyposensate populations. The intensity of pain using such techniques is most commonly measured using a self-report visual analog scale. Rectal hypersensitivity is well studied in IBS and is one of the leading hypotheses for the origin of symptoms in IBS. The basis for rectal hypersensitivity includes alterations both at the peripheral level such as altered barrier function and sensitized afferent nerves and at the central spinal dorsal horn and brain level leading to functional disturbances where physiological stimuli can lead to pain. There is a correlation between the degree of rectal hypersensitivity in IBS patients and symptom severity scores.13 Repeated exposure to experimental provocation stimuli can normalize rectal sensation probably due to habituation.14 However, mechanical stimulation is currently regarded as the most reliable instrument to assess rectal sensitivity.15Provocation tests suffer from significant heterogeneity as distension protocols and definitions for a painful stimulus vary from study to study, although recent international efforts have sought to improve standardization.The primary aim of the study was to assess if pain thresholds to mechanical rectal stimulation are different in the IBD and healthy control population. Secondary aims were to assess if there was a difference between rectal sensitivity in active and quiescent disease.16 The search of the literature was performed using MEDLINE and EMBASE (1970 to June 2018). This was carried out using the set search strategies outlined in The systematic review and meta-analyses were conducted according to the PRISMA recommendations and were registered with PROSPERO (Reference CRD42018095687).Inclusion criteria:Diagnosis of ulcerative colitis or Crohn’s disease.Assessment of IBD and a healthy control population.Measurement of pain/discomfort thresholds using mechanical rectal distension.Prospective study.Exclusion criteria:Testing pain/discomfort thresholds by means other than mechanical such as electrical.Retrospective studies due to the risk of repeat data.The names of the first author, year of publication, location of study, IBD population size, control population size, IBD diagnosis, disease activity, and primary outcome data were recorded in means and standard deviations into an Excel Spreadsheet .17The primary outcome was to determine if there was a difference in pain/discomfort threshold in IBD versus control populations. Secondary outcomes were to determine if the prevalence of rectal hypersensitivity differed in active versus quiescent IBD disease compared to healthy controls. Standard deviations were calculated according to the Cochrane Collaboration guidelines.19 These areas were (1) blinding of assessors, (2) use of aged-matched controls, (3) use of gender-matched controls, and (4) controlling for other known factors that affect pain sensation.Two investigators performed a bias assessment independently for all studies included in the meta-analysis. Bias was scored in 4 areas using a modified checklist for case–control studies.I2 statistical test which gives values between 0% and 100%, with 0% representing no observed heterogeneity. Outcomes were assessed using Hedges’ g effect sizes and are reported with 95% confidence intervals (CIs). A prespecified secondary analysis was performed to determine if the effect size was modified in various subgroups. The statistical criterion was P < .05. Evidence of publication bias was assessed by using a funnel plot and Egger’s test. Propriety software was used to perform the meta-analysis and generate the plots .Data were pooled for meta-analysis and a random effect model using the Hartung-Knapp-Sidik-Jonkman method was chosen. Heterogeneity was assessed using the The search generated 222 citations of which 16 were classed as relevant and 8 met the inclusion criteria comprising 133 individuals with IBD and 99 healthy controls, 39 studies were rejected . The chaP = .16; I2 = 87.3%; There was no significant difference in rectal pain thresholds in IBD patients compared to healthy controls with an effect size of 0.59 . The effect size in those with active disease was 1.32 (95% CIs: −0.13 to 2.77) compared to −0.024 (95% CIs: −1.15 to 1.10) in those with quiescent disease  and the purinergic P2X3 receptor in the mucosa.25–27 After the inflammation subsides, it would be expected that these neurotrophic factors would return to near-normal levels which would lead to a reduction in abdominal pain and rectal hypersensitivity. However, it appears that in people with IBD–IBS overlap, a reduction in levels of these nociceptive channels particularly TRPV1 does not occur,29 and their levels are significantly related to the abdominal pain score. This would indicate that the predominant mechanism of abdominal pain in quiescent disease is likely related to peripheral sensitization of nociceptive receptors despite the healing of inflammation itself.Hitherto, there has been considerable debate as to whether patients with quiescent IBD who complain of abdominal pain have concomitant IBS or mild ongoing inflammation that is not readily identifiable using current techniques.30 Experimentally induced negative emotions during painful rectal distension even in healthy volunteers can lead to increased brain activity in the left thalamus and right dorsal posterior cingulate gyrus.31 Hypervigilance is known to be associated with anxiety and depression; however, none of the studies included in this meta-analysis were corrected for anxiety and depression and the majority did not measure anxiety and depression scores. Currently, the role of hypervigilance in IBD patients with and without rectal hypersensitivity is unknown and requires further study.Hypervigilance to stimuli is known to play a role in the development of pain and rectal sensitivity. Hypervigilance is common in experimental settings as the stimulation represents a “threat” to the participant, but repeated exposure to the stimulus will lead to habitation. Abdominal pain-related fear learning and memory processes are altered, which may contribute to central pain amplification and hypervigilance which may be enhanced in those with comorbid anxiety and depression.32 which includes descending inhibitory control from the brain which can reduce peripheral sensitization. However, it has been shown that descending inhibition is deficient in IBS patients with rectal hypersensitivity.5 It is thus possible that there are differences in the activity of descending inhibitory pathway between IBS and IBD patients in remission such that while in IBS these pathways are less active they may be more active in quiescent IBD patients who do not suffer from chronic abdominal pain. Further research is required to confirm these hypotheses.People with quiescent IBD who do not experience chronic pain are known to have activation of their anti-nociceptive pathways10 We corrected for the difference in study methodology by only evaluating studies that assessed rectal as opposed to colonic sensation. All of the studies included took place in tertiary care settings, so our data may represent a more severe phenotype than what is seen in other settings. A comparison between UC and CD was not attempted as the data were too heterogeneous and the number of eligible studies was small.This study has several limitations. A major issue is to do with the very high level of heterogenicity seen. There are likely to be multiple factors affecting the level of heterogenicity as already described above. Pain itself is a highly variable subjective experience that will inevitably lead to increased heterogenicity.As previously mentioned, only a single article dealt with quiescent IBD patients with abdominal pain, that is, patients who may represent IBD–IBS crossover; further research is required looking to compare IBD–IBS crossover patients to quiescent IBD patients without pain and see if rectal stimulation-induced pain thresholds are different. Similarly, IBD–IBS crossover patients should be compared to IBS patients to see if they represent a similar phenotype. This would be highly clinically useful as it would show whether clinicians should be regarding IBD–IBS crossover as a subtype of IBS that could be treated accordingly or whether these are entirely different disease entities. Further studies should also look at correcting for anxiety and depression between the IBD–IBS population and the control population as these play significant roles in pain perception.This meta-analysis indicates that rectal hypersensitivity is associated with IBD in the presence of active disease but not in the presence of quiescent disease in patients without chronic abdominal pain. Rectal hypersensitivity is therefore not a routinely seen feature in quiescent IBD but may still play a role in those who are suffering from IBS–IBD crossover.otab041_suppl_Supplementary_MaterialsClick here for additional data file.


Existing guidelines advocate an updated therapeutic algorithm for chronic neuropathic pain (NeP), but pharmacotherapeutic management should be individualized to pain phenotypes to achieve higher efficacy. This study was aimed to evaluate the efficacy of medications, based on NeP phenotypes, and to propose symptom-based pharmacotherapy. This retrospective study was enrolled 265 outpatients with chronic NeP related to spinal disorders. The patients were classified into three groups: spinal cord-related pain, radicular pain, and cauda equina syndrome. Data were obtained from patient-based questionnaires using Neuropathic Pain Symptom Inventory (NPSI) and the Brief Scale for Psychiatric Problems in Orthopaedic Patients, and from clinical information. The proportions of patients with ≥ 30% and ≥ 50% reduction in NPSI score for each pain subtype  and drugs were evaluated. The pain reduction rate was significantly lower in patients with spinal cord-related pain, especially for paresthesia/dysesthesia. For spinal cord-related pain, duloxetine and neurotropin had insufficient analgesic effects, whereas mirogabalin was the most effective. Pregabalin or mirogabalin for radicular pain and duloxetine for cauda equina syndrome are recommended in cases of insufficient analgesic effects with neurotropin. The findings could contribute to better strategies for symptom-based pharmacotherapeutic management. The associated significant reduction in the health-related quality of life and increase in economic costs make NeP treatment critical5. A cross-sectional study revealed that more than half (53.3%) of the patients with spinal disorders had NeP using screening questionnaire to identify potential patients with NeP, and the highest incidence (77%) of NeP was among patients with cervical spondylotic myelopathy, followed by ligament ossification (75%), spine/spinal cord injury (65%), nerve root damage (57%), and lumbar spinal stenosis (56%)6. A major concern for our globally aging society is that spinal disorders occur more frequently in aged individuals. Moreover, an epidemiological study indicated that a rate 65.0–78.8% patients with NeP experience chronic pain7. Although further validation of NeP screening questionnaire is needed for epidemiological purposes8, it becomes important to pay particular attention to improve pain recognition and management in NeP related to spinal disorders, particularly in older adults.Neuropathic pain (NeP) commonly develops after interventional procedures that affect somatosensory signaling in the peripheral or central nervous system13. The NeP pharmacotherapy algorithm in Japan recommends pregabalin, mirogabalin, and duloxetine as the first-line drugs, and neurotropin (an extract from inflamed cutaneous tissue of rabbits inoculated with the vaccinia virus) and tramadol as the second-line drugs. However, these statements apply to NeP in general, without considering underlying causes and differences in the types of NeP. It is difficult to predict and assess the treatment response in cases of NeP because the same underlying disease may manifest differently in different patients or because different diseases may present with similar clinical features15. Prescribing doctors currently have the discretion regarding which drug to use. Previous studies recommend symptom-based and/or mechanism-based treatment because pharmacological treatment efficacy is associated with NeP phenotype and severity19. This indicates the need for individualized management of NeP through prediction of treatment responses based on individual pain phenotypes.Guidelines and consensus statements for treatment of NeP have been published worldwideNeP classification based on different triggering stimuli and the use of multidisciplinary approaches may help us better understand the underlying mechanisms of pain in patients and facilitate the development of appropriate pain management protocols. Therefore, this study was conducted to investigate the type and severity of NeP, including the degree of deterioration of psychiatric factors, by using patients-based questionnaires, and to assess the drug-specific effectiveness of treatment, based on the type of pain.Table To assess the drug-specific effectiveness of treatment based on neurological symptoms, the proportions of patients with ≥ 30% reduction or with ≥ 50% reduction in Neuropathic Pain Symptom Inventory (NPSI) score or subscore from baseline to follow-up were determined.Figure The drug-specific NPSI scores and subscores at baseline and at follow-up are shown in Table To assess the drug-specific changes for each pain phenotype, the pain reduction rates in the NPSI scores and subscores in patients with a NPSI score of ≥ 1 at baseline and at follow-up were analyzed. The pain reduction rate of duloxetine for patients with paresthesia/dysesthesia was lower than that of the other drugs. For evoked pain, the average pain reduction rate of duloxetine was below 30%, which was also lower than that of the other drugs, although the difference was not statistically significant Table .Table 5TA comparison of the patient background and BS-POP scores between responder and nonresponder is summarized in Table 21; (3) duloxetine and neurotropin are not expected to have a significant effect on spinal cord-related pain, based on the lower response to paresthesia/dysesthesia. For these patients, mirogabalin may be recommended; (4) Neurotropin could be a first-line drug for radicular pain and cauda equina disorder as a drug with few serious adverse effects. Pregabalin or mirogabalin for radicular pain and duloxetine for cauda equina syndrome may be recommended for patients experiencing poor analgesic effects with neurotropin. These proposals may contribute to better strategies as symptom-based pharmacotherapeutic management for the relief of NeP related to spinal disorders.Existing guidelines advocate first- to third-line treatment in the updated therapeutic algorithm. However, we believe that the response rate can be improved if we determine which medications are more likely to be effective for which symptoms. The aim of the current real-world study, using patient-based assessments, was to investigate the effectiveness of treatment, based on the type of NeP related to spinal disorders, and to propose a symptom-based therapeutic algorithm, based on information about which medications are more likely to be effective for which symptoms. The major findings of our current research were: (1) patients with radicular pain and cauda equina syndrome commonly had spontaneous pain and paresthesia/dysesthesia, whereas patients with spinal cord-related pain prominently had more severe paresthesia/dysesthesia ; (2) the pain reduction rate was significantly lower in patients with spinal cord-related pain, especially for paresthesia/dysesthesia, and the NPSI score at follow-up remained > 10. Our previous nationwide survey and multicenter cross-sectional study of spinal cord-related pain syndrome also showed similar characteristics of patients with spinal cord-related pain2δ subunits of voltage-dependent calcium (Ca2+) channels in the central nervous system and, compared to a placebo, it has significant analgesic effects on postherpetic neuralgia22, diabetic neuropathy23, and pain after spinal cord injury24. Its effectiveness on depression and NeP-associated anxiety have also been demonstrated. Mirogabalin has a higher binding affinity for the α2δ subunits, and the dissociation rate is slower for the α2δ-1 subunit contributes to analgesic effects than for the α2δ-2 subunit contributes to undesirable central nervous system effects resulting in more sustained analgesia compared with traditional gabapentinoids26. Several randomized controlled trials (RCT) have verified the efficacy of mirogabalin for treating NeP such as postherpetic neuralgia and diabetic neuropathy28. In addition, an application for approval for central NeP  is under review in Japan. In our study, pregabalin and mirogabalin each showed good efficacy with 30% responder rates > 70% in patients with radicular pain. An interesting finding is that, for patients experiencing spinal cord-related pain for whom NeP may be very difficult to treat, the 50% responder rate was higher in the mirogabalin group than in the pregabalin group. However, the median dose of both groups was smaller than approved doses used in the clinical trials.Pregabalin inhibits the release of excitatory neurotransmitters by combining with the α29, revealed that many analgesics , were prescribed at lower doses than the approved doses. Prescribing an approved dose is an important factor in achieving a therapeutic effect, but the relatively high incidence of adverse effects such as dizziness and somnolence are also a substantial problem with both drugs31. The results of the current study may be because a therapeutic effect was easier to achieve with mirogabalin, which is easier to increase the dose, rather than because of the effect of the drug itself. However, we believe that the ease of attaining the approved dose is also an important factor when considering which drugs to choose. In addition, a previous study suggested that continued oral mirogabalin treatment increases the pain threshold over time26. A retrospective study indicated that mirogabalin is safe and effective for reducing NeP in patients who ceased treatment with pregabalin because of adverse events or lack of efficacy32.The prescription status of oral analgesics, based on the findings of a large-scale prescription database in Japan36. Furthermore, case-series studies report analgesic effects on peripheral neuropathy accompanying multiple sclerosis and central poststroke pain38. Our results suggested that duloxetine is unlikely to have high efficacy for patients with spinal cord-related pain owing to its low efficacy in paresthesia/dysesthesia. However, another retrospective study indicated that duloxetine had therapeutic effect for postsurgical chronic myelopathic disorders of pain and numbness in the chronic stage after surgery39. For patients with radicular pain in this study, the 30% responder rate also tended to be lower than that of other drugs. However, an interesting finding was that the group of patients with cauda equina syndrome responded well to treatment . In an animal study, the analgesic effects of pregabalin were weaker in the cauda equina compression model without an improvement in the walking distance than in the partial sciatic nerve ligation model; the expression of α2δ-1 subunit significantly increased only in the partial sciatic nerve ligation model and remained unchanged in the cauda equina compression model. However, duloxetine had analgesic effects in both models and improved walking distance in the cauda equina compression model40. The expression of the α2δ-1 subunit may be specific to the injury type. These experimental results seem to be in line with our clinical results, and this finding is important for considering symptom-based treatment for NeP.Duloxetine acts on the serotonin and noradrenalin system, which is involved in the descending pain inhibitory system. Its analgesic effects are induced by inhibiting serotonin-noradrenaline reuptake. Some RCTs indicate that it has analgesic effects for diabetic neuropathy and chemotherapy-induced peripheral neuropathy41. In addition to its analgesic effects, patients have very high tolerability to the drug with no serious adverse reactions. In our study, neurotropin had sufficient analgesic effects for radicular pain and cauda equina syndrome, especially for the patients without severe NeP; however, its effectiveness in treating spinal cord-related pain is not expected.Neurotropin contains nonprotein-type biologically active substances, which are extracted from the inflamed cutaneous tissue of rabbits inoculated with vaccinia virus. The analgesic effect of neurotropin occurs by activating the descending pain inhibitory system, exerting an anti-inflammatory action, inhibiting the release of excitatory neuropeptides, inhibiting the excitation of sympathetic nerves, improving blood flow, and exerting a neuroprotective action42, postherpetic neuralgia43, and post-spinal cord injury44. Concomitant use of tramadol with another NeP medication may enhance analgesic effects because tramadol can prevent abnormal excitability of neuronal firing in ascending and descending pain pathways .Tramadol acts as μ-opioid receptor agonist and as a serotonin-noradrenaline reuptake inhibitor. It exerts its analgesic effects by suppressing the ascending pain pathways and activating the descending pain inhibitory system. Previous RCTs indicate it has analgesic effects in patients with diabetic neuropathy20. Severe pain impairs employment and daily life in approximately 25% of patients21. Furthermore, chronic musculoskeletal pain was associated with future decline in ADL in a longitudinal study45. In drug-specific assessments, nonresponders were significantly more likely to have psychological problems in patients with taking mirogabalin, but no association between treatment efficacy and psychological factors was noted with the other drugs. The finding that more than 40% of patients (which included nonresponders and responders) had psychiatric problems at follow-up was a matter of concern, although our results suggested that the influence of psychiatric problems on treatment efficacy may be small.NeP can also markedly affect mental health, activities of daily life (ADLs), and physical conditions and function. The scores for all short form (SF)-36 subitems among patients with NeP were significantly lower than the national average scoresBased on the results of our study, we proposed a symptom-based pharmacotherapy algorithm as shown in Fig. The retrospective, single-center design and the presence of possible confounding factors for which we were unable to adjust could be construed as some limitations of the current study. Our proposed symptom-based pharmacotherapy for NeP related to spinal disorders was inferred from patient-based assessments in the present study and require verification in a future study. Although it will be beneficial to conduct a larger prospective study to determine the significance of the results, the present study provides useful insights and guidance on the symptom-based therapeutic management of patients with NeP caused by spinal disorders.2. These patients visited our hospital in 2020 and had taken a fixed dose of pregabalin, mirogabalin, duloxetine, or neurotropin for ≥ 3 months with or without concomitant tramadol. Patients taking multiple medications of the former four drugs were excluded. Chronic NeP associated with a spinal disorder was diagnosed, using the following criteria: (1) persistent pain for at least 3 months; (2) the presence of compressive lesions, confirmed by imaging and consistent with neurological findings; (3) poor response to nonsteroidal anti-inflammatory drugs; and (4) clinical confirmation of an absence of neurodegenerative disease, brain disease, history of chemotherapy, and peripheral nerve disorders 18. Patients with no NPSI score or no applicable items  at base-line were excluded from this study.This retrospective study included outpatients with chronic NeP related to spinal disorders. NeP is pain initiated or caused by a primary lesion or dysfunction in the nervous system diagnosed using the algorithm (grading system) formulated by Neuropathic Pain Special Interest Group (NeuPSIG) of International Association for the Study of Pain (IASP)21, spinal cord-related pain was defined as chronic NeP in patients with spinal cord-associated diseases . Radicular pain was defined as upper or lower extremity pain consistent with a neurological dominant region due to lumbar spinal canal stenosis (LSS) or cervical spondylosis. Cauda equina syndrome in patients with LSS was diagnosed, based on symptoms of neurogenic intermittent claudication or motor and/or sensory disturbance, including bladder dysfunction. Three senior spine surgeons conducted all neurological evaluations. Before filling out the questionnaire, written informed consent was obtained from each patient. The study protocol was approved by the Human Ethics Review Committee of Fukui University Medical Faculty, and it strictly followed the Clinical Research Guidelines of the Ministry of Health, Labor, and Welfare of the Japanese Government.The patients were also classified into three groups, based on the type of neurological symptoms: (1) spinal cord-related pain, (2) radicular pain, and (3) cauda equina syndrome. As described previously19. Within the NPSI scoring system, subscores were evaluated for burning  spontaneous pain, pressing  spontaneous pain, paroxysmal pain, evoked pain, and paresthesia/dysesthesia . The second questionnaire administered to patients was the Brief Scale for Psychiatric Problems in Orthopaedic Patients (BS-POP) (doctor and patient versions), which was used to evaluate psychiatric problems46.Two questionnaires were used in the study. The first questionnaire administered to patients was the Neuropathic Pain Symptom Inventory (NPSI)18. In addition, the BS-POP (doctor and patient versions) were evaluated to assess the degree of deterioration of psychiatric factors in responder and nonresponder. The cut-off values indicating the presence of psychiatric problems were defined as ≥ 10 for the doctor version and ≥ 15 for the patient version.Total NPSI score and NPSI subscore at baseline and at follow-up were evaluated to assess the treatment efficacy according to the neurological symptoms , pain subtype  and selected drugs . The pain reduction rate (%) was calculated, as follows: [NPSI score (subscore) at baseline − NPSI score (subscore) at follow-up] × 100/NPSI score (subscore) at baseline. Treatment outcomes were also analyzed, based on the responder rate Data are expressed as the mean ± the standard deviation of the mean. The Kruskal–Wallis test and the Steel–Dwass test were used to compare the NPSI scores, NPSI subscores, and BS-POP scores of the patients’ neurological symptoms and medications. The Fisher’s exact test was used to analyze differences in BS-POP scores between responders and nonresponders. A value of p < 0.05 indicated statistical significance.The study protocol was approved by the Human Ethics Review Committee of Fukui University Medical Faculty  and strictly followed the Clinical Research Guidelines of the Ministry of Health, Labor, and Welfare of the Japanese Government.


AbstractPregabalin has been considered to be a safe treatment for neuropathic pain. Owing to the lack of research regarding the use of pregabalin in the management of pain in under-resourced settings, our study aimed to deduce the effectiveness of a pre-emptive single dose of pregabalin pre-operatively to provide pain relief after laparoscopic cholecystectomy. Treating acute pain is essential to avoid an increased hospital stay. There is a need for non-opioid drugs with lower risks to avoid using opioids, which lead to many side effects.MethodologyPatients diagnosed with cholelithiasis and scheduled to undergo laparoscopic cholecystectomy at the Abbasi Shaheed Hospital were included in this study. The study aimed to determine whether the effect of pregabalin in combination with patient-controlled analgesia can decrease pain scores. This was a double-blind study where patients, caregivers, and analysts were blinded to group allocation and drugs administered until the data was recorded and sealed. The patients were divided into pregabalin and placebo groups through a web-based model; blocks of four were used and stratification was employed at the center. A confidence interval of 95% was considered significant.ResultsIn our study, a total number of 60 patients were included. They were randomly divided by a computer-based model into two groups, the pregabalin group, and the control group. The placebo group had 33 patients while the pregabalin group had 27 patients. The pregabalin group was given a pregabalin tablet of 150 mg before surgery while the placebo group was given an identical-looking placebo. Patient-controlled analgesia was started in both groups and the visual analog scale (VAS) scoring was observed postoperatively. The pregabalin group had a decreased incidence of pain as compared to the placebo group. There were no significant side effects during the trial; episodes of vomiting were managed using intravenous ondansetron.ConclusionPregabalin is effective in reducing pain in an acute postoperative period when compared with a placebo. Patients who were pre-emptively administered pregabalin reported decreased VAS as compared to the placebo. However, both were inefficient in reducing postoperative nausea and vomiting. In settings with few resources, managing acute post-operative pain is very difficult owing to the low availability of medical staff and drugs. Acute post-operative pain is the most serious complaint which requires the use of opioids and non-opioid therapies. Opioid therapy in the acute postoperative period can have many side effects such as nausea, vomiting, pruritus, and respiratory depression -3. Many Pregabalin is part of the gabapentinoid group, which decreases the release of excitatory neurotransmitters substance P, serotonin, and glutamate, leading to a decrease in post-operative pain. Pregabalin is known to reduce post-operative pain and prevent hyperalgesia. Previous studies have shown that pregabalin can reduce pain in the acute post-operative period and that its pre-emptive use decreased overall fentanyl consumption and reduced post-operative pain .The goal of our study was to analyze the effect of pregabalin in combination with patient-controlled analgesia to provide adequate pain relief in the acute post-operative period. A dose of 150 mg was used since it was effective and had minimum side effects. We aimed to determine its role in reducing VAS scores and incidence of post-operative nausea and vomiting. Both factors can adversely affect the recovery of a patient and prolong hospital stay .After approval of the ethical review board (IRB #23545), permission was taken to conduct a double-blind randomized trial at Abbasi Shaheed Hospital. All patients selected were adults aged between 25 and 40. The patients were admitted a day before surgery. The consent of all the participants was taken and the procedure was explained to them.Patients were divided randomly by a computer-based model into two groups, the pregabalin group, and the control group. A total of 60 patients were included in our study to keep the confidence interval at 95%, the analysis failure below 20%, the alpha value of 0.05, and the beta value of 0.08. The study was double-blinded in which the patients, caregivers, and those recording the data were blinded to the treatment. Only after completion of the data record, the treatment was revealed. The patients were divided into the pregabalin group and placebo group through a web-based model where blocks of four were used and stratification was employed at the center. Patients included in the study were ASA 1 and 2; they had no uncontrolled systemic disease.The primary objective of our study was to determine whether pregabalin before surgery could provide adequate pain relief in combination with patient-controlled analgesia using fentanyl. Our second objective was to analyze the effectiveness of pregabalin in reducing the incidence of post-operative nausea and vomiting in patients. The study team kept all the logs of all the patients who had met the eligibility criteria and those who left the trial (on request for early discharge); the reason for discharge was also notedThe pregabalin group patients had received 150 mg of pregabalin six hours before surgery. The control group had been given a placebo six hours before surgery.The sample size was calculated by taking the alpha value of 0.05 and the beta value of 0.08. Twenty-five people were enrolled in each group for the result to be significant. Inclusion criteria required the patients to have no uncontrolled systemic diseases such as hypertension and diabetes. They had no previous abdominal surgery, and all were of ASA I and ASA II. Exclusion criteria were the presence of uncontrolled systemic diseases, psychiatric illness, or chronic pain.All patients were given a similar anesthesia technique. Induction was done with propofol 150 mg and atracurium 40 mg. Endotracheal intubation was done after laryngoscopy, and the endotracheal tube was properly secured. Anesthesia was maintained with halothane at 1.0 Mac. Additionally, nalbuphine 10 mg was given intravenously as part of a multimodal regimen. The reversal was done using a combination of glycopyrrolate 0.001 mg/kg and neostigmine 0.05 mg/kg to antagonize the neuromuscular block.All patients were transferred to the post-anesthesia care unit, where pain scores and intensity of post-operative nausea and vomiting were monitored by an independent anesthetist who was blinded to group distribution.Fentanyl patient-controlled analgesia was started at 25 micrograms with a lockout time of 10 minutes. The maximum dose allowed was 1.9 micrograms per kg per pain measure at intervals of 0 to 3 hours, 3 to 6 hours, and 6 to 12 hours. Post-operative nausea and vomiting were monitored with the criteria of no nausea, mild, moderate, and severe. All patients with mild nausea and vomiting were given ondansetron intravenous 4 mg as rescue therapy.Data were analyzed using SPSS version 26 . After normality assessment for quantitative variables, the mean with standard deviation was reported for the age and weight of the participants. For the duration of the surgery, heart rate and baseline mean arterial pressure (MAP) median with interquartile ranges were calculated. The VAS pain scale along with post-operative nausea and vomiting scores were categorized and reported with frequencies and percentages. Both groups, i.e., the placebo and pregabalin groups, were compared. Age and weight were compared using an independent t-test while the Mann-Whitney U test was applied for other quantitative variables. A chi-square test was used after assessing the assumptions for all the qualitative variables except post-operative nausea and vomiting at six hours, for which Fisher’s exact test was used. A p-value of less than 0.05 was considered significant.Consolidated standards of reporting trials (CONSORT) flow chart showing stages of allocation between the two groups is shown in Figure A total of 60 participants were enrolled in the study, of which 33 were part of the placebo group while 27 were in the intervention group and were given pregabalin pre-surgery. As shown in Table The comparison between postoperative nausea and vomiting was found to be statistically insignificant in both groups at all times, i.e. at 3 hours, 6 hours, and 12 hours with a p-value of 0.184, 0.72, and 0.697 respectively. However, a highly significant difference was observed among the groups for pain scoring, with a p-value of <0.0001 at all times (Table Pregabalin has been used in previous studies preoperatively to decrease acute postoperative pain after surgery . It has The use of pregabalin in combination with other non-opioid regimens as part of multimodal analgesia can provide significant pain relief and decrease postoperative pain scores. This leads to a decrease in the duration of hospital stay and reduces complications such as thromboembolism caused by immobility -12.Previous studies have identified that pre-emptive use of pregabalin can reduce overall opioid consumption . This opGabapentinoids such as pregabalin can reduce the incidence of postoperative nausea and vomiting . This caMany clinicians are of the view that using multimodal techniques enhances recovery and reduces overall hospital stay. Therefore, management of pain becomes vital, and this can be achieved through a multimodal regimen as it employs a different mechanism to reduce actions to reduce post-operative pain. As the sample size of our study was small, large multi-centered and double-blinded studies of longer duration are needed to assess the efficacy of pregabalin in reducing pain and incidence of nausea and vomiting -16.A combination of NSAIDs and pregabalin has been shown to reduce pain scores. Our study has highlighted the beneficial effect of pregabalin on acute post-operative pain after laparoscopic cholecystectomy. The clinical efficacy of pregabalin should be used in under-resourced settings. There were several limitations due to the low resource setting; further randomized control trials are needed to evaluate the effect of long-term pregabalin use in the prevention of hyperalgesia and chronic pain -20.Our study has demonstrated that pregabalin can provide effective pain relief after acute laparoscopic cholecystectomy. Its clinical efficacy can be used to provide pain relief as a part of a non-opioid pain regimen. Pregabalin can be used as part of multimodal pain management. It is effective in reducing pain in the acute postoperative period, which is demonstrated through lower VAS scores in the pregabalin group compared with the placebo group.


Back pain may be caused by many factors and discopathy is one of them. The aim of the study was to assess the impact of age and sex on back pain intensity in rehabilitated patients with discopathy treated conservatively and surgically; (2) Methods: The study included 137 patients: 96 undergoing conservative therapy and 41 after back surgery due to discopathy. VAS and the Laitinen scale were used for pain assessment. All patients underwent a multidirectional rehabilitation program at the Department of Rehabilitation and Physical Medicine of the Medical University in Łódź; (3) Results: No statistically significant effect of age and sex was observed on the level of pain intensity on VAS and the Laitinen scale; (4) Conclusions: Age and sex do not seem to affect back pain intensity in rehabilitated patients treated conservatively and surgically for discopathy. The problem requires further research on a larger group of patients. The prevalence and treatment of back pain have increased significantly in recent years. Back pain and dysfunction syndrome affect more and more individuals and are considered to be associated with lifestyle factors. The lack of exercise, reduced physical activity, and non-physiological body posture, i.e., a negligent and too frequently assumed sitting position, are a strain on the lumbosacral spine and result in early degeneration .Low back pain (LBP) is one of the most common complaints reported by patients . It affeHowever, this percentage may be underestimated considering different levels of pain tolerance. Furthermore, it constitutes economic hardship for the budget, taking into account the cost of hospitalization and medical procedures, incapacity for work, and thus absence at work.Non-specific low back pain (NLBP) is a frequent complication. NLBP has become a major public health problem worldwide. In total, 11–12% of the population is disabled by LBP ,5. MoreoMechanobiology helps to better elucidate the pathophysiology of the intervertebral disc (IVD) and its potential for biological repair. IVD is the largest avascular element in the human body and has a small number of cells. The unfavorable microenvironment is not conducive to bearing high levels of mechanical stress. Hydrostatic pressure strongly affects the nuclear pulposus (NP), whereas the fibrous ring (AF) is able to withstand biaxial tensile and shear forces. The cells of the nucleus pulposus and fibrous ring are exposed to high mechanical stresses due to body weight, voluntary and spontaneous activity, and vertebral stabilization forces. These cells are adapted to anaerobic metabolism with low oxygen pressure and acidic pH. The adaptation of cells to states of acidosis and increased osmotic pressure is regulated by mechanoproteins. They are responsible for the transmission of a mechanical signal to a cellular response .Chronic oxygen and glucose deficiencies have a detrimental effect on cell viability. Oxygen deficiency causes cells to become inactive, while glucose deficiency can cause cell death. The hypoxic and acidotic disc cells as well as disc herniation cells are still biologically active and produce spontaneously nitric oxide; prostaglandin E2 (PGE2); interleukin-6 (IL-6); meta-protease ECM; and pro-inflammatory cytokines: including interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF- α), and factors stimulating the accumulation of granulocytes and macrophages. On the one hand, these factors intensify the inflammatory process and pain, and on the other, they stimulate repair processes .Back pain may be caused by many factors, one of which is discopathy. Discopathy is caused by a three-stage process of discosis. A degenerative disc disease is characterized by bulging, dislocation, and pressure on the nervous structures. The first stage of discosis is an early stage in adolescence and early adulthood and begins with the regression of intradiscal vessels. The disc tissue receives nutrients only by diffusion. The lower body weight of children and their vigorous physical activity generate advantageous biomechanics for the nourishment of the intervertebral disc fiber-producing cells. With the body weight increase, the axial load on the disc also increases, particularly in the lower lumbar region. As children grow up, they become less active, spending much time desk-bound at school and then in adulthood at work . The second stage affects middle-aged adults. The intervertebral disc may be displaced, and therapeutic procedures must be applied because, in this stage, the disc produces intense local and radicular pain. Protrusion, herniation, and sequestration, which can compress nerve roots, are observed ,9.The third stage concerns the old age population. The disc tissue loses water, the disc becomes thinner and does not absorb shocks, it becomes fibrotic and firm. Further calcification of the ligaments results in limited segmental mobility . Studies have shown that degenerative changes within intervertebral discs are observed in the population of subjects over 30 years of age, and the incidence of spondylosis increases with age and reaches 100% in persons aged over 80–90 years [These problems require adequate clinical and imaging diagnostics in order to implement appropriate management. It is important to identify the cause of symptoms and introduce appropriate causal treatment rather than focus only on symptomatic therapy. A patient with back pain initially reports to a primary care physician. This is usually the beginning of the diagnostic process. In addition to the clinical examination of the patient, it is important to perform imaging diagnostics of the spine: X-ray, computed tomography (CT), or magnetic resonance imaging (MRI). MRI is the gold standard in diagnosing intervertebral disc diseases. Moreover, the correlation of changes in the radiological image with clinical symptoms is of great importance. In the first place, the diagnostic process should be based on conservative methods . Kinesitherapy is very important in the rehabilitation process. It improves circulation within peri-spinal soft tissues, causes relaxation and stretching, as well as strengthens soft tissues. Surgical treatment is recommended only when a lack of improvement is observed. However, there is always a risk of failed back surgery syndrome (FBSS). FBSS consists of three issues: 1. Instability associated with the surgery, 2. Patient’s predispositions. 3. Tissue scarring .The problem of the diagnosis and treatment of back pain is of great significance. Early diagnosis and treatment minimize the cost and reduce the risk of spine surgery, which is expensive compared to conservative management. Therefore, patients should be under multidisciplinary care .Due to the social scope of diseases of the spine, the dimension of their distribution among different age groups and sexes is important. The meta-analysis of Souza IMB et al.  includedA large-scale population study shows that with age, disc space narrowing progresses faster in women than in men. Significant disc space narrowing is associated with higher bone mineral density BMD of the spine and hips, back pain, and reduced leg mobility .The obtained results do not indicate the level of pain and disability. In contrast, in another study in China , the incQuite numerous reports indicate that the incidence of low back pain may be related to psychosocial risk factors in the workplace . MoreoveThe aim of the study was to assess the impact of age and sex on back pain intensity in rehabilitated patients with discopathy treated conservatively or surgically.Hypothesis: Age and gender do not affect back pain intensity in rehabilitated patients treated surgically and conservatively for discopathy.n = 29) of hospitalized patients smoked cigarettes, including nine surgically treated.The study included 137 subjects aged 19–89 years : 77 women and 60 men (men constituted 44%), hospitalized at the Department of Rehabilitation and Physical Medicine of the Medical University of Lodz (1 January 2014–31 December 2016) due to back pain. The patients reported back pain due to discopathy, i.e., protrusion, herniated nucleus pulposus, and sequestration. The complaints were confirmed by spine MRI and CT. On admission, the patients were examined, and the medical history was collected. Twenty-one percent .-back pain syndrome caused by discopathy and confirmed by MRI or CT,-chronic pain (>3 months),-the patient’s consent to the suggested treatment and rehabilitation presented in the medical history,-no contraindications for physiotherapy and kinesitherapy.-Exclusion criteria-back pain syndrome without discopathy on MRI or CT,-active neoplastic disease, spondyloarthropathies, and other serious diseases;-lack of the patient’s consent to the proposed rehabilitation,-contraindications to the proposed rehabilitation.Inclusion criteria:n = 96) were treated only with conservative methods. The remaining patients (n = 41) underwent spinal surgery due to back pain in the course of discopathy. Twenty patients (49%) underwent fusion surgery: PLIF (Posterior Lumbar Interbody Fusion) or ACIF . The other 21 (51%) underwent surgery involving the removal of a herniated disc or a sequester without fusion. These were microdiscectomies and discectomies [Prior to admission, some patients (ectomies .n = 137) were qualified for treatment with kinesi- and physical therapy for 6 days a week. Kinesitherapy was based on isometric exercises, active load-free, balance, and loosening, as well as relaxation exercises. The McKenzie and NDT-Bobath methods were also used. Moreover, gait training exercises were applied. Kinesitherapy lasted approximately 2.5 h a day. It included, among others, classical kinesitherapy, exercises using the Bobath method, and exercises with biofeedback on a balance platform. Physical therapy was based on the application of magnetic field, laser, and electrotherapy. The treatment regimen was the same in both groups. Rehabilitation was carried out by the same rehabilitation team.After admission, all patients .All rehabilitation procedures were supervised by one physician. No complications were observed during the rehabilitation cycle. All patients were discharged in good general condition and referred for further outpatient treatment. p-value < 0.05 was considered statistically significant. Continuous and ordinary data were presented as median and interquartile ranges. The Shapiro–Wilk test was used to test the normality of the distribution in each group. Spearman’s rank correlation coefficient was also used to evaluate the relationship between age and change in the scale score. The Mann–Whitney test was used for group comparisons. All statistical analyses were carried out with the use of STATISTICA 13.1 . A The presented tables and figures demonstrate the results of the effect of age and sex on the level of pain intensity in the VAS and Laitinen scales in the group of patients with back pain treated surgically or non-surgically due to discopathy. Back pain syndrome affects a very large social group. International reports present precise data on the incidence of spine pathologies, including those of intervertebral discs. The recognition of the causes of ailments, the implementation of proper causal treatment, and not focusing only on the symptomatic treatment are of great importance.Back pain can originate from three different sources. These are axial lumbosacral, radicular, and transferred pain. The annual prevalence of low back pain in the US adult population is 10–30%, and the lifetime prevalence is as high as 65–80% [The patient’s medical history, physical and functional examination, and diagnostic tests are important elements of accurate diagnosis and identification of the patient’s pathophysiology. There are many types of back pain: myofascial, intervertebral joint, sacroiliac joint, discogenic, spinal stenosis, and failed back surgery pain. Patients with chronic back pain require a multidisciplinary, patient-centered treatment that should include multimodal medical, psychological, physical, and interventional approaches. Back pain is a complex and difficult-to-treat therapeutic problem that affects millions of Americans every year . In the The possible differences in the outcomes of LBP therapy between women and men can be determined by biological differences in immune function that may underlie these observed effects. Women far outnumber men as sufferers of chronic pain syndromes. However, social and psychological factors also play a role in the prevalence of chronic pain in both sexes. These differences can be attributed, among others, to diversity in cell populations (T lymphocytes), differences in hormone suppression, and different cellular responses in males and females. These sex differences also affect human cellular responses and may be the mechanism by which disproportionate chronic pain is demonstrated. Identifying the path of mechanisms underlying sex differences in pain may be a clue for therapy and provide better options for patients .The studies of Canadian scientists indicated the sex-dependent activation of brain centers in chronic pain of inflammatory nature—ankylosing spondylitis. Females showed higher functional segregation in the medial cingulate cortex and anterior cingulate cortex, and lower network connectivity with the default mode and frontoparietal modules, while males showed stronger connectivity with the sensorimotor module. On the basis of these observations, it was possible to determine whether a given person suffered from chronic pain and even what gender he/she was with an accuracy of 77–92%. These findings highlight the organizational abnormalities of the neural network in the resting state of the brain in people with chronic pain and are the basis for the production of sex-specific analgesics in the future .Some sources informed about the impact of age on the susceptibility to spine diseases; age over 50 was treated as a risk factor, most likely related to pain caused by degenerative spine disease. Moreover, a correlation was seen between the spine pain syndrome and the symptoms of accelerated brain aging . DiffereOn the other hand, in a large study of 202,077 men and 237,754 women in a UK bio-bank, the genetic factor of chronic back pain shows a mild sex and age relationship [A systematic review of clinical trials programmed to the risk of chronic disease in adults with acute or subacute musculoskeletal pain was conducted by C. Meyer et al. and showed moderate results . The rehp = 0.004) and the TLF elasticity index. Patients with LBP had a 25–30% lower TLF modulus of elasticity than healthy subjects [It is possible that the cause of low back pain is significantly influenced by patients’ sex representation. In the studies of Tamartash H. et al., various hypotheses concerning the role of connective tissue of the thoracolumbar fascia TLF in low back pain were presented. The changes were examined on USG bilaterally at levels L2–L3 and L4–L5 in both the group of patients with non-specific LBP and the control group without pain. The examined parts of the fascia were located 2 cm to the side of the center of the interspinal ligament. There were no significant differences in age, sex, and BMI between LBP and healthy subjects. There was also no significant relationship between age, BMI, and sex with the TLF elasticity index. There was a strong inverse relationship between pain intensity , interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and the observation of their changes during treatment and rehabilitation.Age and sex did not affect back pain intensity in rehabilitated patients treated conservatively and surgically for discopathy. However, imaging tests proved that pain does not always correlate with the severity of the degenerative process. Further research is required in a larger group of patients taking into account both the clinical and radiological picture of the disease and subjective disorders.


This study aimed to assess the effect of extraoral 940 nm low-level diode laser on pain, edema, and trismus following surgical extraction of impacted mandibular third molars.2, continuous-wave mode, 20 s) at three points in the master muscle in contact mode immediately after surgical extraction of third molar. The third molar in the placebo quadrant was extracted after 2 weeks by the same surgeon using the same standard approach. The pain score was measured at 2 and 7 days postoperatively using a visual analog scale (VAS). To assess trismus, the distance between the incisal edges of the upper and lower central incisors was measured in maximum opening. To assess edema, the distance between the tragus and chin point was measured before and immediately after surgery and after 2 and 7 days. Data were analyzed using t-test, ANOVA, and Bonferroni test.This split-mouth, randomized, placebo-controlled clinical trial evaluated 25 patients with bilaterally impacted mandibular third molars. One side of the jaw was randomly assigned to the laser and the other side to the control group. The laser quadrant received 940 nm diode laser irradiation . Edema and trismus were the same in both groups (P > 0.05). Number of analgesics taken was significantly lower in the laser group (P < 0.05).The mean pain score in the first 7 days was significantly lower in the laser group (Single-session irradiation of 940 nm diode laser can effectively decrease pain following third molar extraction surgery.Trial registration number: IRCT20141209020258N91 on 29/12/2018. Surgical extraction of impacted mandibular third molars is a common surgical procedure, which is often associated with postoperative complications such as pain, edema, and trismus due to intraoperative trauma , 2. The Several strategies have been suggested to minimize postoperative complications, such as the systemic use of corticosteroids, enzymes, or non-steroidal anti-inflammatory medications, surgical closure techniques with/without placement of a drain, use of ice packs, cryotherapy, and laser therapy –9. ConsiLow level lasers have several applications in dentistry, and are used for enhancement of wound healing, acceleration of tissue regeneration, gingival depigmentation, treatment of temporomandibular disorders, alleviation of chronic orofacial pain, and induction of bone regeneration . The antThe efficacy of LLLT for pain relief following surgical extraction of third molars is still a controversial topic. Limited number of studies have reported the optimal clinical efficacy of LLLT for reduction of postoperative pain, edema, and trismus –18 while(IRCT20141209020258N91) on 29/12/2018. The patients signed informed consent forms prior to participation in the study.This split-mouth, randomized, placebo-controlled clinical trial evaluated 25 healthy patients over 18 years of age (range 18–40 years) with asymptomatic, bilaterally impacted, mandibular third molars. The study was approved by the National Committee for Ethics in Biomedical Research and registered in the Iranian Registry of Clinical Trials Sample size was calculated considering alpha = 0.05, beta = 0.2 and study power of 80%.The inclusion criteria were: ASA class 1 patients, no medication intake for 1 week prior to the surgical procedure, no allergy to anesthetic agents, no systemic diseases, no chronic pain, no intake of anti-inflammatory medications or analgesics for 2 weeks prior to the study, no intake of corticosteroids, absence of pericoronitis, no smoking, and no pregnancy or lactation. Also, in each patient, the bilaterally impacted mandibular third molars had to be in the same class according to the Winter’s classification  , Pell anThe exclusion criteria were: unwillingness for participation in the study, postoperative pharmaceutical complications and side effects, allergy to the used materials, postoperative infection or acute abscess, not showing up for the second surgery after 2 weeks, not consenting to laser therapy after surgery, and not completing the questionnaire after surgery.Considering the randomized split-mouth design of the study, the laser side was determined by flipping a coin in each patient. The contralateral quadrant served as the placebo group.2 power, maximum output power of 2.75 W, and spot size of 8 × 35 mm. An oral medicine specialist laser-irradiated the surgical site while the placebo side received no laser irradiation. The fiber tip was in contact with the skin and laser was irradiated to a triangular area hypothetically formed between the point of insertion of the masseter muscle at the angle of mandible, the tragus lobe of the ear, and the mesial side of the mandibular second molar . An incision was made using a #15 scalpel  and a mucoperiosteal flap was elevated using an elevator . Bone was removed from the buccal and distal areas using a #8 round carbide bur  and a low-speed hand-piece . The impacted tooth was sectioned into pieces by a 703 fissure bur  and a low-speed handpiece under saline irrigation and removed. The surgical wound was closed by non-absorbable 3–0 silk sutures using a 3.8 reverse cutting needle . After termination of the surgical procedure of the laser side and immediately after suturing, the patients received 940 nm extraoral diode laser irradiation (Epic) with 0.5 W/cmAfter surgery, the patients were prescribed 500 mg amoxicillin every 8 h for 7 days, 400 mg ibuprofen every 12 h for 3 days, and chlorhexidine mouthwash for 7 days.Presence/absence of edema was determined by measuring the distance between the chin point and the inferior border of the external auditory canal as described by Markovic and Todorovic .Trismus was determined by measuring the distance between the incisal edges of the upper and lower right central incisors in maximum opening using a calibrated digital caliper before and immediately after surgery and also after 2 and 7 days.Pain was determined using a visual analog scale (VAS). The patients were requested to express the level of pain experienced using a 10-cm VAS; 0 indicated no pain while 10 indicated most severe pain imaginable. To enhance the patients’ understanding of the VAS scores, the Faces pain scale was also used in addition to the linear VAS. A questionnaire was designed for this purpose and the patients were requested to record their pain score for 7 days, postoperatively. They were also asked to record the number of analgesics taken during this time period.Data were analyzed using SPSS version 23 . The measures of central dispersion were reported for descriptive variables. Comparisons were made using independent t-test, paired t-test, ANOVA, and Bonferroni test. Level of significance was set at 0.05.A total of 25 patients with a mean age of 26.84 ± 3.61 years were evaluated, including 14 females (56%) and 11 (44%) males.P = 0.00).The mean number of analgesics taken was significantly lower in the laser group . Repeated measures ANOVA revealed that the mean score of edema increased within each group in the first 2 days and then decreased; this trend of change was statistically significant in both groups (Table P < 0.05). However, the two groups were not significantly different in this regard; although the increase in edema was slightly greater in the first 2 days in the control group (P = 0.258).Figure P = 0.011) and 7 days (P = 0.027), postoperatively . Although the trend of change in mouth opening was greater in the intervention group, the difference in this respect was not significant between the two groups (P = 0.13). The Bonferroni test showed that the mean amount of mouth opening trismus decreased in both groups in the first 2 days and then increased . The difference in this respect was also significant between the two groups, and the mean change in pain score was lower in the laser group. Table Table 2 energy for pain reduction and reported promising results [2), different wavelength (940 nm), extraoral irradiation and found the same results. Another study confirmed the optimal efficacy of low-level laser for reduction of pain and edema, postoperatively [2 low-level laser irradiation to the operative side, intraorally and extraorally.This study assessed the effect of extraoral 940 nm low-level diode laser on pain, edema and trismus following surgical extraction of mandibular third molars. The results showed that although pain and edema were lower in the laser group after surgery, this difference was only significant for pain. In a recent study, the authors used 810 nm diode laser with 32 J/cm results . Howeverratively . However2 in their study and 10 J/cm2 in our study. In a recent study and inconsistent with our research, LLLT with 660 nm or 810 nm lasers or their combination was demonstrated to be ineffective for pain relief following tooth extraction [On the contrary, some others did not confirm the efficacy of LLLT for reduction of postoperative pain and edema –23, 30. traction . Reductitraction . Althoug2 is considered as the minimal energy density required for pain relief and elimination of edema, postoperatively [2 for extraoral single-session LLLT.In this study, laser was irradiated extraorally; thus, the epidermis can serve as a barrier against the penetration of laser energy and reaching to deep tissues. This may explain the inefficacy of laser irradiation in our study for resolution of trismus. Another reason may be the fact that the medial pterygoid muscle was not in the field of extraoral laser irradiation, and only the masseter muscle was irradiated. As we know, inflammation of the medial pterygoid muscle plays a major role in trismus, and the masseter muscle has a very small role in the occurrence of trismus. The low energy density of laser may be another reason for its inefficacy in resolution of trismus because the lower the laser energy, the lower its thermal effects on muscle relaxation would be , 32. Theratively , 21, 22.LLLT activates the macrophages and regulates the intracapillary pressure by decreasing the vascular permeability, and exerts anti-inflammatory effects as such , 33. In Amarillas-Escobar et al.  irradiatIn this study, we adopted the split-mouth design to minimize the effect of demographic factors and inter-individual differences on the results. Some studies have reported that younger patients and males often experience more pain , 37. In The lower the level of pro-inflammatory mediators, the lower the level of pain mediators and consequently the lower the pain score would be. In this split-mouth clinical trial, decision regarding the order of surgical procedures  was made by tossing a coin. Thus, controlling the intensity of pain after the second surgical procedure was impossible because the pain threshold of patients would change after the first surgery . In thisSingle-session extraoral irradiation of 940 nm diode laser can effectively decrease pain following third molar extraction surgery.


Pain is considered a common symptom in amyotrophic lateral sclerosis (ALS). However, the results of studies on pain in ALS are limited and inconsistent. The aim of our study was to comprehensively evaluate the potential factors of pain and effects on quality of life (QoL) in patients with ALS from China.Patients were eligible if they fulfilled the criteria of probable and definitive ALS according to the revised El Escorial criteria. Pain was assessed by the Brief Pain Inventory (BPI). Disease severity, sleep quality, fatigue, anxiety, depression, and quality of life (QoL) were evaluated in ALS patients by the ALS Functional Rating Scale-revised (ALSFRS-R) and ALS severity scale (ALSSS), Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), Hamilton Anxiety Rating Scale (HARS), Hamilton Depression Rating Scale (HDRS) and McGill Quality of Life Questionnaire (MQOL). Then, the clinical characteristics of ALS patients with pain were compared with those without pain. Last, associated factors of pain, as well as impact on QoL in Chinese ALS patients, were assessed.A total of 86 ALS patients were included. ALS patients with pain tended to have higher FSS scores and poorer QoL. The FSS score and ALSSS [lower extremity (LE) + upper extremity (UE)] were associated with pain in ALS patients. The ALS Functional Rating Scale-revised (ALSFRS-R), Pain Severity Index (PSI), HARS and HDRS scores were significantly associated with both the physical and psychological domains of QoL.Our study was the first to comprehensively evaluate factors associated with pain in Chinese ALS patients, finding that fatigue can be a risk factor for pain and ALSSS (LE + UE) score was related with pain intensity. Additionally, we identified the adverse effects of ALSSS (LE + UE), HARS and HDRS scores on QoL in Chinese ALS patients. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of unknown etiology characterized by the progressive loss of upper and lower motor neurons, causing weakness and atrophy of upper and lower limbs, dysphagia and dysarthria, which eventually result in death due to respiratory failure typically within 2–4 years of onset . No effePain is considered a common symptom in ALS, with frequencies varying from less than 15% to 85% . GuideliDisease duration, disease severity and depression were the common variables included to investigate pain and the influences on quality of life in patients with ALS . StudiesConsidering the potential impact of pain on QoL in ALS patients and their caregivers, the identification and evaluation of factors associated with pain and its impact on quality of life in ALS patients are of great importance. Therefore, we speculated that some motor or nonmotor symptoms of ALS patients may be associated with pain and that ALS patients with pain may have a much poorer QoL.Accordingly, the objective of our study was to comprehensively evaluate the potential factors associated with pain and the impact of pain on QoL in ALS patients from China.The study was conducted in West China Hospital of Sichuan University in Southwest China. All patients with ALS were recruited from November 2020 to August 2021. Patients were eligible and consecutively recruited if they fulfilled the criteria of probable and definitive ALS according to the revised El Escorial criteria . We usedPain was evaluated using the Chinese version of the Brief Pain Inventory (BPI), a multidimensional scale . Brief PThe physical functional status of ALS patients was evaluated with the ALS Functional Rating Scale-revised (ALSFRS-R), a 12-item scale. Each item is rated from 0 (worse) to 4 (best), corresponding to a total score ranging from 0 to 48, with higher scores indicating greater physical status and function .The amyotrophic lateral sclerosis severity scale (ALSSS) has been developed to provide a means of rapid functional assessment for patients with ALS. The scale included four categories of speech (SP), swallowing (SW), lower extremity (LE), and upper extremity abilities (UE). Each section has ten possible rating scores (1–10) based on the progressive decline of function. The bulbar function [ALSSS (SP + SW)] can be described by adding the scores for SP and SW. Similarly, spinal function [ALSSS (LE + UE)] can be described by adding the scores for LE and UE. A total score can be assigned by adding the four subscores (SP + SW + LE + UE) . Other cSleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). A PSQI score > 5 indicates poor sleep . FatigueDepression and anxiety were assessed using the 24-item Hamilton Depression Rating Scale (HDRS) and 14-item Hamilton Anxiety Rating Scale (HARS), respectively. The HDRS consists of 24 items; the severity of each item is rated from 0 (not present) to 4 (very severe) or 2 (present), and the scores range from 0 to 76 . The HARThe McGill Quality of Life Questionnaire (MQOL), a 17-item [a single-item scale (MQOL-SIS) and 16 other items] multidimensional tool, was used to evaluate QOL in ALS patients. There are five MQOL subscales, which are designed to measure physical well-being, physical symptoms, psychological symptoms, existential well-being and social support, as well as overall quality of life. Each question uses a 0–10 scale. Each subscale score is the mean of the items forming that subscale. The MQOL Total (summary) score is the mean of the 5 subscale scores , 1997.The study was approved by the Research Ethics Committee of West China Hospital, Sichuan University . All participants were informed of the purpose of the study before enrollment and gave written informed consent for participation.t test (with the Mann–Whitney U test when necessary) was used to compare continuous variables, and the chi-square test was used to analyze categorical variables.Continuous parameters that were normally distributed were described as the means ± standard deviation (SD). Those with a non-normal distribution are presented as the median values. Categorical variables were summarized using patient counts and percentages. Student’s p value < 0.05) in the univariate regression analysis or considered clinically relevant were included in the multivariate analysis. The Box-Tidwell test was used for the assumption of linearity in the logit for the continuous variable. Multicollinearity was assessed using an examination of the variance inflation factor in a multiple regression model with the same variables. The results were expressed as odds ratios (ORs) with their corresponding 95% CIs . The sample size in our study met the demands of events per variable (EPV) during logistic regression analysis.The risk factors for pain in ALS patients were investigated by univariate regression analysis, and the results were controlled using a binary logistic regression model. Binary logistic regression analysis (forward stepwise LR method) was used to evaluate the association between the variables and pain. Variables with statistical significance .A total of 86 ALS patients were included in the study, 50 men and 36 women, with a mean age of 52.6 years and a mean disease duration of 11 months. There were no significant differences in sex, age, age at onset, site of onset, disease duration, ALSFRS-R, ALSSS (LE + UE), ALSSS (SP + SW), or ALSSS (LE + UE + SP + SW) between ALS patients with pain and without pain (Thirty-eight ALS patients (44.2%) reported pain, with a mean PSI score of 3.2, among which thirty-three patients had a spinal onset. Nineteen males (38%) and nineteen females (52.8%) reported pain, with mean PSI scores of 2.9 and 3.5, respectively. Twenty patients (52.6%) had mild pain (1 ≤ PSI ≤ 3), thirteen patients (34.2%) had moderate pain (4 ≤ PSI ≤ 6), and only two patients (5.3%) had severe pain (7 ≤ PSI ≤ 10).p = 0.023; p = 0.044, p = 0.001, p = 0.007, p = 0.030, respectively; Compared with ALS patients without pain, ALS patients with pain were more likely to have higher FSS score  and FSS scores were included in the binary logistic model. Multivariate analysis  showed tp = 0.003, 95% CI ; Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R), ALSSS (LE + UE), ALSSS (LE + UE + SP + SW) and HDRS scores were included in the multiple linear stepwise regression model to find the clinical variables associated with pain severity. The PSI score, which was not associated with ALSFRS-R, ALSSS (LE + UE + SP + SW) or HDRS scores, showed a negative correlation with the ALSSS (LE + UE) score [The results of the effect of clinical variables on quality of life were shown in In our previous study, the prevalence, severity, site, type of pain and treatment, as well as the relationship between pain and clinical parameters, were reported in ALS patients and healthy controls . ConsistIn our study, no significant differences were found between ALS patients with and without pain relative to sex, age at interview, age at onset, site at onset, disease duration, ALSFRS, ALSSS or HDRS score, in accordance with previous reports . HoweverRegarding the intensity of pain, previous studies found there was a weak negative correlation between the ALSFRS-R and PSI score ; additioA previous study indicated that ALS patients described their QoL as involving physical, psychological and other aspects . ConsideIn our study, there was no significant effects of pain intensity on different aspects of QoL in ALS patients, consistent with the findings of some former studies . In contQuality of life (QoL) was found to be negatively affected by depression score in ALS patients, including MQOL-physical well-being, psychological symptoms, existential wellbeing domains and MQOL-Total. Previous studies have also reported that depression scores can significantly decrease QoL  in both Likewise, anxiety score seriously affected MQOL-physical symptoms of QoL. Prior studies also indicated that anxiety can undermine quality of life in ALS patients . One stuFunctional status (ALSFRS) was reported to be significantly correlated with QoL measured by the MQOL-SIS  or ALSAQThere were some strong strengths in our study that should be noted. First, this was the first study to comprehensively investigate factors associated with pain in Chinese ALS patients and found that fatigue can be a risk factor for the presence of pain and ALSSS (LE + UE) score was related with pain intensity, which has never been reported worldwide. Second, considering that ALS patients described their QoL as involving physical, psychological and other aspects, we innovatively used a multidimensional MQOL scale to comprehensively evaluate the clinical symptoms on quality of life  in ALS patients. Lastly, besides disease duration, disease severity and depression, which were the common variables included in previous studies, we added other potential factors, such as anxiety, sleep and fatigue in our study, and all the assessments were conducted by using standard specialized measures.The limitations of our work were as follows: first, the sample size was relatively small, and only two variables  could be included in the binary logistic regression analysis. Further studies with a larger sample size of ALS patients from different ethnic populations could be conducted to confirm our findings. Then, we analyzed and found factors associated with pain and pain intensity; however, the impact of the nature of pain, type of pain, duration and frequency of pain were not included in our analysis. Last, our study was a cross-sectional design without follow-up, and we could not determine whether the effects on QoL varied over time or whether effective treatments for limb dysfunction, anxiety and depression symptoms could improve QoL. Concerning this disease being uncurable now, limb and mood disturbances offer another potentially important treatment target for improving QoL. Whether effective management of those symptoms can help improve various aspects of QoL in ALS patients deserves further study.In conclusion, our study found that fatigue may be a potential risk factor for pain and ALSSS (LE + UE) score was related with pain intensity in Chinese ALS patients. Additionally, it highlighted the adverse effects of ALSSS (LE + UE), anxiety and depressive symptom scores on various domains of QoL. Accordingly, clinicians should routinely pay more attention to limbs dysfunction, anxiety and depressive symptoms in ALS patients and treat them in a timely and appropriate manner.The original data of the current study are available from the corresponding author on reasonable request.This study was reviewed and approved by the Institutional Ethics Committee of West China Hospital, Sichuan University . The patients/participants provided their written informed consent to participate in this study.All authors contributed to the study conception and design. RA, YW, YL, XL, and SA performed material preparation, data collection, and analysis. RA wrote the first draft of the manuscript. CH and YX designed the research project and revised the manuscript. All authors commented on previous versions of the manuscript, read, and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.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.