Constipation, a condition characterized by heterogeneous symptoms, is common in Western society. It is associated with reduced physical health, mental health, and social functioning. Because constipation is rarely due to a life-threatening disease , current guidelines recommend empiric therapy. Limited surveys suggest that fewer than half of treated individuals are satisfied with treatment, perhaps because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. For example, although a substantial proportion of constipated patients have a defecatory disorder that is more appropriately treated with pelvic floor biofeedback therapy than with laxatives, virtually no pharmacological trials formally assessed for anorectal dysfunction. Recent advances in investigational tools have improved our understanding of the physiology and pathophysiology of colonic and defecatory functions. In particular, colonic and anorectal high-resolution manometry are now available. High-resolution anorectal manometry, which is increasingly used in clinical practice, at least in the United States, provides a refined assessment of anorectal pressures and may uncover structural abnormalities. Advances in our understanding of colonic molecular physiology have led to the development of new therapeutic agents . However, because clinical trials compare these newer agents with placebo, their efficacy relative to traditional laxatives is unknown. This article reviews these physiologic, diagnostic, and therapeutic advances and focuses particularly on newer therapeutic agents. Classically, the term “constipation” refers to infrequent bowel motions or hard feces. However, the disorder is heterogeneous; patients report a variety of symptoms including reduced bowel motion frequency, straining, hard stools, the sensation of incomplete emptying, the sensation of anal blockage, or the use of digitation or positioning to aid defecation  or another disease . Hence, guidelines recommend initial empiric therapy for constipated patients rather than investigating for a cause 10. Consequently, osmotic and stimulant laxatives are the two most commonly prescribed agents12. Osmotic laxatives  retain water in the intestinal lumen, accelerating colonic transit and reducing the consistency of evacuated stool. Stimulant laxatives  stimulate colonic contractions and the urge to defecate. Although laxatives increase bowel motion frequency13, satisfaction is variable14. In an internet-based survey of 1,355 patients with self-reported constipation in 10 European countries in 2009, 855 patients were taking laxatives. Of these patients, 28% were very satisfied or satisfied with their treatment, 44% were neutral, and 28% were dissatisfied with therapy. In particular, the symptom of bloating persists15. Conceptually, satisfaction may be suboptimal because the efficacy of drugs is limited, they are associated with undesirable side effects, or they may not target the underlying pathophysiology. In particular, a substantial proportion of constipated patients have a defecatory disorder that may be associated with normal or slow colonic transit. Defecatory disorders are more appropriately treated with pelvic floor biofeedback therapy than with laxatives18.Slow colonic transit is associated with hard stools19. The presence of these dysfunctional channels may be suggested by a family history of a functional bowel disorder19. Documented “channelopathies” include those affecting the voltage-gated sodium channel NaV1.5, present on smooth muscle cells; the voltage-gated sodium channels NaV1.7 and NaV1.9, present on neurons; and ion exchange channels, present on enterocytes19. Altered ion channel expression or function occurs because of genetic mutations, post-translational modification, or accessory protein malfunction. In particular, the voltage-gated sodium channel NaV1.5 has been associated with constipation20. In one study, mutations, predominantly resulting in loss of function, were found in 7% of patients (4 out of 59) with constipation-predominant IBS (IBS-C)20. Further studies are necessary to determine whether these mutations were responsible for the bowel symptoms.Abnormalities of ion channels within the intestine have been shown to affect secretion, absorption, motility, and sensation, potentially resulting in constipation, diarrhea, and irritable bowel syndrome (IBS)21. Conversely, a small fraction  of patients with IBS-C have low fecal concentrations of bile acids22. It is unclear to what extent these findings represent a primary disturbance  or are secondary to slow colon transit. Nonetheless, because bile acids stimulate colonic secretion of water and high-amplitude-propagated contractions24, it is hypothesized that a paucity of colonic bile acids may cause constipation. Indeed, the corollary is also true: excess bile acid administered orally24 or modification of the enterohepatic recycling pathway25 can exert a laxative effect.In selected studies, about one in four patients with diarrhea-predominant IBS has high concentrations of fecal bile acids26, and the pathophysiology of defecatory disorders is heterogeneous. A clinical history is insufficient for differentiating the subtypes of constipation27. A detailed digital rectal examination28 may suggest the presence of manometric features of a defecatory disorder—positive predictive value (PPV) of 97% and negative predictive value (NPV) of 37%—but is less useful for predicting an abnormal rectal balloon expulsion test (PPV of 33% and NPV of 65%)30. Indeed, agreement among anorectal tests is variable, perhaps partly because they assess different aspects of structure or function or both32. Consequently, the Rome criteria recommend that when standard empiric laxative therapy fails to provide relief for patients with constipation, defecatory disturbances be documented with two tests32. However, where manometry or defecography is not available, a digital rectal examination and balloon expulsion test are sufficient for screening.Defecation is an intricate viscerosomatic process33. Relative to water-perfused manometry, high-resolution manometry is simpler to perform34. However, in clinical practice, the incremental utility of high-resolution manometry above water-perfused manometry is unclear33.A detailed rectoanal manometry and rectal balloon expulsion test can provide information regarding rectoanal neuromuscular functions36. In high-definition anorectal manometry, similar to high-resolution anorectal manometry, 70% of healthy individuals exhibit a dyssynergic manometry pattern during simulated evacuation36. More recent studies observed that both high-resolution and high-definition anorectal manometry can identify rectoceles, intra-anal intussusception, and rectal prolapse40. However, whether these techniques will augment or supplant defecography, or fall by the wayside, for diagnosing these conditions has yet to be determined.In contrast to high-resolution anorectal manometry, high-definition anorectal manometry provides a three-dimensional evaluation of pressures within the anal canal. To date, relatively small studies suggest that high-resolution and high-definition anorectal manometry have similar performance characteristics for evaluating anorectal disorders41. While high-resolution colonic manometry remains primarily a research tool, attempts are being made to incorporate these data into clinical practice. For example, among 18 pediatric patients with slow transit constipation and six children with normal transit constipation, manometric findings were predictive of neuropathy with a sensitivity of 100% and a specificity of 86%42.Within the colon, high-resolution manometry is better than standard water-perfused manometry for visualizing propagated colonic contractions43 and retentive rectoceles45, which are less frequently identified during MRI defecography, barium and MRI defecography have similar performance characteristics.Radiological tests are also useful for evaluating anorectal and colonic functions. Barium defecography is used to exclude or diagnose rectoceles and pelvic organ prolapse causing obstructed defecation. Magnetic resonance imaging (MRI) defecography offers a radiation-free alternative. Furthermore, it provides a comprehensive evaluation of pelvic organ structure and function during defecation without the need to instill radiopaque material into the small bowel, bladder, or vagina. With the exception of internal intussusception48. Inohet al. evaluated the relationship between colonic diameter and gastrointestinal symptoms in 20 patients with self-reported chronic constipation by using abdominal MRI49. Ascending colon diameter correlated with a sense of incomplete evacuation, and rectal diameter correlated with constipation scores49. However, although the sum of all the segmental diameters  correlated with an increasing severity of constipation, the sum of certain segmental diameters also positively correlated with diarrhea. Furthermore, no statistical adjustment appears to have been made for the multiple comparisons performed in this study. Although the hypothesis is interesting, further studies are required to understand the relationship among colonic fecal volume, colonic diameter, and bowel function. Parket al. demonstrated that rectal gas volume was a marker of defecatory disorders; at a specificity of 90%, a rectal gas volume of 30 mL had a PPV of 77.3% for an evacuation disorder51.MRI has been used as a research tool to evaluate colonic motor function in constipation and IBSA few medications that selectively target intestinal secretion or motility are available. Serotonin receptor agonists have been used to accelerate intestinal transit. Activation or inhibition of intestinal ionic transporters can increase luminal fluid content and accelerates the rate of colonic transit. Inhibition of ileal bile acid transporters exposes the colon to a greater concentration of these ionic detergents, resulting in the secretion of water into the colonic lumen and accelerated colonic transit.53, were withdrawn from the market because of cardiovascular events56. By targeting differing pharmacophores, with greater receptor selectivity, novel 5-HT(4) receptor agonists avoid this pro-arrhythmic risk58.Cisapride and tegaserod, the initial 5-HT(4) receptor agonists used to treat functional bowel disorders59. Prucalopride accelerated colonic transit in healthy individuals61 and gastric, small bowel, and colonic transit in constipated patients62. The initial phase 3, double-blind, parallel-group, placebo-controlled trials demonstrated that prucalopride was substantially more efficacious than placebo for increasing the number of spontaneous complete bowel movements by one per week  and promoting more than three complete spontaneous bowel motions (CSBMs) per week . Patients reported less-severe symptoms and improved satisfaction with their bowel function63. Subsequent findings include improved constipation-related quality of life64, satisfaction with prucalopride in patients who were dissatisfied with previous laxative treatments66, and efficacy for treating constipation in men67, elderly patients68, and patients with chronic intestinal pseudo-obstruction69, opioid-induced constipation70, or spinal cord injury71. Moreover, prucalopride remains efficacious after 18 months of therapy72. Only one study, a double-blind, placebo-controlled trial over 24 weeks, demonstrated no benefit above placebo73. Even in older patients, the risk of cardiac events, including QT prolongation, is not increased75. Only 5% of patients discontinue the medication because of adverse effects 72. Prucalopride is approved by the European Medicines Agency (EMA), but not by the US Food and Drug Administration (FDA), for the treatment of constipation.Prucalopride is a selective, high-affinity, 5-HT(4) receptor agonist with prokinetic gastrointestinal activity77. A phase 2 trial of about 400 patients demonstrated a significant increase above placebo in the number of spontaneous bowel motions  and CSBMs per week  for all doses of velusetrag78. A phase 2 trial of naronapride (ATI-7505) demonstrated beneficial physiological and clinical effects79. These studies with velusetrag and ATI-7505 were published almost a decade ago. In November 2016, after a considerable delay, the FDA recommended that efficacy and cardiovascular safety of naronapride be evaluated in two additional phase 3 studies with 1,000 patients each80. However, no phase 3 trials of velusetrag for constipation are currently registered on ClinicalTrials.gov. Another highly selective 5-HT(4) receptor agonist, YH12852, accelerated upper and lower intestinal transit in animal models81. Human studies are awaited.Velusetrag (TD-5108), a newer selective 5-HT(4) receptor agonist, accelerates colonic and gastric transit82.The secretion of ions, and thereby fluid, into the intestinal lumen through ion channels can be pharmacologically driven by lubiprostone, linaclotide, and plecanatide. Activation of the cystic fibrosis transmembrane conductance regulator (CFTR) on the apical surface of enterocytes results in chloride secretion into the intestinal lumen, which is followed by a net secretion of sodium and subsequently water83. In a 4-week randomized parallel-group placebo-controlled phase 3 trial involving 237 patients with chronic constipation, lubiprostone (24 μg daily) was superior to placebo84. Lubiprostone-treated patients experienced more frequent spontaneous bowel motions than those treated with placebo . Lubiprostone reduced bloating85 but did not affect pain thresholds during colonic distention86. It is efficacious for treating constipation associated with cystic fibrosis83, diabetes87, and opioids88. In general, lubiprostone is well tolerated. However, nausea (20%), diarrhea (10%), abdominal distension (7%), headache (7%), and abdominal pain (5%) are reported frequently85.Lubiprostone is a prostaglandin E analog that activates apical type 2 chloride channels, prostaglandin EP receptors, and the apical CFTR89 and chronic constipation90. Larger studies confirmed these findings, and only 4% of patients stopped the medication because of adverse side effects93. Linaclotide 145 μg and 290 μg increased the mean number of CSBMs per week to about 2.5 versus 0.9 with placebo (p <0.001)92. In rodent models of visceral pain, linaclotide reduced visceral sensitivity94. Perhaps this explains, at least in part, why linaclotide reduced abdominal pain and improved bowel motion frequency and consistency in patients with IBS-C95. These benefits appear to persist with longer-term administration96.Linaclotide and plecanatide are uroguanylin analogs that activate cell-surface guanylate cyclase-C receptors on enterocytes, inducing translocation of the CFTR to the apical surface of the cell. Initial studies of linaclotide demonstrated a dose-dependent increase in colonic transit with an associated increase in bowel motion frequency and consistency and reduced straining scores in patients with IBS-C97 based on a phase 3, multi-center, double-blind, placebo-controlled study of 1,394 patients98. Plecanatide increased the weekly number of CSBMs  and spontaneous bowel motions  per week above those seen with placebo during a 12-week study. Adverse effects (most commonly diarrhea) occurred in about 6% of patients taking plecanatide and 1% of patients receiving placebo. Similar findings were reported elsewhere99. An open-label follow-up study of 2,370 patients who had been enrolled in phase 2b or phase 3 studies demonstrated that 82% had completed or were still receiving the study drug100. These patients reported a median satisfaction score for treatment of 4.0 (quite satisfied) and were “quite likely” to continue the medication. Animal models suggest that plecanatide, similar to linaclotide, also reduces visceral sensitivity101, and phase 3 trials in patients with IBS-C have demonstrated a significant improvement in bowel motion frequency, stool consistency, and abdominal pain above that seen with placebo102. Sustained response with the 6 mg dose of plecanatide was seen in 30% of patients in the first study  and 24% in the second trial 102. Additional CFTR activators (CFTRact-J027 and its derivatives) have demonstrated efficacy for treating constipation in mouse models104.In 2017, plecanatide, which works via mechanisms similar to those of linaclotide, was approved by the FDA for treating chronic idiopathic constipation105. Inhibiting the absorption of bile acids from the ileum exposes the colonic mucosa to a higher concentration of these ionic detergents. This accelerates colonic transit, increases stool frequency, and potentially relieves the symptoms of constipation106. In a randomized phase 2b trial, 190 patients with chronic constipation received 5, 10, or 15 mg of elobixibat or placebo once daily for 8 weeks. The times to the first spontaneous bowel motion and CSBM were significantly shortened in the 10 and 15 mg groups. Stool frequency and constipation-related symptoms were significantly improved107. A phase 3 trial confirmed the efficacy of elobixibat for the treatment of chronic constipation but demonstrated that adverse drug reactions occur in up to half of patients108. These are usually mild abdominal pain or diarrhea. Though approved for clinical use in Japan, elobixibat is not currently approved for use by the EMA or the FDA.Elobixibat (A3309) is the first-in-class ileal bile acid transporter inhibitor25. The rationale for this study was the observation that NGM282 induced diarrhea in phase 2 trials relating to type 2 diabetes, primary biliary cholangitis, and non-alcoholic steatohepatitis. However, NGM282 is a potent inhibitor of bile acid synthesis, and in this study, in contrast to the effect of elobixibat, bile acid concentration in stool was reduced. Further physiological studies are needed to elucidate how NGM282 exerts its effects.In patients with functional constipation, the fibroblast growth factor 19 analog NGM282 accelerated gastric and colonic transit, resulting in an increased number of bowel movements, looser stool form, and increased ease of stool passage109. The effect is more pronounced when tenapanor is administered pre-meal110. A phase 2 randomized placebo-controlled trial of 356 patients—87% women, mean ± standard deviation (SD) of 46 ± 13 years—with IBS-C demonstrated a CSBM responder rate of 61% with tenapanor 50 mg twice a day as compared with 34% in the placebo group (p <0.001). Additionally, abdominal pain was significantly reduced in the tenapanor group111. The most common adverse events were diarrhea, headache, nausea, urinary tract infection, and abdominal pain. Diarrhea occurred in 9% of patients and resulted in medication cessation in 3%. Of note, data regarding the effect of tenapanor on hyperphosphatemia in patients with chronic kidney disease, which encompassed an older patient cohort (mean ± SD of 59 ± 14 years), demonstrated a similar side effect profile112. Thereafter, two phase 3 trials in IBS-C, each with about 600 patients treated for 12 and 26 weeks, have been reported. In the first phase 3 trial, tenapanor met its primary endpoint 113. Significance was met for the secondary endpoint of abdominal pain relief but not for the CSBM endpoint. In the second study, tenapanor met all primary and secondary endpoints114; the company plans to submit an application to the FDA in the second half of 2018. Tenapanor is not licensed by the EMA.Tenapanor (AZD1722) is a first-in-class, minimally absorbed, small-molecule inhibitor of the gastrointestinal sodium/hydrogen exchanger NHE3. It inhibits the absorption of dietary sodium and phosphate, which increases intestinal fluid volume and transit115. Polyethylene glycol with electrolytes was non-inferior to prucalopride for promoting more than three CSBMs per week and was better tolerated.Although these new agents are efficacious, only two studies have directly compared the clinical efficacy of newer and older laxatives. The first study compared polyethylene glycol with tegaserod, which has since been withdrawn from the market, in a randomized open-label, parallel-group study of 237 patients. Polyethylene glycol was better for improving symptoms of constipation. In the second, a randomized, double-blind, double-dummy study of 240 patients with chronic constipation, polyethylene glycol with electrolytes was compared with prucalopride116.Indeed, a network meta-analysis comparing prucalopride, lubiprostone, linaclotide, tegaserod, velusetrag, elobixibat, bisacodyl, and sodium picosulfate was undertaken, albeit with limited data for some medications, and observed that these drugs were of comparable efficacy for the endpoints of at least three CSBMs per week or an increase over baseline of at least one CSBM per week. Bisacodyl was superior to the other agents for inducing a greater change from baseline in the number of spontaneous bowel motions per weekFurthermore, the newer laxatives are much more expensive than the older, over-the-counter agents. In the United States, a 30-day supply of lubiprostone, linaclotide, or plecanatide costs about $450. By comparison, a 30-day supply of psyllium, polyethylene glycol, bisacodyl, or senna costs less than $10, whereas lactulose costs less than $15.8. However, none of the pharmacological studies described above rigorously evaluated anorectal function and excluded patients with defecatory disorders. Therefore, the relative efficacy of these drugs in patients with isolated normal or slow transit constipation is unknown.Consensus guidelines recommend that pelvic floor biofeedback therapy, not laxatives, is the cornerstone for managing defecatory disordersSCN5A gene, which encodes the alpha-subunit of the voltage-gated sodium channel NaV1.520.Where constipation does not respond to empiric therapy and a defecatory disorder has been excluded, investigation could guide tailored therapy. For example, the 5-HT(4) receptor agonist prucalopride might be a preferential choice for patients with diffusely slow intestinal transit. Ileal bile acid transporter inhibitors could be of benefit for constipated patients with a deficiency of bile acids reaching the colon. A single case report observed that mexiletine normalized bowel functions in a patient with IBS-C and a mutation in theFuture studies should evaluate the efficacy of novel and standard laxatives in patients with defined normal or slow transit constipation and the efficacy of targeted therapy .Constipation is common, but the underlying pathophysiology remains unclear in many cases. Many patients can be effectively and inexpensively treated with simple laxatives. Newer intestinal secretagogues and promotility agents are more expensive and should be considered in patients who do not respond to simple laxatives. A few new agents are being evaluated in clinical trials. There is a critical need to compare the efficacy of these newer agents relative to established laxatives and also clarify their efficacy in the subtypes of constipation .


Patients after cardiac surgery experience significant pain, but cannot communicate effectively due to opioid analgesia and sedation. Identification of pain with validated behavioral observation tool in patients with limited abilities to self-report pain improves quality of care and prevents suffering. Aim of this study was to validate Polish version of behavioral pain scale (BPS) in intubated, mechanically ventilated patients sedated with dexmedetomidine and morphine after cardiac surgery.Prospective observational cohort study included postoperative cardiac surgery patients, both sedated with dexmedetomidine and unsedated, observed at rest, during a nociceptive procedure (position change) and 10 minutes after intervention. Pain control was achieved using morphine infusion and nonopioid coanalgesia. Pain intensity evaluation included self-report by patient using numeric rating scale (NRS) and BPS assessments carried out by 2 blinded observers.R > 0.65, P < .001). Both mean NRS and BPS scores were significantly higher during nociceptive procedures as compared to assessments at rest, in both sedated and unsedated patients (P < .001).A total of 708 assessments were performed in 59 patients (mean age 68 years), predominantly men . Results showed very good interrater correlation between raters (interrater correlation scores >0.87). Self-report NRS scores were obtained from all patients. Correlation between NRS and BPS was relatively strong during nociceptive procedures in all patients for rater A and rater B (Spearman The results of this observational study show that the Polish translation of BPS can be regarded as a useful and validated tool for pain assessment in adult intubated patients. This instrument can be used in both unsedated and sedated cardiac surgery patients with limited communication abilities. Its treatment must be based upon multimodal analgesia regimens including intravenous opioids, nonopioid analgesics , rarely nonsteroidal anti-inflammatory medications (NSAIDS) or anticonvulsants. Effective pain treatment relies on regular and systematic assessment. The gold standard in pain evaluation is patient's self-report using numeric rating scale (NRS) or visual analog scale (VAS). However, pain in critically ill patients often goes unidentified and untreated, because of limited communication abilities in this specific patient population. The most valid and reliable behavioral tools for pain assessment in the critically ill patients who are unable to self-report are critical-care pain observation tool (CPOT) and behavioral pain scale (BPS). Both recommended behavioral scales (BPS and CPOT) have been validated for clinical use in the critically ill adults. This applies to medical, surgical (postoperative), or trauma patients (excluding brain injury) who cannot report pain. Therefore, their validation is still required for other specific patient population, such as cardiac, trauma, or burn patients. One must remember that the use of CPOT and BPS is reliable only in patients with intact motor function and observable behavior.Epidemiologic studies have shown that critically ill patients after major surgery frequently experience significant pain during their treatment in the hospital. Critical care teams must be equipped with dedicated monitoring tools to provide optimal analgesia to all patients. Therefore, the aim of this study was to validate the Polish version of BPS (POL-BPS) in a study including a homogenous group of patients under repeatable intraoperative and postoperative conditions undergoing cardiac surgery.It must be underlined that other measures of pain assessment, such as changes in vital signs  have been identified as unreliable measures for pain evaluation. Variation in vital signs, especially after a major operation or during critical illness, may be associated with hemodynamic instability or may be the side-effect of concomitant medications. Only systematic pain assessment, including patients’ self-assessment, as well as evaluation by healthcare professionals  or family members using a validated BPS warrants better identification of patient's needs.22.1,9 All procedures are briefly summarized in Figure ,11 The next steps were: bilingual medical and nonmedical translation, blind backtranslation, review by the expert panel reaching consensus, staff education prior to pretesting, scale pretesting, and preparation of the final version of the test. Afterwards the POL-BPS was published in Polish critical care press and is available for general use with free access. This led to a period of theoretical and practical training regarding the BPS and was the basis for a validation study.The validation study for POL-BPS is based on previously published recommendations.2.2Due to the detailed process of translation and back translation, the linguistic and cultural differences were eliminated, and the Polish version of the scale does not differ from the original. The details of the BPS with its 3 domains  are depicted in Table 2.3The Bioethical Committee of the Pomeranian Medical University approved the study and waived a need to obtain consent from participants of this study due to its observational  character, waiver number: KB-0012/180/05/17. Both patients’ self-report of pain as well as behavioral scale pain assessments formed part of the routine care performed by the bed-side nurses in the postoperative intensive therapy unit. The main investigator re-evaluated inclusion and exclusion criteria for all patients enrolled into the study after initial evaluation by 2 members of the study team.This prospective observational cohort study underwent registration at the ClinicalTrials.gov website and received acceptance (identifier: NCT03127306).2.4Patients who fulfilled inclusion criteria were enrolled into this prospective observational cohort study on the 6-bed postcardiac surgery unit and a 6-bed cardiac intensive care unit (ICU) at a tertiary teaching hospital in June and July 2017. All patients underwent a planned cardiac operation with the use of cardiopulmonary bypass (CPB) according to standard practice. Anesthesia was performed using general anesthetic technique with intravenous induction using fentanyl, etomidate, and pancuronium and maintenance of anesthesia using sevoflurane and fentanyl, as per local protocol. All patients were transferred to the postoperative unit where analgesia and sedation was initiated. The unit has implemented a minimal analgesia protocol for intubated postoperative patients, including morphine intravenous infusion with the concomitant use of nonopioid analgesics (metamizole or paracetamol).2.5•Age 18 years and above•Ability to understand Polish language•Intubated with mechanical ventilation •Richmond agitation sedation scale (RASS) no lower than −2•Unrestricted sight and hearing•Planned cardiac surgery•No body position change restrictions2.6Requirement for deep sedation: severe respiratory failure with patient-ventilator dyssynchrony, preventing awareness during neuromuscular blockade, patient with status epilepticus, surgical conditions requiring immobility, and intracranial hypertensionFacial trauma or abnormality RASS −4 or −5Neurologic or psychiatric disordersRegular narcotic usersChronic pain syndromesEmergency operation2.7During the study, pain assessment consisted of NRS and BPS for each patient, collected at prespecified time-points. Each NRS result was obtained from the patient by the bedside nurse. The BPS was performed by 2 ICU Registered Nurses (rater A and rater B) trained in the use of BPS and using it on regular basis in the ICU. Both raters (rater A and rater B) were blinded to each other and to the NRS result collected from the patient by the bedside nurse. They were supervised by the primary investigator who also verified inclusion criteria. All pain assessments were carried out during rest and routine nursing procedures in the postoperative cardiac unit and cardiac ICU with the nociceptive procedures (NPs), including patient positioning and turning in bed.Two sets of assessments were performed during prespecified timepoints: at rest 5 minutes prior to the NP, during the NP, and 15 minutes after the NP. Each evaluation consisted of 2 elements: self-report of pain by the patient (using NRS) and BPS assessment carried out by 2 blinded observers. The study procedures were performed in 2 clinical situations: set I in patients sedated with dexmedetomidine (0.4 μg/kg/h) at 3 hours after the procedure and set II in patients unsedated with dexmedetomidine at 6 hours after the procedure. Analgesia was provided as per local protocol with a continuous intravenous infusion of morphine (0.05–0.1 mg/kg/h) and coanalgesia with either paracetamol (1 g every 6 hours) or metamizole (1 g every 6 hours) for opioid sparing effect. Therefore, a total of 6 assessments were performed by each rater  to +4 (combative patient). The target RASS was 0  and only patients with points more than −3 were included in the study. ICU delirium screening was done using the Polish version of confusion assessment method for ICU (CAM-ICU). Each patient was asked to self-report pain using the NRS using a large-scale print-out and indicate a number between 0 (no pain) and 10 (the worst pain ever).2.8 Spearman rank correlation coefficient (Rs) was used for testing criterion validity between BPS and NRS scales and to analyze correlations between NRS and BPS results and physiologic parameters. Statistical significance was established at P < .05. To address the issue of multiple testing, we calculated Bonferroni-corrected threshold P-value. Since overall 52 tests were performed to calculate P-values presented in Tables P < .05/52 = 0.00096 were considered to be significant after the correction for multiple testing. The statistical analysis was performed with the use of Excel (Microsoft) and Statistica 13 with Medical Bundle 4.0 .Descriptive statistics were used to analyze the baseline characteristics of the study group and were shown as either mean ± standard deviation (quantitative parameters) or numbers and percentages . Standardized Cronbach alpha was used as an internal consistency estimate of reliability for BPS domains. Interrater reliability for BPS was calculated using intraclass correlation coefficient . Referring to published studies, the sample size required for validating BPS assuming precision of ICC 3,1 at 0.85 ± 0.10 was established between 55 and 65 patients.3During the 2-month study period 186 patients underwent cardiac surgery with the use of cardiopulmonary by-pass and were screened for eligibility. Out of this group only 80 patients met inclusion criteria and further 21 were excluded from participation in the study . Altogether the data were completed for 59 patients who were included into the study, with a mean age of 67 years ± 9.6, predominantly males 75% (44/59). All patients underwent an open heart surgery with the use of CPB. Majority of the patients underwent coronary artery bypass grafting (CABG), 46% (27/59), followed by valve replacement 36% (21/59) and combined valvular intervention + CABG . All patients were intubated and mechanically ventilated in the postoperative period, mostly using synchronized intermittent mechanical ventilation mode (SIMV), 93% (55/59). We also found that ICU delirium was present in nearly 41% (24/59) of patients, who screened CAM-ICU positive. All patients received intravenous morphine and dexmedetomidine infusion during T1 to T3 and only morphine infusion during T4 to T6. For opioid-sparing effect coanalgesics were administered with frequencies as follows: paracetamol 29% (17/59) and metamizole 71% (42/59). All the baseline data for our study population are shown in Table 3.1Standardized Cronbach alpha values for T2 and T5 assessment times (NP) are presented in Table 3.2Altogether 708 assessments were performed to calculate the interrater reliability (59 patients × 2 raters × 6 assessment times). The intraclass correlation coefficients (ICCs) were above >0.86 during all assessment times for both raters (rater A and rater B). Therefore, high intraclass correlation coefficients were measures of interrater reliability of the POL-BPS in both sedated and unsedated postcardiac surgery patients. These data are shown in Table 3.3Concomitant assessments of patients’ self-reported NRS and BPS evaluation performed by rater A and rater B are shown in Table 3.4P < .00001). The results of NRS were available for all 59 patients.The data in Table Scatterplots depicting strong correlation between BPS and NRS results for both rater A and rater B at T2 (NP in sedated patients) and T5 (NP in unsedated patients) are shown in Figures 3.5P < .05) correlations exist only between systolic blood pressure or respiratory rate and NRS during T2 and between respiratory rate and BPS for rater A at T2, but they do not pass Bonferroni correction (P > .00096). Overall no statistically significant correlation was found between physiologic parameters and BPS.Spearman rank correlation coefficients for tested physiologic parameters  and patients’ NRS score and BPS score for rater A and rater B are shown in Table 4The POL-BPS study was performed to validate the POL-BPS in a special population of patients undergoing cardiac surgery who were assessed both sedated and unsedated, but intubated and mechanically ventilated at time of data collection. Two important elements occurred in this study. First, we have performed a validation of the POL-BPS. Second, we were able to reliably assess pain in sedated postoperative cardiac patients using BPS and their self-assessment.,7,12 BPSs (CPOT and BPS) were originally available only in French or English, but translation into Polish was performed by the authors of this study. A study validating the Polish version of CPOT has already been published and aids Polish-speaking healthcare professionals and patients worldwide. Our present study concentrated on the validation of the POL-BPS along with other recent attempts to validate the BPS in different countries.–17According to international recommendations and guidelines, adequate pain assessment is a prerequisite not only for optimal pain treatment, but also for effective therapy of agitation and delirium associated with critical illness.The results of POL-BPS study showed very high intraclass correlation coefficients (ICC > 0.86), indicating very good interrater reliability of the POL-BPS. Moreover, we have shown good discriminant validity, identified by higher BPS results during painful procedures than at the time before or after these procedures, both with and without sedation. These results indicate that the POL-BPS is a reliable tool for pain assessment.P < .00001). Other authors have shown similar results. Ahlers et al have shown a strong correlation between nurses’ BPS ratings and conscious sedated patients’ VRS-4 ratings during the painful procedure .We have also shown a good correlation between patient's self-reported pain using NRS and pain observed by both raters with the use of BPS (Rs > 0.57) which indicates a relatively good criterion validity , as compared to 0.86 from the results of our study.The original study performed by Payen et al that introduced BPS to clinical practice showed that it can validly and reliably be used in sedated mechanically ventilated patients. It showed good internal consistency for BPS as determined by standardized Cronbach α=0.89 with good agreement percentages (80%) and acceptable interrater reliability . Other validation studies of BPS in different patient population and languages have shown similar results.,20–22There are not many studies assessing pain in the postcardiac surgery patient group. The uniqueness of our study lies in the fact that we included observations in both sedated and unsedated patients. Despite receiving sedation (dexmedetomidine) and analgesia (morphine), they were able to interact with the bed-side nurses and raters and self-assess pain using the NRS. Although difficult to obtain in the vulnerable postcardiac surgery period, this led to an appropriate validation of a BPS against patient self-report of pain. Similar recent studies performed in conscious patients suggested that concomitant use of both BPS and CPOT during painful interventions or nursing care may improve the evaluation of pain. as this leads to better optimization of the pain treatment in postcardiac surgery patients. Possibly the reason that the correlations between NRS and BPS in our study are below 0.8 is because the NRS and BPS assess pain differently and do not measure exactly the same thing. The assessment of pain should be multi-dimensional and take into account both patient's report as the gold standard (VAS or NRS), as well as observer's report  using a behavioral scale and other issues, namely patient's previous experience or expectations. It has been much debated recently that carers should move beyond pain scores and acknowledge not only pain intensity measurement, but also patient's personal pain experience, pain threshold, verbal pain evaluation, and opinion. It has been highlighted that some healthcare professionals and patients differ in their interpretation of the postoperative NRS scores, therefore we should take into account the patient's preference for pharmacologic treatment.,25Moreover, our study group was very homogenous due to a standard anesthesia protocol during the procedure (same set of medications for each patient) and in the postoperative period . Opioid delivery was a part of routine postoperative analgesia and did not differ between patients, which adds to the homogeneity of the study group. Continuous morphine infusion along with nonopioid analgesics provides a well-balanced analgesia, but may influence patient responsiveness. This was possible in our study, but usually when the patient is able to do self-evaluation, they do not require assessment with a behavioral scale. Some authors suggest that to obtain most reliable results both verbal and nonverbal tools should be used,Our study is not without limitations. This observational research was performed in a specific group of patients: postoperative cardiac surgery patients, critically ill people who were intubated and mechanically ventilated. This indicated that this validation study does not cover all potential critically ill patients and that further studies may be required to address specific population . We excluded emergency patients to provide homogeneity of the analyzed population, but there is a need to validate the BPS tool also in this group of patients.5The results of this study show that the POL-BPS can be regarded as a useful and validated tool for pain assessment in adult intubated patients. This instrument can be used in both unsedated and sedated cardiac surgery patients with limited communication abilities. This study should be regarded as one of the many steps along the way to improve pain assessment and control.The authors of this study are grateful to the patients, physicians, nurses, and physiotherapists at the Pomeranian Medical University in Szczecin, Poland, for their collaboration. They also thank J.F. Payen for agreeing to allow us to translate the BPS into Polish, and Ms Paulina Spólnicka RN from Teaching Hospital No. 2 for her great effort in data collection. The authors thank Ms Heather Hart RN and Ms Joanna Stollings RN from Vanderbilt University for their kind support with BPS back translation and expert consult.KK designed the study, collected the data, analyzed the results and wrote the manuscript. MS collected the data and provided critical review of the manuscript. KS designed and performed statistical analysis. MZB, MŻ, MB, and WE made substantial contributions to the conception of the work and critically reviewed the manuscript. All of the authors read and approved the final manuscript.Conceptualization: Katarzyna Kotfis, Marta Strzelbicka, Małgorzata Zegan-Barańska, Krzysztof Safranow, Mirosław Brykczyński, Maciej Żukowski, Eugene Wesley Ely.Data curation: Katarzyna Kotfis, Marta Strzelbicka, Małgorzata Zegan-Barańska, Krzysztof Safranow.Formal analysis: Katarzyna Kotfis, Marta Strzelbicka, Krzysztof Safranow, Mirosław Brykczyński, Maciej Żukowski, Eugene Wesley Ely.Funding acquisition: Maciej Żukowski.Investigation: Katarzyna Kotfis, Małgorzata Zegan-Barańska.Methodology: Katarzyna Kotfis, Marta Strzelbicka, Małgorzata Zegan-Barańska, Krzysztof Safranow, Eugene Wesley Ely.Project administration: Katarzyna Kotfis.Resources: Katarzyna Kotfis.Software: Katarzyna Kotfis, Marta Strzelbicka.Supervision: Małgorzata Zegan-Barańska, Mirosław Brykczyński, Maciej Żukowski, Eugene Wesley Ely.Validation: Katarzyna Kotfis, Krzysztof Safranow.Visualization: Katarzyna Kotfis, Marta Strzelbicka.Writing – original draft: Katarzyna Kotfis, Krzysztof Safranow.Writing – review & editing: Marta Strzelbicka, Małgorzata Zegan-Barańska, Mirosław Brykczyński, Maciej Żukowski, Eugene Wesley Ely.Katarzyna Kotfis orcid: 0000-0001-8430-1369


Background and Objective: The objective of this study was to explore the nociceptive effect of platelet-rich plasma (PRP) intramuscular injections in myofascial pain of masseter muscles in patients with TMD.Methods: Patients diagnosed with myofascial pain were assessed for eligibility for the study. Masticatory muscle disorder was diagnosed based on the Research Diagnostic Criteria for Temporomandibular Disorders (Ia and Ib). A total of 80 patients were enrolled in the study; 58 of them  met the inclusion criteria and were randomized to one of the two groups: Group I (n = 29) and Group II (n = 29). The first group received injections with PRP and the second group received injections with isotonic saline as the control group (0.9% NaCl). The Visual Analog Scale (VAS) was used to determine the pain intensity changes during follow-up visits in each group.Results: A significant improvement in pain intensity in VAS scale was observed, with 58% reduction in the experimental group and 10.38% in the control placebo group, 5 days after the injections (Day 5). The pain intensity reduction (VAS) 14 days after the injections (Day 14) in experimental group was 47.16 and 4.62% in control group, according to the baseline values (Day 0).Conclusions: Intramuscular injection of PRP was a successful method for reducing myofascial pain within masseter muscles in temporomandibular disorders patients. However, the use of PRP for the treatment of myofascial pain within masticatory muscles requires further, clinical trials evaluation.Clinical Trial Registration: Bioethical Commission at the Silesian Medical Chamber in Katowice, Poland 44/2017 as well as at ClinicalTrials.gov NCT03323567 . PRP con plasma) . PRP hasPolish version of Research diagnostic criteria for temporomandibular disorders (RDC/TMD) was used in the study . MyofascMuscle regeneration and myogenesis are closely related to growth factors such as insulin-like growth factor-1, fibroblast growth factor-2, hepatocyte growth factor, transforming growth factor beta 1(TGFβ-1), tumor necrosis factor-α, platelet-derived growth factor, and prostaglandins. These factors stimulate proliferation, and differentiation of myoblasts . HepatocThe aim of this study was to explore the nociceptive effect of platelet-rich plasma (PRP) intramuscular injections in selected patients with myofascial pain of masseter muscles.Eighty adult patients were selected from the population of subjects referred to the Department of Temporomandibular Disorders. Fifty nine subjects  suffering from myofascial pain of the masseter muscles were found eligible and enrolled to the study.Age ≥18 and ≤80.Presence of myofascial pain within masseter muscles according to the RDC/TMD (Ia and Ib) .Patient's agreement for participation in this study.The inclusion criteria were:Patients being treated with or addicted to analgesic drugs and/or drugs that affect muscle function.Patients with neurological disorders, and/or neuropathic pain, and/or headache.History of the head or neck trauma in preceding the enrollment 2 years.Edentulous patients.Patients after radiotherapy.Presence of mental disorders.Pregnancy or lactation.Pain of dental origin.Diagnosis of malignancy.Drug and/or alcohol addiction.Patients with needle phobia.The exclusion criteria were:This study was approved by the Bioethical Commission at the Silesian Medical Chamber in Katowice, Poland (number 44/2017), and retrospectively registered at ClinicalTrials.gov (NCT03371888). The study was performed in accordance with the Declaration of Helsinki as well as the International Conference on Harmonization: Guidelines for Good Clinical Practice. All included patients gave their consent to participate in the study and received verbal and written information describing the trial.n = 59), of both genders were randomized into one of two groups: experimental , and control   while checking the pain level in Visual Analog Scale (VAS). PRP was prepared for both groups: I and II before the injection on Day 0. PRP in controls was prepared and frozen at −20°C for the future use  . Patientture use .Pain intensity was measured with VAS scale  before (Day 0), during (Day 5), and after (Day 14) of the therapy with PRP injections.Baseline visit: injection of study substances—Day 0Control no. 1 after 5 days–Day 5Control no. 2 after 14 days–Day 14The trial consisted of three visits:The activities undertaken by the investigators during the trial are presented in Approximately 40 mL of venous blood was harvested from the cubital vein in four anticoagulant vacutainer tubes , with a dedicated large-bore needle . The blood was mixed (5 times to prevent micro bunches creation) with an anticoagulant (3.2% sodium citrate). Pure-PRP was prepared as described by Ehrenfest , 15. ThrDuring the intervention, painful muscle parts within the masseter muscles were identified with palpation of the masseter muscle and in each group the same amount of the appropriate substance was injected. In all groups, disposable syringes (5 mL) and needles  were used for injections. Group I PRP and in Group II isotonic saline (0.9% NaCl) were injected bilaterally into the right and left masseter muscles at 3 painful points at each site (6 × 0.5 mL = 3 mL) near the origin, under the zygomatic arch. Injections were deposited 0.5–1.0 cm under the skin surface.For measuring a treatment outcome, VAS scale was used at Day 5 and Day 14 follow-up visits.The minimum sample size necessary to achieve the presumed accuracy of the estimation is determined by the two-stage Stein method.For the statistical analysis the Statistica software, version 13.1. by Statsoft Polska was used.t-test for two means;tests for two variances .To demonstrate the effect of the applied treatment on the level of pain, the following parametric tests were used for two independent tests  hypothesis H0 was the equality of the corresponding means in the experimental Group I and the control Group II; for variance tests, it was the equality of the corresponding variances.In the At the end, we will verify the null hypothesis about the equality of the distribution of pain levels in both groups of patients, usingWald-Wolfowitz runs test;U Mann-Whitney test.p > 0.05)  . There w > 0.05) –4.In the case of the experimental group I (PRP), the values of key descriptive statistics and the limits of confidence intervals for the mean and standard deviation of pain level at the confidence level of 0.95 (or 95%) were as in For control experiments, the confidence intervals for the mean and standard deviation at the confidence level 1–α = 0.95 were constructed.Relevant results for Group I are represented in For both control visits: after 5 days and after 14 days, we have rejected the null hypothesis about the equality of the average level of pain in the experimental and control groups. The tests confirm the earlier observation that the level of pain in the experimental group, Group I, is significantly lower than the corresponding level in the control group, Group II, both after 5 and after 14 days. The tests results are given in Non-parametric tests confirm the thesis that the level of pain in Group I is significantly lower than the analogous level in Group II, both after 5 and after 14 days. The results are given in After the injection of PRP or isotonic saline in the masseter muscle, three patients in Group I, and one patient in Group II, reported edema and muscle pain. Seven patients had an adverse side effect: bruising, as a result of blood harvesting procedure from the blood vessel. These symptoms were only temporary and completely reversible. There were no serious adverse effects during the trial.The 58% reduction in pain intensity, 5 days after PRP injection in masseter muscles was achieved, comparing to the control group, where the 10.24% reduction in pain intensity was observed. An intramuscular administration of PRP is being used more frequently as a popular treatment for skeletal muscle injuries in athletes . Better In patients suffering from TMD it is important to stop the pain in the first place and after pain relief other types of therapies should be included, such as treatment with intraoral occlusal appliances, anti-inflammatory treatment, and muscle tension-pharmacotherapy, psychotherapy: parafunction prevention, and treatment of bruxism .The use of PRP is an innovative method. It carries almost no risk of complications and although not all authors agree with its high effectiveness of action, according to this research study it is an effective treatment for masseter muscle myofascial pain , 16, 17.in vivo is ~7–10 days (In Franchini meta-analysis, the author has proved the lack of effectiveness of the PRP in orthopedics . Accordi–10 days . The eff–10 days . AccordiIn selected patients with TMD, suffering from myofascial pain, the intramuscular injection of PRP could be considered as additional, successful therapy in pain relief, when other conservative methods do not bring relief. The further investigation on safety and efficacy of the method are needed.The datasets supporting the conclusions of this article are included within the article. Access to these data will be considered by the corresponding author upon request.AN-B created trial concept, performed intramuscular injections of PRP and wrote and edited the manuscript. KW-D collected information concerning pain intensity changes using VAS. SB conducted the randomization and edited the manuscript. Statistical calculations were carried out by WK. All authors 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.


Postoperative pain control and enhanced mobilization, muscle strength and range of motion following total knee arthroplasty (TKA) are pivotal requisites to optimize rehabilitation and early recovery. The aim of the study was to analyze the effect of local infiltration analgesia (LIA), peripheral nerve blocks, general and spinal anesthesia on early functional recovery and pain control in primary total knee arthroplasty.n = 81) or epidural catheter  in combination with general anesthesia or spinal anesthesia, respectively, and LIA combined with general anesthesia  or spinal anesthesia . Outcome parameters focused on the evaluation of pain (NRS scores), mobilization, muscle strength and range of motion up to 7 days postoperatively. The cumulative consumption of (rescue) pain medication was analyzed.Between January 2016 until August 2016, 280 patients underwent primary TKA and were subdivided into four groups according to their concomitant pain and anesthetic procedure with catheter-based techniques of femoral and sciatic nerve block  in combination with spinal anesthesia, especially in SP&EPI. The LIA groups, in contrast, revealed significant higher mobilization (up to 26%) and muscle strength (up to 20%) in the early postoperative period. No analgesic technique-related or surgery-related complications occurred within the first 7 days. Due to insufficient pain relief, 8.4% of the patients in the catheter-based groups and 12.2% in the LIA groups resulted in a change of the anesthetics pain management.The LIA technique offers a safe and effective treatment option concerning early functional recovery and pain control in TKA. Significant advantages were shown for mobilization and muscle strength in the early postoperative period while pain relief was comparable within the groups. Postoperative pain after total knee arthroplasty (TKA) is still a challenging issue. For a successful outcome, pain control following TKA is essential to achieve early mobilization, good functional outcome, optimal rehabilitation and enhanced recovery . TherefoThere is a considerable debate on the optimal form of postoperative analgesia in total knee replacement . SeveralRegional anesthesia techniques are widely used to deliver intraoperative analgesia and to minimize postoperative pain after TKA , 3. In gAs an alternative method for postoperative pain control after TKA, LIA around the soft tissues of replaced knee joints was introduced by Kerr and Kohan in 2008 with an increasing interest in recent years . The anaSeveral studies successfully demonstrated significant pain relief and reduced opioid requirements in the early postoperative period by use of LIA compared to placebo –13 or  catheter-based techniques and their combination with general or spinal anesthesia in one patient collective on pain control, mobilization, muscle strength and range of motion for up to 7 days postoperatively. The hypothesis of this study was that each anesthetic procedure directly influences the immediate postoperative status of the patient in terms of pain control, mobilization, muscle strength and range of motion. Therefore, the aim of the study was to analyze the effect of femoral nerve block and general anesthesia (group GA&FNB), epidural catheter and spinal anesthesia (group SP&EPI), LIA combined with general anesthesia (group GA&LIA) and spinal anesthesia (group SP&LIA), respectively, on early functional recovery and pain control in primary TKA.During the period from January 2016 until August 2016, 300 patients underwent primary TKA in a single center for alloplasty. Finally, a total of 280 patients were eligible for the study having received general or spinal anesthesia in combination with a FNB, epidural catheter or LIA. The inclusion criterion was primary TKA for osteoarthritis. Patients were excluded if they had a primary constrained prosthesis, secondary arthritis due to rheumatoid arthritis or trauma, osteonecrosis or revision surgery. This study was performed in conformity with the Declaration of Helsinki and was approved by the Ethics Committee of the Bavarian State Chamber of Physicians (ID: 2017–109). Patient demographics, surgery details, and clinical data are shown in Table Patients were retrospectively divided into 4 groups according to their received anesthetic and peri-and postoperative analgesic procedure as follows:n = 81.Group GA&FNB: General anesthesia + FNB/SNB n = 51.Group SP&EPI: Spinal anesthesia + epidural catheter n = 86.Group GA&LIA: General anesthesia + LIA n = 61.Group SP&LIA: Spinal anesthesia + LIA After induction of general anesthesia, patients allocated to GA&FNB had a FNB catheter inserted with real-time monitored ultrasound imaging. A total of 20 ml of 0.1% ropivacaine was injected around the femoral nerve; additionally ultrasound-guided sciatic nerve block with 20 ml of 0.1% ropivacaine was established as single shot block. Postoperatively, 0.2% ropivacaine was continuously infused at the rate of 3 ml/h for 3 days through the femoral catheter.In SP&EPI, a catheter was preoperatively sited at the cranial lumbar vertebrae combined with a spinal anesthesia (1 ml of 0.5% bupivacaine and 10 μg sufentanil in the subarachnoid space) in a single needle technique. After recovery from spinal anesthesia under the level L3, an initial 10 ml bolus containing 0.5% bupivacaine, 0.6 μg/ml sufentanil and saline was introduced. Thereafter, patients were self-medicated with a bolus of 4 ml via a patient-controlled epidural anesthesia (PCEA) system with a lockout of 20 min. PCEA was discontinued three days after surgery.For the patients in the LIA groups, the surgeons undertook periarticular injection of local anesthetic during surgery. The injection technique used was similar to the technique described by Kerr and Kohan . However® complete Knee System  was used; the tibial component was fixed with cement. Bone resections and implant insertion were conducted according to the manufacturers manual. The patella was generally not resurfaced; however, patella osteophytes were removed and circular patella denervation was regularly performed.All surgeries were performed by three senior surgeons. Intraoperatively, single-shot cefazolin 2 g (or clindamycin 600 mg in case of incompatibility of penicillin) for infection prophylaxis was given to all patients. The surgeries were performed with a standard midline vertical incision and medial parapatellar approach. A tourniquet was inflated to 250 mmHg at the beginning of the surgery and deflated after removal of the surgical dressings. In all cases, the LCSPostoperative management was identical in all groups. After surgery, every patient was given peripheral pain medication  for about 2 weeks to relieve pain and low molecular weight heparins subcutaneously for about 2 weeks to prevent deep vein thrombosis. The cumulative doses of rescue analgesia (hydromorphone p.o. or piritramide i.v.) were also registered.Postoperative physiotherapy was started immediately after surgery in a progressive manner and continued daily. A specially trained pain service regularly visited all patients twice a day for the first four postoperative days.Self-reported pain scores in terms of numeric rating scores (NRS) at rest and with activity  from day of surgery until postoperative day 4 were collected and analyzed. For evaluation of functional outcomes, grade of mobilization ranging from values of 1 to 6 according to our institutional grading system of mobilization was analyzed: 1 = bedridden, 2 = sitting, 3 = standing, 4 = walking in room, 5 = walking on the floor, 6 = walking stairs. Furthermore, muscle strength according to the British medical research council (M0/5-M5/5) and passive range of motion (degrees of extension and flexion) were examined. Functional outcomes of mobilization, muscle strength and range of motion were documented daily from pre-operative day until postoperative day 7, respectively. The patients’ medical files were also studied for potential analgesic technique-related or surgery-related complications within the first 7 days, such as rates of neurologic events, cardiovascular events, falls, knee joint infections, prosthesis loosening, or revision surgery. All data were collected from the patients´ medical records and nurses´ observational charts.Statistical analysis was performed with SPSS statistical software 20.0 . Descriptive statistics were calculated for all variables of interest. Continuous measures such as age were summarized using means and standard deviations whereas categorical measures were summarized using counts and percentages.The Kruskal-Wallis test was used for analysis of one nominal variable and one ranked variable. In a further detailed analysis, post-hoc comparisons of factor-level combinations were conducted by use of Mann-Whitney-U test, depending on previous  significance testing. In this explorative study, no adjustment of an alpha-error level was conducted.Baseline characteristics of patients were comparable among all groups Table . About 6n = 4) patients received a patient-controlled intravenous analgesia (PCIA) with an initial bolus of 4 mg piritramide followed by an optional bolus of 2 mg piritramide with a lockout of 10 min. In the other groups, most anesthetic techniques with insufficient pain relief were converted to a secondary application of a FNB. These patients were excluded from outcome measurements. No analgesic technique-related or surgery-related complication occurred in any group within the first postoperative 7 days. At day of surgery, the demand for piritramide was significantly higher  in groups with general anesthesia compared to groups with spinal anesthesia, while it was not significantly different between each other anymore at the first postoperative day (p = 0.77). All LIA patients received 160 ml of the LIA injection with 16.4 mg ± 3.1 (group GA&LIA) and 15.7 mg ± 3.1 (group SP&LIA) dexamethasone, respectively.Pain exacerbation after surgery due to insufficient pain relief (NRS > 7) with the current anesthetic technique led to another analgesic technique. In GA&FNB, 4.9% (p = 0.182), did not show any significant differences at any time (p > 0.05). The development of the NRS scores with activity was comparable among groups (p > 0.05); only both groups with spinal anesthesia demonstrated slightly but non-significantly increased pain values at the day of surgery (p = 0.132).The NRS scores Fig.  at rest,p < 0.001; Fig. At the day of surgery as well as at postoperative days 1, 2 and 3, the dose of hydromorphone was on average 42 to 58% lower in SP&EPI compared to all other groups  and GA&LIA . From postoperative day 2 on, no further significant differences among the groups could be detected (p > 0.05).The grade of mobilization (0 to 6) revealed a gradual increase after surgery Fig. . Hereby,p < 0.001 and p = 0.001, respectively) and day 2 ; at day 3 only GA&LIA showed higher muscle strength compared to GA&FNB . Additionally, the values of SP&EPI were significantly lower compared to GA&LIA from day 1 to 3 .The results of the muscle strength Fig.  accordinp > 0.05, Fig. The mean range of motion (flexion and extension of the knee joint) was comparable and not different among the groups p > 0.0, Fig. 5 The aim of the LIA technique is to release the therapeutic effect by blocking pain conduction at its origin. Here, the distribution and the quantity of the injected local anesthetics are of great importance. Therefore, our injection was performed according to a standardized protocol to systematically reach every part of the knee joint’s surrounding tissue. In an anatomic study, the anatomical spread of a LIA used in TKA was examined to identify the nerve structures reached by the injected fluid . The resIn literature, most trials reported reduced pain and opioid requirements in the early (< 48 h) postoperative period with LIA compared with placebo or no injection –13. In ap < 0.001). Furthermore, the spinal anesthesia group with an epidural catheter (SP&EPI) revealed an up to 58% lower dose of hydromorphone from the day of surgery until day 3 compared to all other groups. Consistent with our results, Harsten et al. described a significantly reduced pain score with spinal anesthesia within the first 12 h in contrast to general anesthesia while both anesthetic procedures seem to generate the same overall pain ratings [Compared to  analgesic catheters, LIA generally achieves comparable results with regard to postoperative pain –23. A re ratings . This isBut most mentioned studies just focused on pain relief and did not consider further functional aspects including mobilization, muscle strength or range of motion. In contrast to LIA groups, patients of GA&FNB were less likely to be able to stand in front of their bed on the day of surgery or even start to ambulate at postoperative day 1; an effect attributed to possible residual muscular weakness from the two peripheral nerve blocks. These findings were supported by Safa et al., who also demonstrated a significantly minor mobilization in the FNB/SNB group compared to LIA at day 1 . HoweverA common concern of the LIA technique is the potential toxic side effects, which might be elicited by a joint and tissue infiltration of local anesthetics like ropivacaine. Knudsen et al. defined the toxic threshold in arterial samples for unbound concentration of ropivacaine to be 0.56 μg/ml and for maximum total concentration to be 4.3 μg/ml . A pharmThere are some limitations that pertain to that study. The length of hospital stay was not a measured outcome of this study, however, all of our TKA patients followed a clinical pathway with standardized discharge criteria. This included the ability to ambulate and negotiate stairs with an assistive device, independent activities of daily living as well as knowledge of how to progress and continue an independent exercise program with an established plan for discharge physiotherapy. Furthermore, due to its retrospective design, the study was not blinded or randomized, which may have introduced reporting bias. The choice of anesthesia by the patient might also have induced some selection bias, although the group characteristics appeared to be identical among the four groups. Although it was a retrospective investigation, the strengths of the study include a large number of patients managed according to clear inclusion and exclusion criteria. The surgical and anesthetic procedures followed a consistent standard-treatment protocol in the same hospital by the same surgeons with extensive surgical experience in the treatment of total knee arthroplasties and its concomitant analgesic procedures.In conclusion, the findings from this study suggest an advantage of LIA in the early postoperative periods in terms of mobilization and muscle strength. Range of motion was comparable among all groups. Pain control was also similar in all groups, while the use of rescue pain medication was significantly lower with SP&EPI compared to all other groups within the first postoperative days. Thus, clinicians should consider the risk-to-benefit ratio for each case individually.


High pain self-efficacy and low kinesiophobia seem related to a better prognosis in patients complaining of low back pain (LBP). The literature stresses the potential negative effects of anatomical defect diagnosis (e.g. lumbar spondylolisthesis) on the psychological profile. The aim of this study is to investigate the relationships between awareness of having a spondylolisthesis, pain self-efficacy and kinesiophobia.A secondary retrospective analysis was done. Ninety-eight subjects with subacute and chronic LBP were included: 49 subjects with diagnosed symptomatic lumbar spondylolisthesis and 49 subjects with diagnosed non-specific LBP. The pain self-efficacy measured with the Pain Self-Efficacy Questionnaire and the fear of movement measured with the Tampa Scale of Kinesiophobia were considered variables to investigate, whereas diagnosis and demographic/clinical variables were considered predictors or potential confounders.p = 0.82), nor kinesiophobia (p = 0.75). Higher perceived pain reduces pain self-efficacy and increases kinesiophobia in both groups .By comparing the two groups, the awareness of having a spondylolisthesis did not significantly influence neither pain self-efficacy (It seems that the awareness of an anatomical defect as spondylolisthesis does not significantly affect the beliefs of carry out activities and movements despite the pain. Other studies with wider samples are required, to confirm these preliminary results. Low back pain (LBP) is one of the most important causes of disability worldwide and is associated with enormous social and economic costs . LBP is Spondylolisthesis is defined as the slipping of a vertebral body in relation to the one below and is classified in isthmic and degenerative . The golIn fact, most signs in symptomatic spondylolisthesis are comparable with those of non-specific LBP, not allowing the clinician to make differential diagnosis by the clinical examination itself . The onlIt is known that pain is not only a direct consequence of pathology or anatomic lesion but is influenced by some psychological factors. Pain seems to be the result of an individual past experiences of pain and healthcare, as well as cultural and educational characteristics. High pain self-efficacy and low fear of movement are considered relevant in reducing the consequences of LBP in terms of catastrophizing and depression . AttitudBeliefs of pain due to anatomical lesion may focus the subject on negative concepts of damage, illness and harm may be associated to greater fear-avoidance beliefs and correspondingly higher disability –13. FearPain self-efficacy may depend on three factors: experience, observation of others with similar problems, and education . Poor seSeveral authors suggest avoiding communication with patients by “anatomical diagnosis”, posing instead higher stress on the favorable prognosis of LBP, the importance of having active coping strategies, the explanation of pain mechanisms, etc. . In the The main aim of this study is to investigate the relationships between awareness of having a spondylolisthesis, pain self-efficacy and kinesiophobia, by comparing two different samples of LBP patients: patients diagnosed with spondylolisthesis, and patients diagnosed with non-specific LBP. Our assumption was that the awareness of having an “anatomical failure”, obtained after seeing x-ray imaging and/or after receiving medical diagnosis of spondylolisthesis, could lead to higher kinesiophobia and less self-efficacy, together with higher disability levels. Our hypothesis was that patients with spondylolisthesis, who know they have a slipped vertebra that it could not come back, may have less self-efficacy and more fear-avoidance behaviors, compared to patients with non-specific LBP.Moreover, we aimed to investigate the relationships between main socio-demographical and clinical characteristics, and psychological patient profile.The STROBE recommendations for observational studies were followed .Monocentric retrospective analysis.The medical records of 100 consecutive outpatients with subacute or chronic LBP submitted to a conservative treatment in a physiotherapy clinic located in northern Italy were retrospectively reviewed. More specifically, these records were already used for two previous studies , 25.The eligible patients for this secondary analysis were 223 subjects . First, we selected the records coming from only one physical therapy clinic and collected by the same physical therapist (to avoid bias related to different way of communication with patients), leaving a sample of 53 outpatients with spondylolisthesis and 49 with non-specific LBP. To compare two groups with equal size, we deleted the last three records from the Vanti et al. spreadsheet. Therefore, this secondary analysis included 98 outpatients with subacute or chronic LBP , who were retrospectively studied . Inclusion criteria concerned outpatients older than 18 years, complaining of LBP lasting for at least 1 month, with or without referred pain. Exclusion criteria were previous lumbar surgery, systemic diseases , neuromuscular disorders or cognitive deficits.This sample was composed of women (59%) and men (41%), with a mean age of 49 years and a LBP mean duration of 14 months. Socio-demographical and clinical characteristics and scales scores  were collected in a MS Excel spreadsheet.All participants filled in the PSEQ-I, the TSK-I, and the NRS at the starting of their treatment period and after having received their clinical diagnosis, that was symptomatic lumbar spondylolisthesis, or non-specific LBP.The PSEQ-I was used to measure the degree of pain self-efficacy . Each paThe TSK-I aimed to measure the beliefs in relation to pain and physical activities. It is composed of 13 items ranging from 1 = completely disagree, to 4 = completely agree, with total score from 13 to 52 . It is dPain intensity (subjective perception of pain) is usually measured with a Numerical Rating Scale (NRS), which demonstrated good sensitivity and responsiveness .It is composed of 11 values ranging from 0 (no pain) to 10 (unbearable pain), indicating the main intensity of pain experienced by a patient in the last week. A significant relationship between changes on the Pain Intensity and the Patient Global Impression of Change was demonstrated .Pain self-efficacy measured with the PSEQ-I and fear of movement measured with the TSK-I were considered the variables to investigate, and assume the role of response variables, whereas the other variables  were considered predictors or potential confounders. One research assistant provided all the participants with written information concerning the questionnaires and procedures.Based on the study design, Institutional Review Board approvals were previously obtained, consent forms had already been signed, and further forms were not required. The privacy rights of participants were observed, and the procedures followed were in accordance with Italian ethical standards and with the Helsinki Declaration of 1975, as revised in 2000.Given the retrospective nature of the study, a post-hoc power analysis was done to avoid underpowered results at the time of the final statistical analysis.All continuous variables were summarized using descriptive statistics and in particular were reported as mean ± standard deviation (SD). Categorical or dichotomous variables were reported with their absolute and relative frequencies. Linear regression analysis was adopted to explore the correlation between the PSEQ-I, TSK-I, and socio-demographic and clinical characteristics.To analyze in a deeper way the results in relation to the level of self-efficacy, we stratified our sample in two different subgroups: high self-efficacy (PSEQ-I score > 40) and low self-efficacy (PSEQ-I score ≤ 40). Similarly, for kinesiophobia we stratified our sample in two subgroups: high kinesiophobia (TSK ≥ 37) and low kinesiophobia (TSK < 37).p values less than 0.05 and 95% confidence intervals were provided for variables subjected to statistical inference. All statistical analyses were performed using STATA, version 15.1.All tests were considered significant with The medical records of 98 consecutive outpatients with subacute or chronic LBP  afferent to one physical therapy clinic were retrospectively screened. Student’s t-test did not show any relevant differences in baseline characteristics between groups.Table p = 0.82), nor kinesiophobia (p = 0.75), compared with patients having received a diagnosis of non-specific LBP. Moreover, low PSEQ-I and high TSK-I rates appeared significantly related to higher pain intensity .Post-hoc power analysis based on effect size = 0.61, α = 0.05, and sample size = 98 demonstrated high power of the present study (1-β error probability = 1.000). The relationships between PSEQ-I, TSK-I and the following demographic and clinical characteristics were investigated: diagnosis, age, sex, marital status, educational level, smoking, amount of pain, duration of pain, and use of drugs. Concerning the influence of these characteristics on psychological patient profile, linear regression showed that having received a diagnosis of symptomatic lumbar spondylolisthesis does not influence neither pain self-efficacy (p = 0.06) with higher self-efficacy, but not significantly related with lower kinesiophobia (p = 0.12). No other demographic or clinical characteristics significantly modified self-efficacy or kinesiophobia in this sample. Moreover, higher self-efficacy levels were significantly associated to lower kinesiophobia . After having stratified the subjects for high versus low levels of self-efficacy and kinesiophobia, these results did not significantly change in both groups.High educational level (university degree) was borderline related  may modify pain self-efficacy and kinesiophobia, in subjects complained of subacute or chronic LBP. Our assumption was that the awareness of permanent damage and potentially chronic pain could lead to modification of beliefs with passivity, inactivity, pain-avoidance, all of which may provoke kinesiophobia and less self-efficacy, with higher disability in the future. This consideration of damage about your own spine could also be enhanced by practitioner or spine surgeon explanations about the diagnosis and related complications. Some studies confirmed that not verbal communication, the words used for the diagnosis and the received prescriptions could influence the patient’s thoughts and believes after a physician visit –35. DespThe second aim of this study was to investigate the relationship between some demographic and clinical characteristics, and pain self-efficacy and kinesiophobia.The results of the present study did not confirm our expectations, which were based on the current literature on catastrophizing and fear of movement. In fact, we cannot confirm any significant correlation between the awareness of having a spondylolisthesis, self-efficacy and kinesiophobia. Having received an “anatomical defect diagnosis”, like spondylolisthesis, does not correspond to an excessive patient “attention”, which can affect the way in which a subject handles their thoughts, pain, and daily living activities.Current literature considers diagnostic labelling referred to anatomical basis for LBP, frequently endorsed by healthcare professionals, as significantly influencing patients’ beliefs , especiaMoreover, many studies showed that disc surgery patients are at a higher risk of suffering from depression and anxiety than the general population. These studies emphasized the relevance for clinicians to consider psychological concerns in patients undergoing disc surgery , 43.At the best of the authors’ knowledge, no previous similar study was performed on beliefs and behaviours in lumbar spondylolisthesis. However, some studies showed that pain self-efficacy and lumbar function may improve in symptomatic lumbar spondylolisthesis through a rehabilitation program centred on cognitive and behavioural principles, both in conservative setting , and aftA possible explanation for the results of the present study comes from a qualitative study conducted on chronic pain patients with high kinesiophobia . One of ”, the fully understanding of the diagnostic jargon and the implications of diagnostic label could be relevant. Among patients with fibromyalgia, who do not make sense to their symptoms will more likely catastrophize [For patients with chronic pain, more than the diagnosis “per setrophize . Moreovetrophize .The second result of the present study concerns the relationship between higher pain, reduced pain self-efficacy and increased kinesiophobia in both groups. This finding is coherent to other studies on chronic LBP, showing that pain severity is related to high Fear Avoidance Beliefs Questionnaires scores , 50.Concerning self-efficacy, there is evidence that high level of self-efficacy correlates to lower intensity of pain and disability, in patients with chronic pain –53. On tConcerning demographic characteristics, we did not find any relevant correlations between psychological profile, age and gender, according to the results of Rahman and colleagues  on chronOur study is the first one investigating the relationship between pain self-efficacy, kinesiophobia and clinical diagnosis of spondylolisthesis. The relevance of our study is the investigation of main characteristics potentially influencing the psychological patient profile in lumbar spondylolisthesis.The results of the present study did not confirm any significant correlation between the awareness of having a spondylolisthesis, and self-efficacy and kinesiophobia. No significant correlation has also been found between the awareness of having a spondylolisthesis and the patient’s sociodemographic characteristics. Only higher pain levels were significantly related to a worse psychological condition.The main limitation of this study is the generalization of the results, due to the characteristics of our sample, composed of subjects with a medium-high level of instruction, residents in northern Italy. Moreover, the dimension of the sample may have influenced the results. Further studies on higher samples are suggested on the relationship between medical diagnosis, self-efficacy and fear of movement, both in spondylolisthesis and in other clinical conditions.Another limitation of our study concerns the lack of data about the time elapsed between the diagnoses of spondylolisthesis received by a physician or surgeon and the moment in which patients filled the questionnaires. Consequently, we could not investigate the influence of the time on the beliefs about the presence of spondylolisthesis.This study showed that in Italian population complained of subacute and chronic LBP, the awareness of an anatomical defect as spondylolisthesis does not significantly affect the beliefs in carrying out activities and movements despite the pain. Conversely, the amount of pain seems significantly influence the psychological patient profile.From a clinical point of view, the knowledge of main characteristics potentially influencing the patient perspective on his/her condition may be useful to better manage the clinician communication and patient education.


Patients with carpal tunnel syndrome (CTS) often show bilaterally increased pain sensitivity and widespread symptoms. We evaluated the influence of centrally mediated symptoms on functional outcomes of carpal tunnel release (CTR). A total of 120 patients with surgically treated CTS were enrolled. Centrally mediated symptoms were preoperatively measured by administering a self-reported central sensitization inventory (CSI) questionnaire and peripheral sensitization was measured by assessing patient’s pressure pain thresholds (PPT) in the forearm. Boston Carpal Tunnel Questionnaires (BCTQ) were assessed preoperatively and postoperatively at 3 and 12 months. CSI scores slightly correlated with symptom duration and moderately correlated with preoperative BCTQ scores, while PPT slightly correlated with the BCTQ scores. At 3 months, BCTQ symptom and function scores moderately correlated with lower PPTs and higher CSI scores. At 12 months, only severe electrophysiological grade was associated with BCTQ function scores. Multivariable analysis revealed that preoperative PPT, CSI, and female gender were associated with BCTQ scores at 3 months; these factors failed to be associated for 12-month outcomes. Centrally mediated symptoms measured by CSI and peripheral sensitization measured by PPTs correlated with symptom severity and duration. They were associated with poorer functional outcomes after CTR up to 3 months. However, they did not show persistent effects in the long term. Reported incidence of CTS ranges from 1 to 5 per 1000 person-years1. The number of CTS patients surgically treated in the United States is between 400,000 and 500,000 per year2. Although there are many potential causes of increased pressure on the median nerve, idiopathic CTS is the most common one3.Carpal tunnel syndrome (CTS) is the most common cause of pain due to peripheral nerve entrapment and occurs when the median nerve under the transverse carpal ligament is compressed at the wrist5, demonstrating a generalized disturbance of somatosensory function. CTS might be associated with pain sensitization both at peripheral level and central level6. Generalized decrease in pressure pain threshold in patients with CTS is associated with pain intensity and duration of symptoms, supporting a role of peripheral drive in initiating and maintaining central sensitization5. Functional deficit of nociceptive system has been considered as a pathophysiology of this condition where chronic pain is associated with sensitization in the peripheral afferents, dorsal root ganglion, and the central nervous systems, leading to neuroplastic changes7. Studies on subjects with CTS have revealed changes along the afferent pathway in the spinal cord, brain stem, and somatosensory cortex8.Symptoms of CTS are typically restricted to median nerve distribution, yet a significant number of patients with CTS show bilaterally increased pain sensitivity  and widespread symptoms12. Although the severity of central sensitization in patients with CTS might have contributed to postoperative outcomes of carpal tunnel release (CTR), clinical studies addressing the relationship between preoperative measures of central sensitization and surgical outcomes are lacking. Therefore, the objective of this study was to determine the influence of centrally mediated symptoms on outcomes of CTR.Research suggests that pain sensitization in peripheral musculoskeletal conditions  is associated with poorer clinical outcomes in response to a surgical or conservative intervention13 with 7 grades, ranging from grade 0  to grade 6 (extremely severe) was used in this study based on conduction time and amplitude. Grades 0 and 1 were grouped as mild. Grades 2 and 3 were grouped as moderate. Grades above 3 were grouped as severe. In cases of bilateral involvement, the more severely affected side was chosen for comparative analysis. Exclusion criteria were: those who had severe pain or disability at other joints, previous carpal tunnel surgery, history of psychiatric disorders, peripheral vascular disease, polyneuropathy, cervical radiculopathy, focal nerve entrapment other than carpal tunnel syndrome, pregnancy, hypothyroidism, rheumatoid arthritis, or inability to complete self-reported questionnaire; based on those, 132 (92%) patients were approached for this study. Of those, twelve (9%) were lost to follow up before 12 months, leaving 120 for analysis here  and with Good Clinical Practice standard. Between January 2014 and October 2017, one surgeon (YHR) surgically treated 143 patients for carpal tunnel syndrome at an urban tertiary referral hospital. Inclusion criteria were: those who were diagnosed with CTS based on clinical symptoms and physical examinations with confirmation by nerve conduction studies, and undertook unilateral CTR. History and symptoms included parasthesia and/or pain in at least two of median nerve-innervated fingers. Other symptoms included weakness and loss of dexterity of the hand. Physical examination for sensory loss, decreased thenar muscle strength, Tinel’s sign, and Phalen’s test were used to reinforce the diagnosis. Electrophysiologic studies were performed prior to surgery. Bland classification3 and wit15. The CSI provides comprehensive information regarding various centrally mediated symptoms15, and it demonstrates good reliability16 and construct validity15. This questionnaire assesses 25 somatic and emotional symptoms, which are frequently observed when central sensitization is a contributory factor to chronic pain conditions . The questionnaire also contains pain sensitivity related questions that can be found in everyday life . Each item was graded with a 5-point scale  representing low to high degree of symptom. The total score ranged from 0 to 100 points.Centrally mediated symptoms were preoperatively evaluated using Central Sensitization Inventory (CSI) questionnaire12. PPT are cut-off points when a sense of pressure changes to pain18. PPT were assessed in the mid-volar forearm of the affected side using a digital algometer  consisting of a 1-cm2 rubber-tipped plunger mounted onto a force transducer. The pressure was applied at a rate of 30 kPa/second. Pressure algometry was repeated three times, and a standardized average of three times of PPT value was used. Although the lack of standardization of the assessment algorithms and the relative paucity of normative data may limit clinical application of PPT20, the reliability of pressure algometry has been found to be high 21.In addition, peripheral pain sensitization was measured by assessing pressure pain thresholds (PPT)Carpal tunnel release was performed by a hand specialist using the same technique. Local anesthesia with intravenous sedation was used before each operation. After applying tourniquet to the upper arm, a longitudinal incision of about 2–3 cm along the thenar crease was made on the palm 1 cm distal to the wrist crease in line with the 3rd web-space. Transverse carpal ligament was incised and decompressed without neurolysis of the epineurium of the median nerve. The wound was closed with primary cutaneous suture. A short-arm splint was applied for the first 3 days postoperatively. Early active finger motion was performed for all patients.22. The self-administered, patient-based BCTQ has been shown to be reliable, valid, and responsive without notable ceiling of floor effects23. It consists of symptom severity scale and functional scale. Symptom severity scale includes 11 items concerning severity, frequency, and duration of symptoms. Functional status scale comprises 8 questions to assess difficulties for eight daily tasks. Each question offers 5 responses in increasing severity. It is scored from 1 (none) to 5 (most severe), and mean values are calculated for all items. Higher scores indicate the presence of more severe symptoms or impairment.Patients returned for functional assessments at 3  and 12 (12–14) months after the surgery  for regression analysis with five main predictors.Power analysis indicated that a sample consisting of 120 patients would provide 91% statistical power with α of 0.05 to detect a medium effect size (F2) provide measures of the relative influence of explanatory variables on overall variation of the response variable. Categorical variables were dummy-coded with a subgroup for the largest sample size (reference group) Statistical significance was considered when p value was less than 0.05. Statistical analysis was performed using SPSS software version 16.0 .Descriptive statistics were used to describe patients’ demographics and clinical characteristics. The confounding variables examined included: age, gender, BMI, education, affected side, bilaterality, symptom duration, electrophysiological grade, and baseline BCTQ scores Table . KolmogoAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.Preoperatively, CSI scores slightly correlated with symptom duration  and moderately correlated with BCTQ symptom and function scores ; PPT slightly correlated with BCTQ symptom and function scores .BCTQ symptom and function scores exhibited significant clinical improvements compared to baseline BCTQ scores . The mean BCTQ symptom scores were 1.7 ± 0.7 at 3 months and 1.4 ± 0.6 at 12 months, and the BCTQ function scores were 1.6 ± 0.7 at 3 months and 1.4 ± 0.5 at 12 months, respectively. At 3 months postoperatively, BCTQ symptom and function scores moderately correlated with lower PPT  and higher CSI scores , and female patients had higher BCTQ symptom and function scores than did males  At 12 months postoperatively, only severe electrophysiological grade was significantly associated with BCTQ function scores (p = 0.03) , CSI , and female gender  at 3 months postoperatively, and these three factors accounted for 35% and 31% of the variance in BCTQ symptom and function scores, respectively. However, BCTQ scores were not associated with any potential predictive factors at 12 months postoperatively .24. Although the median nerve of the affected limb might be more sensitized in individuals with CTS, vibration25, thermal26, and motor impairments27 have been identified bilaterally in patients with unilateral CTS. This suggests that central mechanism might involved in CTS. Increased recruitment of central neurons by peripheral nociceptive inputs, enhanced spatial summation, and increased pain intensity have been suggested to be potential mechanisms involved in pain sensitization29. Studies on subjects with CTS have revealed changes along the afferent pathway in the spinal cord, brain stem, and somatosensory cortex8, decrease in grey matter volume6, and loss of spatially segregated representations of digits 2 and digits 3 in the contralateral somatosensory cortex8.Our results revealed that preoperative centrally mediated symptoms slightly correlated with BCTQ scores and moderately correlated with CTS symptom duration, consistent with previous findings showing that PPT were negatively correlated with pain intensity and duration of symptoms30. This study suggests that physician should attend to patients’ pain sensitization when their impairment or disability is expected to worsen, particularly during early recovery after carpal tunnel release. In this regard, various pharmacological therapies, targeting metabolic factors, cognitive-behavioral therapy, and exercise therapy are effective in improving pain sensitization to reduce symptoms and disability in chronic pain conditions32. Future research is warranted to determine whether these approaches can enhance treatment outcomes in patients with CTS and severe pain sensitization.In this study, centrally mediated symptoms measured by CSI and peripheral sensitization measured by PPT were associated with poor functional outcome at 3 months postoperatively. However it did not show persistent effect at 12 months postoperatively. Although there were no special or intensified treatments after 3 months postoperatively, the influence of pain sensitization on patients’ function and symptom was diminished at 12 months postoperatively. These results are consistent with previous findings showing that physical makeup is important in healthy state, but less important than psychological factors in the context of recovery after upper extremity injuries1, which was comparable to that in the present study. Second, this study lacked objective measurement for improvement after surgery. Therefore, factors indicating good prognosis might not be based on objective outcome assessment. In addition, large timeframe between the 3- and 12-month postoperative follow-up prohibited the ability to identify when improvement of symptoms and function occurred. Third, identifying pain sensitization clinically is challenging due to the absence of a gold standard. However, quantitative sensory testing is frequently used, and PPT have been shown to be a reliable and sensitive measure of pain sensitization33. Fourth, we did not address any psychologic factors such as personal psychologic traits or negative affect that can influence postoperative pain. However, we did exclude patients with a history of psychologic disorders such as depression, psychosis, and somatization disorder from the study. Fifth, 9% of patients were lost during follow-up before the 12-month evaluation, and there were also some missing questions and questionnaires in our cohort. These might have resulted attrition bias. Finally, these patients were limited to a single ethnic population drawn from an urban area of South Korea, and therefore their characteristics and results might not be generalizable to other populations.This study has several limitations. First, this study was conducted mostly on female patients with a relatively small sample size. They may not represent the general population with carpal tunnel syndrome. However, our previous epidemiologic study demonstrated that age-adjusted female to male incidence ratio of surgically treated CTS was 5.82 Pain sensitization in patients with CTS measured by PPT and CSI correlated with preoperative CTS symptom severity and duration, and it was associated with poor patient-reported outcomes after CTR up to 3 months postoperatively. Therefore, physicians might be able to improve early recovery after carpal tunnel release by addressing patients’ pain sensitization prior to surgery. However, more research is needed to determine whether early identification and treatment of pain sensitization through pharmacological therapies targeting metabolic factors, cognitive-behavioral therapy, and exercise therapy can enhance treatment outcomes of patients with CTS and severe pain sensitization.