Evidence suggests that substance P (SP) is involved in chronic joint inflammation, such as the pathogenesis of rheumatoid arthritis and osteoarthritis. The goal of the research was to evaluate the correlation between chronic pain and changes in the SP level in patients with chronic inflammation of the connective tissue.Patients with osteoarthritis and rheumatoid arthritis were enrolled in this study. The relationship between chronic pain intensity and the serum SP concentration was evaluated in these groups of patients with osteoarthritis and rheumatoid arthritis.The results showed a positive correlation between the serum SP concentrations and chronic pain intensity.1. The SP serum concentration was significantly different between the groups of patients with OA and RA. 2. There was a positive correlation between the serum SP concentration and chronic pain intensity in OA and RA patients. Von Euler and Gaddun discovered substance P (SP) in 1931 , to, to4], tRheumatoid arthritis (RA) is a systemic autoimmune disease associated with chronic inflammation of the connective tissue.Substantial recent evidence suggests that SP and its receptors are involved in joint inflammation and are associated with some aspects of the pathophysiology of RA , 7]. Ch. Ch7]. CConsidering this aim, we evaluated the intensity of pain and the serum SP concentrations in patients with chronic inflammatory connective tissues. Chronic inflammation is a common symptom in osteoarthritis (OA) and RA.Patients with OA or RA were randomly enrolled in the study.Osteoarthritis was diagnosed according to the symptoms and results of X-ray joint examination.Patients with RA were fully diagnosed according to the criteria of the American Rheumatism Association .All patients were regularly taking non-steroidal anti-inflammatory drugs (NSAIDs).The exclusion criteria were as follows:Weight: BMI > 30Severe liver or kidney diseaseThe presence of other inflammatory diseasesFor all patients with RA, the disease activity was assessed using both subjective and objective methods. The total painful and swollen joint numbers, according to the 28-joint index were assessed using subjective grading. The sedimentation according to the Westergren procedure (mm/h) was assessed as the objective grade. The DAS 28 (Disease Activity Score) according to four variables was estimated using the DAS 28 formula with DAS 28 Calculator v1.1-beta (Alfons & Michiel).The intensity of pain was evaluated using a numeric pain scale (NPS) from 0 to 5, where 0 corresponded to no pain, 1 –slight, 2 –moderate, 3 –intensive 4 –severe and 5 –worst imaginable pain. The patients performed the evaluation.The concentration of SP was measured in all collected serum samples. The 4–5 ml venous blood samples were collected into the serum test tubes, delivered to an analytical laboratory and centrifuged (2000 rpm/10 min). The sera were placed into 200 μl test tubes and stored at -70°C. The SP concentration was measured using the Substance P Immunoassay Test (R&D System) in accordance with the instructions from the manufacturer. The minimum detectable level for this assay was 8.0 pg/ml.The immunological and laboratory tests were conducted at the Department of Immunopathology and the Diagnostic Laboratory at the Institute of Rheumatology in Warsaw.U test. The correlation analyses were performed using the Spearman rank correlation test. To identify interdependencies, further tests were performed to find a regression function, the power of which was checked by the Snedecor F test. P values < 0.05 were considered significant.STATISTICA v.10 was used to perform all statistical analysis. Because the NPS values are quality variables, nonparametric tests were used. Differences between the variables for the factors were analysed using the Mann-Whitney Factor analysis was performed to find patterns among the measured variables. Factor loadings > 0.70 were considered. The factor analyses were performed with Varimax, using Kaiser normalisation as a rotation method.The Medical Ethics Committee of Institute of Rheumatology in Warsaw approved the protocol. The experiments were conducted according to the principles expressed in the Declaration of Helsinki.Written informed consent was obtained from all patients.Seventy patients suffering from chronic pain due to OA or RA were classified.These patients were divided into two groups according to their primary disease (OA–Osteoarthritis or RA–Rheumatoid Arthritis). In OA group were 23 patients and RA group included 47 patients. OA patients had a mean ±SD age 63±12 years while RA patients had a mean ±SD age 55±11 years. In RA patients the disease lasted a mean ±SD 17±7.18 years and the disease activity according to DAS28 was a mean ±SD 5.2±1.16.P < 0.005) in the patients’ mean age between the groups.In both groups, there were more women than men. There was a significant difference , but it was stronger for the OA group  than for the RA group .There was a correlation between SP and NPS , SP and NPS (0.426), SP and DAS (0.365), and age and RA disease years for the group of RA patients is shown in Factor analysis performed on the RA group yielded two factors with eigenvalues > 1, explaining 66% of the total variation between the measured variables . The DASP = 0.049. In this full analysis, it appeared that the constant does not have a statistically significant effect (P = 0.808); therefore, it was removed from a regression function. The final results of the regression analysis without a constant are presented in P < 0.001 and P = 0.002.For logarithmic values of SP and all values of DAS, the regression analysis showed that ln (SP) and DAS have a statistically significant effect on the severity of chronic pain, with a critical significance level of According to the given values of the regression coefficient, the following regression function was formed.The value of an improved determination coefficient indicates that in 96.82% of this group of RA patients, both DAS and ln (SP) exert an influence on chronic pain severity. A graphical interpretation of the function of this surface is shown in This trend is extended over the entire range of disease activity (DAS), which is clearly visible in The results obtained have indicated a high serum concentration of SP in all of the patients enrolled in this study. This finding suggests a connection with both the chronic inflammatory state and chronic pain, which was defined as pain lasting more than three months.From the outcome of the investigation one can conclude that in the patients with OA, a high serum SP level can be treated as evidence supporting the role of inflammation in the pathogenesis of osteoarthritis. In addition the significantly higher serum SP level was demonstrated in RA patients compared with OA patients. The most likely explanation of the results is the connection between the long-lasting advanced auto immunological disease and systemic chronic inflammation.Similarly, Grimholm et al. showed a correlation between high SP serum levels and long-lasting RA  whereas 2 released from inflammatory cells , , . AccordiIt is worth emphasising that this study also focused on patients with OA because there are few studies about the contribution of SP in the pathogenesis of osteoarthritis. Our results seem to confirm the essential role of SP in the inflammatory component of OA.Patients with obesity were excluded from our study. Several clinical studies demonstrated the role of SP in the development of obesity, which is defined as a type of chronic and systemic inflammatory disease , 26], , .In our patients, the mean severity of chronic pain was classified as intensive (3 points), and there was no statistically significant difference between the evaluated groups of patients.The positive correlation between the serum SP level and chronic pain intensity was found in both groups, but this correlation was clearly stronger in OA patients.The obtained results for the value of the determination coefficient indicate that the pain intensity was dependent on the serum SP levels in 64% of the patients with OA. The remaining 36% of the cases could be accounted for by factors such as the nerve dysfunction associated with a long-lasting inflammatory state. Therefore, the presented results confirm the participation of SP in modulating the pain in both groups of patients with inflammatory diseases.Referring to the group of patients with RA, a high correlation between disease activity and pain intensity has been shown. Disease activity, as determined using the DAS28 scale, appeared to have a greater impact on the intensity of chronic pain than did the SP concentration in patients with RA. These findings show that smaller values of DAS28, even at very high SP concentrations, correspond to less pain, whereas higher values of DAS28 are related to stronger pain, even at lower SP concentrations. This relationship is confirmed by clinical examination because pain is the major complaint of RA patients with high disease activity. In their studies, Garip and Eser assessed the connection among fatigue, disease activity, pain and functional status in RA patients . They coIn this study, we present the first evidence of a link among the DAS28, pain and SP.In healthy tissues, SP has the unique feature of being released from only C type fibres with strong stimuli. In contrast, in inflamed tissues, which have many more receptors on neurons due to the inflammatory processes, the nocicepive impulse may be spontaneously trigged without external stimulation . TherefoConfirming the correlation between chronic/acute pain and the SP serum concentration in our study should be an aim of further research on the use of the NK–1 antagonist as a component of new drugs for pain therapy. The hypothesis concerning the analgesic properties of the SP antagonist has yet to be proven.The SP serum concentration was significantly different between the groups of patients with OA and RA.There was a positive correlation between the serum SP concentration and chronic pain intensity in OA and RA patients.


Temporomandibular joint (TMJ) inflammation in patients with juvenile idiopathic arthritis (JIA) can lead to orofacial pain and malfunction of the TMJ. Intra-articular corticosteroid injections (IACI) have been suggested as a treatment modality against TMJ arthritis-related orofacial signs and symptoms. However, knowledge of the effect-durability of these injections remains unanswered. The aim of this pilot study was to evaluate the short and long-term effects of IACI on orofacial symptoms in a prospective observational study based on pre-specified clinical examination standards.Thirteen patients with JIA and arthritis-related orofacial signs and symptoms were included in this prospective pilot study . All patients received TMJ IACI  due to an insufficient response to previous pain-management treatments. Three standardized clinical examinations were carried out: T1 prior to treatment, T2 short-term follow-up (mean 34 days post-treatment), T3 long-term follow-up (mean 333 days post-treatment).Significant pain reduction was observed at the short-term follow-up (T2). Resolution of orofacial pain after IACI was a rare finding at T2. Generally, the pain significantly worsened between T2 and T3 examinations. The reported pain levels rose between T2 and T3 indicating a loss of effect of the IACI at the long-term follow-up examination (T3). Non-significant improvements in TMJ mobility were observed at T2 and T3.Our results suggest a palliative (not curative) effect of IACI for TMJ arthritis-related orofacial symptoms in patients with long-term orofacial pain complaints. The short-term improvements in signs and symptoms were partly resolved at the long-term follow-up. In patients with juvenile idiopathic arthritis (JIA), temporomandibular joint (TMJ) involvement may interfere with craniomandibular joint and muscle function , 2. TMJ The current limited level of evidence suggests potential beneficial properties of intra-articular corticosteroid injections (IACI) in patients with JIA and TMJ arthritis-related orofacial symptoms. However, knowledge of the durability of the effect of these injections needs to be elucidated. In addition, knowledge of the long-term impact of IACI on mandibular growth is unavailable when this treatment modality is administered in growing patients .The aim of the present study was to conduct a pilot study to evaluate the short-term and long-term effects of a single IACI against TMJ arthritis-related orofacial signs and symptoms in a prospective, observational, intention-to-treat-analysis based on pre-specified clinical examination standards.Thirteen patients diagnosed with JIA according to the ILAR criteria  were incPatients were asked to report the frequency of their orofacial symptoms on a 5-point Likert scale: 0) Never pain; 1) pain less than once a week; 2) pain 1–3 times a week; 3) pain 4–6 times a week; 4) pain several times a day; and 5) pain all the time.The patients were asked to assess the average orofacial pain intensity on a non-verbal visual analogue scale (VAS) of 100 mm, where the left extreme represents “no pain” and the right extreme represents the “worst imaginable pain”.A composite variable combining the aspects of orofacial pain frequency and intensity; calculated as the pain frequency multiplied by the pain intensity, with a score range between 0 and 500. This variable was used to calculate the relative change in pain between the pre-treatment levels and the short and long-term follow-up pain levels.Secondary outcome variables describing changes in TMJ mobility were measured in accordance with a previously described standardized examination protocol .The maximal unassisted incisal opening capacity was measured inter-incisally with a metallic ruler positioned on the incisal edge of the lower incisors. The inter-incisal vertical overlap was accounted for in the measurement.The maximal unassisted lateral movement of the lower jaw from the most left position to the most right position measured in mm.The maximal unassisted forward movement of the lower jaw measured in mm.t-tests serving as post-ANOVA tests. Post-Anova tests were only performed in outcome variables where a statistical significant difference was observed in the primary ANOVA test. Changes in the categorical data concerning pain frequency were statistically analyzed using a Kruskal Wallis Rank-sum test with Wilcoxon matched-paired rank tests serving as post-tests. A p value of less than 0.05 was considered significant.After the data were tested for normal distribution general differences in pain variables and functional variables between T1, T2 and T3 were assessed by ANOVA tests with paired Student’s Radiological signs of osseous TMJ degenerations were observed in all TMJs receiving IACI. Patient characteristics are depicted in Table Pre- and post-treatment pain and functional values are depicted in Table High pre-treatment pain levels were seen at T1 with a mean pain intensity of 62.7  and a reported average pain frequency of “several times a day”. At the short-term follow-up (T2) pain-frequency, pain-intensity and pain-index were all significantly reduced when compared to the pre-treatment T1 levels. However, at the long-term T3 follow-up only the pain-frequency remained significantly reduced compared to the pre-treatment T1 level. The pain-intensity and also the pain-index variables significantly worsened between T2 and T3 as illustrated in Table Pain cessation was rare at the follow-ups and was only experienced in three patients at the short-term follow-up (T2) and in one patient at the long-term T3 follow-up Fig. . At T2, The ANOVA test documented no significant intra-group changes in any of the outcome variables reflecting TMJ mobility Table . DespiteWe observed a significant pain-level reduction in the majority of patients at the short-term follow-up evaluation pointing towards a beneficial short-term effect of IACI. Although statistical significant symptomatic improvements of TMJ arthritis were observed, this pilot study shows a considerable inter-patient variation in the response to IACI treatment and total resolution of orofacial pain was a rare finding. Between the short-term (T2) and the long-term (T3) follow-up, exacerbation of pain-levels was seen in seven out of thirteen patients suggesting a loss of effect of the IACI at the long-term follow-up examination for some of the patients. Aggravation of pain between the short-term and the long-term follow-up was most pronounced in patients with high T1 pre-treatment pain levels. This finding is somewhat in conflict with previous reports on IACI for the treatment of TMJ arthritis-related signs and symptoms where a better response has been reported from IACI TMJ treatment –12. ThisThe present group of patients gives the impression of a pain problem not only related to TMJ arthritis but also to the morphological changes within the TMJ caused by the arthritis. The results presented in this study, therefore, are probably not generalizable to a whole JIA population since the present group of patients is a unique group of patients suffering from refractory TMJ arthritis-related pain. However, from a clinical point of view our results contribute with new knowledge since it illustrates that achievement of an acceptable treatment result in this group of patients is indeed a very challenging task. Secondly, this is the first longitudinal study to address the treatment effect with IACI in this specific patient group with refractory orofacial symptoms. It is possible that a population-based group of JIA patients with TMJ involvements could have a better outcome of IACI in relation to arthritis-induced orofacial pain.Despite the fact that no significant improvements in TMJ mobility changes were observed throughout the study, minor short-term and long-term improvements were seen after the treatment with IACI. The clinical relevance of the long-term TMJ mobility improvements described is debatable since only short-term improvement in TMJ mobility exceeds the variation within the measurement technique used to assess the outcome variables examined . Our TMJThe current limited evidence available suggests potential beneficial properties of IACI against TMJ arthritis-related symptoms. At this point no clear scientific evidence substantiates the effect of IACI in terms of improvement in orofacial function . From a Important strengths of this study were the prospective, standardized, intention-to-treat design. This is the first study to use this design within this specific field and treatment modality. Notable limitations were the low number of included patients, the lack of a control group to account for the bias of the placebo-effect, and the selection bias during the referral procedures. Another limitation was the fact that no pre-treatment MRI was performed in any of the patients. However, recent research suggests only a limited association between clinical findings and TMJ MRI findings in patients with JIA . In addiIn conclusion, our results suggest a palliative (not curative) effect of IACI for TMJ arthritis-related orofacial symptoms in patients with long-term orofacial pain complaints not responding to other pain management strategies. The short-term improvements in signs and symptoms after IACI were partly resolved at the long-term follow-up. Future studies in accordance with evidence based standards, involving more patients, are needed in order to make more solid conclusions. Based on the findings of this pilot-study with TMJ IACI, future, prospective, long-term follow-up studies are planned.


Poor postoperative pain control is frequently associated with complications and delayed discharge from a hospital. Preemptive analgesia is one of the methods suggested for reducing postoperative pain. Opioids are effective for pain control, but there known addictive properties make physicians cautious about using them. Parecoxib and ketorolac are potent non-opioid NSAIDs that are attractive alternative drugs to opioids to avoid opioid-related side effects. However, there are no good head-to-head comparisons between these two drugs in the aspect of preemptive analgesic effects in lumbar spinal fusion surgery. This study aimed to compare the efficacy in terms of postoperative pain control and safety of parecoxib with ketorolac as preemptive analgesia in posterior lumbar spinal fusion patients.A prospective, double-blinded randomized controlled trial was carried out in patients undergoing posterior lumbar spinal fusion, who were randomized into 3 groups (n = 32). Parecoxib, ketorolac or a placebo was given to each patient via injection around 30 minutes prior to incision. The efficacy of postoperative pain control was assessed by a verbal numerical rating score (0–10). And various postoperative things were monitored for analysis, such as total opioid consumption, complications, and estimated blood loss.p < 0.05). There were no differences between the pain scores of ketorolac and parecoxib at any time points. Complications and bleeding were not significantly different between all three groups.Both the ketorolac and parecoxib groups showed significantly better early postoperative pain reduction at the postanesthesia care unit (PACU) than the control group (Preemptive analgesia using both ketorolac and parecoxib showed a significantly better early postoperative pain control in the PACU than the control group in patients undergoing lumbar spinal fusion.NCT01859585. Registered 15 May 2013.ClinicalTrials.gov  Inappropriate postoperative pain control has been associated with a number of complications such as delay in discharge from the hospital, atelectasis, pulmonary edema, hypoxemia, and cardiovascular system complications. It can also delay early mobilization and increase the risk of thromboembolism, and lead to reduced bladder and intestinal motility ,2. ApproOpioid therapy is recommended as the first choice medication for postoperative pain control but is associated with a number of adverse effects . MultimoKetorolac  is an injectable NSAID with strong analgesic activity. Ketorolac is an established non-selective NSAID administered in an active form -11. The Parecoxib is a specific inhibitor of cyclo-oxygenase2 enzymes (COX-2). Parecoxib is metabolized by the human liver to produce valdecoxib which produces analgesic effects. Many studies have shown the efficacy of parecoxib in reducing postoperative pain -21 whilePostoperative pain following lumbar spinal fusion surgery can be perceived by the patient immediately in the recovery room as they are recovering after general anesthesia. Pain management in the postanesthesia care unit (PACU) is very important and better management of pain in the PACU setting would likely improve patient satisfaction and facilitate shorter PACU stays.The efficacy of using NSAIDs as preemptive analgesia is still controversial . Both KeThis was a prospective double-blinded randomized controlled trial. This study was approved by the Ethics Committee at the Faculty of Medicine, Prince of Songkla University. The trial was conducted in accordance with the Helsinki II declaration. The Consolidated Standards of Reporting Trials (CONSORT) recommendations for reporting randomized controlled clinical trials were followed  Figure . All pathttp://www.randomizer.org/). The sequential random number code was enclosed in a sealed opaque envelope to ensure allocation concealment. To ensure blinding, the nursing personnel were not involved in evaluation of the patients. The code was kept confidential until the time of data analysis. All patients, data collectors, and health care providers involved in postoperative management were blinded to the group allocation.All patients were randomly allocated to receive parecoxib or ketorolac or placebo by block of 6 randomization using a computer generated random number  from 0 (no pain) to 10 (worst imaginable pain).The anesthetic technique was standardized among the participating anesthesiologists. The same anesthetic protocol for preoperative medication, induction, and maintenance was used by all anesthesiologists. Anesthesia was induced with propofol (2 mg/kg) and fentanyl (2 microgram/kg). Orotracheal intubation was facilitated with vecuronium (0.15 mg/kg). Nitrous oxide-oxygen-narcotic anesthetic was used for all surgical procedures with inhalation agents used as adjuncts to control blood pressure. There was no local anesthesia usage before or after surgery. The surgical technique was also standardized among the participating surgeons, who performed a decompressive laminectomy with posterolateral fusion (one to three levels) with pedicular screws fixation. Local bone graft plus hydroxyapatite and tricalcium phosphate composite  were used for spinal fusion. Operating microscopes were not used. All patients received the same postoperative pain management, consisting of paracetamol (500 mg) and intravenous morphine for rescue postoperative pain control. No other analgesic supplement was given during the study period.The basic characteristics of the patients, including age, gender, height, weight, type of surgery, including variables such as the number of levels, duration, intraoperative blood loss, and amount of postoperative bleeding, were recorded. After surgery, patients were requested to rate their pain intensity using the VNRS. When the patients regained consciousness from general anesthesia after surgery the study procedure was recorded as time 0. The VNRS was recorded at 0, 1, 2, 3, 4, 6, 12, 18 and 24 hours after surgery by data collectors. The amounts of intravenous morphine requested were also recorded. Side effects of the analgesic procedures were also recorded, such as dyspepsia, nausea/vomiting, constipation, dizziness, respiration depression (respiratory rate less than 8 breaths per minute), and pruritus. The amount of drain output was recorded until removal.P values less than 0.05 were considered statistically significant.We used Shapiro-Wilk test to check the distribution of the data. For normally distributed continuous data, ANOVA was used to compare among three groups and independent t test to compare between each 2 groups. For non-normally distributed continuous data, Kruskal Wallis test was used to compare among three groups and Mann–Whitney U test to compare between each 2 groups. Chi-square or Fisher’s exact test was used to analyze categorical data . Ninety-nine consecutive patients from March 2011 to July 2013 were enrolled in the study. Three patients were excluded due to requiring a fusion of more than three levels, leaving a total of 96 patients who were randomized: 32 into the group given ketorolac, 32 into the group given parecoxib, and 32 into the placebo group. There were no patients lost to follow-up and no patients were moved from one group into another group during the study. Also none of the patients withdrew from the study because of severe pain requiring additional analgesics beyond the intravenous morphine. The patient gender distribution was 33 males and 63 females. Thirty-six patients underwent surgery at one-level, 43 patients underwent surgery at two-levels and 17 patients underwent surgery at three-levels. There were no significant differences among the groups regarding gender, age, height, weight, ASA classification, operative level, operative time, blood loss during surgery, or the amounts of intraoperative narcotic  is very important and at least one study has suggested that better management of pain in the PACU setting would likely improve patient satisfaction and facilitate shorter PACU stays . AlthougTraditional NSAIDs are not recommended as a first choice supplemental analgesic in the perioperative setting due to the increased risk of perioperative bleeding ,42. But Some studies have found an association between NSAID use and bone osteogenesis, which has important clinical implications for patients undergoing spinal fusion surgery ,44. ReceThe only head-to-head comparison between parecoxib and ketorolac as a preemptive intravenous analgesia was in a study by Ng A. et al.  which coThis is the first study to compare parecoxib, ketorolac, and placebo in posterior lumbar fusion surgery in the same setting in the same time period, following the CONSORT recommendations to provide increased confidence with unbiased results in estimating the effectiveness of an intervention .This approach showed us the efficacy of both single-dose parecoxib and ketorolac in preemptive analgesia. Our calculated sample size had adequate power to detect key subgroup effects.The limitation of this study is that we studied only single-dose ketorolac and parecoxib. Further studies, especially on the analgesic efficacy of repeated doses of parecoxib and ketorolac in surgical procedures are required.Preemptive analgesia using either ketorolac or parecoxib showed significantly better early postoperative pain control in the postanesthesia care unit (PACU) than the control group in patients undergoing lumbar spinal fusion.


Pain following craniotomy has frequently been neglected because of the notion that postcraniotomy patients do not experience severe pain. However a gradual change in this outlook is observed because of increased sensitivity of neuroanaesthesiologists and neurosurgeons toward acute postcraniotomy pain. Multiple modalities exist for treating this variety of pain each with its own share of advantages and disadvantages. However, individually none of these modalities has been proclaimed as the best and applicable universally. A considerable amount of dispute remains to ascertain the appropriate therapeutic regimen for treating postcraniotomy pain in spite of numerous trials using different drugs and their combinations. This review aims to highlight the genesis, characteristics, and different strategies that are undertaken for management of acute postcraniotomy pain. Chronic postcraniotomy pain which can be debilitating sequelae is also discussed concisely. Postcraniotomy patients are often assumed to experience lower degree of pain. Suggested reasons include lesser number of pain receptors in dura, pain insensitivity of the brain, reduced pain fibre density along the incision lines, or development of autoanalgesia . Hence pPostcraniotomy pain is usually pulsating or pounding in nature similar to tension headaches. Sometimes it can be steady and continuous. Postcraniotomy pain normally afflicts women and young patients , 12. TheThe International Classification of Headache Disorders (ICHD-3) published by the International Headache Society which lays down diagnostic criteria for different headaches has classified postcraniotomy headache and subdivided into acute and persistent varieties. The descriptions of the varieties are as follows.Description. Headache is of less than 3 months' duration caused by surgical craniotomy.Diagnostic Criteria. They are as follows:Any headache fulfilling criteria (C) and (D).Surgical craniotomy which has been performed.Headache which is reported to have developed within 7 days after one of the following: the craniotomy,regaining of consciousness following the craniotomy,discontinuation of medications that impair ability to sense or report headache following the craniotomy.Either of the following: headache resolved within 3 months after the craniotomy,headache not yet resolved but 3 months have not yet passed since the craniotomy.Not better accounted for by another ICHD-3 diagnosis. Description. Headache is of greater than 3 months' duration caused by surgical craniotomy. Diagnostic Criteria. They are as follows:Any headache fulfilling criteria (C) and (D).Surgical craniotomy which has been performed.Headache which is reported to have developed within 7 days after one of the following:the craniotomy,regaining of consciousness following the craniotomy,discontinuation of medication that impairs ability to sense or report headache following the craniotomy.Headache persisting for >3 months after the craniotomy.Not better accounted for by another ICHD-3 diagnosis .Exact quantification of pain in postcraniotomy patients is problematic as the patients should be capable of perceiving and expressing pain which might not be always possible following neurosurgical procedures. Subjective assessments by observing acute pain behavior may be required. However alert and oriented patients can be asked to rate their pain numerically 1–10) [–10 [1] oPostcraniotomy pain management is an unorganised sphere owing to the dearth of standard analgesic protocols. Besides the intraoperative anaesthetic techniques or opioid usage may be variable in different patients or surgical settings which have a bearing on the postoperative pain. Moreover, altered neurological status following neurosurgical procedures and the subjective nature of pain assessment hampers the appropriate quantification of pain. Perioperative clinicians often restrict prescribing analgesics  in apprehension of their potential side effects and variable regimens are followed. Hence as of now, we lack a consensus on the ideal line of management of postcraniotomy pain.Scalp block: scalp block includes infiltrating local anaesthetics to seven nerves on either side of the scalp. The nerves and a brief description of the technique are as follows , 19:After cleaning the skin with chlorhexidine or Betadine, the following nerves are blocked on the scalp by infiltrating local anaesthetics using a 23-gauge needle:supraorbital nerve : the supraorbital notch is palpated, needle is inserted perpendicularly at the upper orbital margin, and 1–3 mL of the drug is injected,supratrochlear nerve : the needle is inserted medial to the point of supraorbital nerve injection site and 1–3 mL of the drug is spread medially while injecting above the eyebrow line,zygomaticotemporal nerve : local anaesthetic needs to be infiltrated superficial and deep to the temporalis muscle. The needle is inserted at the lateral edge of the supraorbital margin  where 3–5 mL of drug infiltration is done and continues to the distal aspect of the zygomatic arch,auriculotemporal nerve : local anaesthetic is infiltrated 1 cm anterior to the auricle above the level of the temporomandibular joint. Superficial temporal artery should be palpated beforehand to avoid intra-arterial injection,greater auricular nerve : infiltration of 3–5 mL local anaesthetic is done subcutaneously at the level of tragus, behind the auricle,lesser occipital nerve : infiltrate 3–5 mL of local anaesthetic subcutaneously behind the auricle starting from the top-down to the auricular lobule and then continue to infiltrate along the superior nuchal line to thegreater occipital nerve,greater occipital nerve : after palpating the occipital artery, which is found about 3-4 cm lateral to the external occipital protuberance along the superior nuchal line, 3–5 mL local anaesthetic is injected medial to the occipital artery between mastoid process and occipital protuberance.δ and C fibres is a favourable agent.The prominent benefit offered by scalp block is the ability to perform accurate neurological assessment postoperatively as it does not affect other motor or sensory modalities. Scalp block has shown to decrease the frequency of request for rescue analgesics, increase the time between completion of surgery and first request of analgesics, and decrease pain scores in the initial postoperative phase . RopivacInfiltration of wound margins: preincisional infiltration of local anaesthetics produces negligible effect on postoperative pain following craniotomies. However infiltrating the wound margins can cause a modest decrease in the pain intensity . This ouPossibly local anaesthetics exert their effects through preemptive analgesic mechanisms . HoweverIn spite of the controversies surrounding their use in the neurosurgical population, opioids form the mainstay of management of moderate to severe pain. Commonly used opioids for postcraniotomy analgesia include morphine, codeine, fentanyl, and tramadol. Their action is mediated via specific opioid receptors in the central and peripheral nervous system. Concerns related to respiratory depression, sedation, hypercarbia, increased ICP, and delayed weaning from ventilator exist with opioid therapy. Concerns regarding their addictive potential or them being the last resort treatment are also present. These traditional conceptions have limited the widespread use of opioids following neurosurgery thereby compromising the adequacy of analgesia. However, systemic opioids are frequently needed for providing adequate pain relief following craniotomies. Opioid administration can be either parenteral or enteral.(a)Morphine: parenteral morphine can be administered through intravenous (including PCA) or intramuscular routes. The potent analgesic effects blunt the haemodynamic surges during recovery from anaesthesia or in the early postoperative period safeguarding against possible intracranial hemorrhage. PCA facilitates the patients to control pain by themselves and also decreases the overall opioid consumption. Reduction in pain scores, higher patient satisfaction, and absence of side effects (with coadministered antiemetics and vigilant monitoring) are the advantages achieved with this mode of analgesia . However Administering intramuscular injections of morphine is also an accepted practice although the drawbacks include a slower onset, variable systemic absorption, and pain at the injection site.(b)Fentanyl: compared to morphine, it is more potent, lipophilic, and faster acting. Because of its shorter duration of action it is prudent to administer this drug via PCA; nevertheless it can be used intravenously for breakthrough pain. Previous trials have demonstrated that pain control is superior when fentanyl has been used through PCA either alone  or in co(c)μ receptor agonism) as well as nonopioid mechanisms . Though the analgesic efficacy is 10–15 times lesser as compared to morphine, the side effects are relatively less. Repeated administration does not lead to dependence, ceiling effect is absent, and respiratory depression is rare. Addition of tramadol along with other narcotics in the postoperative analgesia regimen has shown to reduce postoperative pain, decrease side effects of other opioids, decrease length of stay, and reduce overall hospitalization costs [Tramadol: it is a synthetic analgesic which provides analgesia via opioid mechanisms  or pharmacological therapies. Combination of the two therapies can also be tried to obtain favorable outcomes. The common medications prescribed are NSAIDs, paracetamol, or narcotics  . Local aElectromyography provides a noninvasive means to detect muscular imbalance in patients following craniotomy . ApplicaOver the past few years, there has been a growing awareness and sensitivity amongst the neuroanaesthesiologists and neurosurgeons towards the necessity of providing superior quality of postoperative pain relief to the patients who have undergone craniotomy. This has translated into better pain management practices and strategies. A fundamental requirement in this class of patients is a relatively clear level of consciousness for neurological evaluation. Consequently simultaneous maintenance of appropriate neurological objectives and adequate analgesia is a delicate balancing job. Since a sizeable number of therapeutic options in addition to opioids exist, multimodal analgesia offers the rational promise of superior quality of analgesia with minimal side effects of the individual drugs. Though there is a growing volume of literature on the various modalities of treating acute pain following craniotomy, absence of consensus or uniformity in the analgesic protocol has still left this issue as a grey zone. Majority of the patients following craniotomy receive antiseizure drugs concurrently. The influence of these drugs on analgesic needs is not apparent. Thus the ideal pain management protocol along with uniform pain management practices following craniotomy still remains elusive.α2-adrenergic agonists are combined to maximize pain control and minimize side effects. Application of preemptive approaches can reduce the postoperative pharmacological burden on the patients. A viable option consists of the following regimen: an appropriate block for the anticipated craniotomy can be placed before the head is secured with pins. Intraoperatively, a balanced opioid  based technique can be utilized. Low dose intravenous NMDA antagonists have been suggested intraoperatively and should be stopped 40 minutes before the end of the procedure. In case the maximum allowable dose of local anaesthetics has not been exceeded, a scalp block or infiltration can be repeated before extubation. With the use of intraoperative remifentanil, postoperative hyperalgesia and provision of adequate transitional analgesia are additional concerns which should be controlled with long acting opioids like morphine. Pain in the postoperative period should be assessed using objective and validated methods. Opioids and intravenous paracetamol can be the first-line drugs for immediate postoperative pain relief. Though intravenous fentanyl boluses have good potency, it is limited by its short duration of action. Morphine provides longer and consistent analgesia and with careful titration and cautious monitoring, serious side effects can be avoided [Nonetheless the observations made by the various trials can be translated into realistic therapeutic approaches for treating postcraniotomy pain. A multimodal or “balanced” approach is advocated where smaller doses of opioids, NSAIDS, local anesthetics, N-methyl-D-aspartate antagonists, and  avoided . NSAIDs  avoided . The patThe need for conducting further well designed, high quality randomized control trials remains in order to establish the ideal combination therapies amongst the hosts of available options along with their dosages and regimens. This would help in making substantial progress in providing better and patient specific analgesic therapy to this subset of patients. Early and aggressive relief from pain is also imperative to prevent the transition of acute pain to chronic pain.


Transcranial direct current stimulation (tDCS) of the primary motor cortex has been shown to modulate pain and trigeminal nociceptive processing.Ten patients with classical trigeminal neuralgia (TN) were stimulated daily for 20 minutes over two weeks using anodal (1 mA) or sham tDCS over the primary motor cortex (M1) in a randomized double-blind cross-over design. Primary outcome variable was pain intensity on a verbal rating scale (VRS 0–10). VRS and attack frequency were assessed for one month before, during and after tDCS. The impact on trigeminal pain processing was assessed with pain-related evoked potentials (PREP) and the nociceptive blink reflex (nBR) following electrical stimulation on both sides of the forehead before and after tDCS.Anodal tDCS reduced pain intensity significantly after two weeks of treatment. The attack frequency reduction was not significant. PREP showed an increased N2 latency and decreased peak-to-peak amplitude after anodal tDCS. No severe adverse events were reported.Anodal tDCS over two weeks ameliorates intensity of pain in TN. It may become a valuable treatment option for patients unresponsive to conventional treatment. Several studies showed that transcranial direct current stimulation (tDCS) modulates the cortical excitability of the motor cortex depending on the direction of the electric current  and that its neuroplastic effects sustain after stimulation. The priTN is a rare facial pain disorder with a prevalence of 0.1 – 0.2/1000 that leads to paroxysms of short lasting but very severe pain. In mostSeventeen patients were enrolled in the study. Five patients finished anodal stimulation and discontinued the study without sham stimulation, one patient discontinued after sham stimulation without anodal treatment and one patient did not stimulate at all as recorded in the stimulator. Three of the patients that were only treated anodal, reported the application of the stimulation as too difficult, one patient reported an increase of attacks and one patient reported no further interest in the stimulation. In total, 10 patients completed the study with a mean age of 63 years  as self-evaluation ranges from 0 (no pain) to 10 . VRS and attack frequency were assessed as an averaged value per day for one month before, during and after tDCS using an individual patient diary. The average value of three days prior to tDCS was used for baseline and the average of the last three days after day 14 (=post-stimulation) was used for further analysis. We used this to exclude a failure by single days with higher pain raitings which may occur in TN. Furthermore, participants documented the frequency of pain attacks per day in the same fashion and analysis was also based on the average of the last three days prior to assessment day .2 over M1 and 12 μA/cm2 at the reference electrode. After the first stimulation, participants and at least one relative were instructed for the correct application of tDCS and were able to stimulate at home. Subsequently the patients applied the stimulation daily by themselves and were instructed to record daily, whether or not any potential side effects occurred in their diary. To ensure the correct application of tDCS, the stimulator records the correct current application in an electronic protocol. In cases of malfunctions or handling problems, the patients had the possibility to call the study team, which has not been used. Stimulation was performed for 14 days, 20 minutes per day. Following a cross-over study design participants were administered sham stimulation or anodal stimulation in a randomized order with an interval of at least one month after the first stimulation to avoid carry over effects.TDCS was delivered by a battery-driven constant current stimulator  with a maximum output of 5 mA using a pair of surface rubber electrodes in a NaCl-solution soaked synthetic sponge with an extension of 4×4 cm over the primary motor cortex M1) and 5×10 cm above the contralateral orbit. The use of non-metallic rubber electrodes avoids electrochemical polarization  were attached to the skin 10 mm above the entry zone of the supraorbital nerve. The outer rim of the first electrode was placed 1 cm from the forehead midline, the second electrode approximately 2 cm apart and lateral. Left side and right side were stimulated 15 times per session in each patient . Perception and pain thresholds were determined on the forehead with an ascending and descending sequence of 0.2 mA intensity steps. The stimulus intensity was set at 2 times the individual pain threshold. Stimuli were delivered to each side in random order in terms of start site . NBR and PREP were recorded simultaneously following trigeminal stimulation of the forehead. The nBR was recorded using surface electrodes placed infraorbitally referenced to the orbital rim. Recording parameters: bandwidth 1 Hz to 1 kHz, sampling rate 2.5 kHz, sweep length 300 ms . PREP were recorded with electrodes placed at Cz referenced to linked earlobes (A1-A2) according to the international 10–20 system. The first sweep was rejected to avoid contamination by startle response. The remaining 14 sweeps were averaged. For nBR onset latencies, waveforms were rectified and analysed for each sweep separately. A mean value for each session was calculated. Area under the curve was calculated between 27-87 ms. Concerning PREP N2 (negative peak), P2 (positive peak) latencies and peak-to-peak amplitudes were analysed. Intraindividual mean ratios for latencies, amplitudes, and area under the curve were determined in all patients for the symptomatic and non-symptomatic pain side separately. Offline-analysis was performed with a custom-written PC-based software using Matlab .Two planar concentric electrodes , attack frequency, individual pain threshold, AUC, latency, and amplitude of electrophysiological experiments at baseline and after 14 days tDCS. Correlation analysis was performed investigating the association of electrophysiological response with clinical response to tDCS. All statistics were calculated with SPSS 22 . The level of significance was set to p <0.05.All patients tolerated tDCS well without adverse effects. With initiation of tDCS, patients feel a slight itching or tingling, while no motor symptoms were observed or reported during the stimulation. Six patients discontinued the trial prematurely as they did not have their expected treatment response. One patient did not stimulate at all. For characterization of patients see Table Pain intensity (VRS) difference comparing anodal stimulation effect (post-stimulation minus baseline) with the sham effect (post-stimulation minus baseline) was 29% . Attack frequency decreases in either anodal or sham group not significantly .TN patients with concomitant persistent pain alone did not respond to tDCS at all (0%) change after anodal stimulation and 14.8% (SD ± 13.8%) after sham stimulation (p = 1.0). Attack frequency was not significantly different  contralateral to the symptomatic side moderately ameliorates pain in patients with classical TN with purely paroxysmal pain by modulation of trigeminal nociceptive processing. Patients with concomitant permanent pain do not seem to benefit from tDCS-21.To our knowledge, the effects of anodal tDCS on facial pain were investigated in only one study, including 22 patients with different pain syndromes. Three patients suffered from TN and one patient from persistent idiopathic facial pain. However, the efficacy of pain relief in these patients was not analyzed separately, so that a clear effect on TN specifically cannot be derived from these data. CompariTDCS has been used more and more frequently over the past decade as a non-invasive neuromodulation for targeted alteration of cortical excitability for the treatment of different diseases like depression, reorganization after stroke and pain-25. EffeWhen pain becomes chronic tDCS modulation might be less prominent. This coCentral facilitation and hyperexcitability of the trigeminal system was recently demonstrated in TN patients using PREP and nBR. Other rSupposing that the intensity of TN pain depends on combined peripheral and central mechanisms, the attack frequency may be more dependent on peripheral mechanisms e.g. nerve-vessel contact as trigger and, therefore, may not be equally well modulated by cortical stimulation. This might explain why the tDCS effect on attack frequency was insignificant.The limitations of this study have to be considered. The relatively high drop out rate with more female than male patients shows that self-tDCS application at home may pose a huge problem for the mostly elderly TN target population, even though side effects were not reported and tolerability of participating patients was high. The stimulation with tDCS appears to be more difficult for the patients than previously suspected and probably requires a considerable education effort before it can be used sufficiently. Stimulation frequency (every day for 14 days) may not be optimal as a shorter duration may be just as effective or longer duration may be even more effective, but that will have to be tested in future studies. Due to the enormous interindividual variability in regard to tDCS treatment response it might be difficult to find the optimal stimulation parameters that suits all patients.All patients received therapy with different anti-epileptic medications that may have influenced clinical and electrophysiological data. We tried to minimize this impact by requiring a stable dose for six months prior to study inclusion. Carry-over effects due to the cross over trial design must be considered despite the 30-day interval between treatment conditions. There is evidence that patients with a special polymorphism in the BDNF receptor gene showed a pronounced facilitation after anodal and inhibition after cathodal tDCS. This maIn summary, tDCS is a promising non-invasive treatment option for trigeminal neuralgia without side effects in patients without satisfying response to medical treatment. Nonetheless, larger studies are needed to clarify the mechanism of action of tDCS in trigeminal pain and to reconfirm its efficacy in TN.Tim Hagenacker has received research support from Astellas and CSL Behring.Vera Bude, Steffen Naegel have nothing to disclose.Dagny Holle has received research support from Grünental and Allergan.Mark Obermann has received scientific support and/or honoraria from Biogen Idec, Novartis, Sanofi-Aventis, Genzyme, Pfizer, Teva. He received research grants from Allergan, Electrocore, and the German Ministry for Education and Research (BMBF).Hans-Christoph Diener has received honoraria for participation in clinical trials, contribution to advisory boards or lectures from Addex Pharma, Allergan, Almirall, AstraZeneca, Bayer Vital, Berlin Chemie, Coherex Medical, CoLucid, Böhringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Grünenthal, Janssen-Cilag, Lilly, La Roche, 3M Medica , Minster, MSD, Novartis, Johnson & Johnson, Pierre Fabre, Pfizer, Schaper and Brümmer, SanofiAventis, and Weber & Weber; received research support from Allergan, Almirall, AstraZeneca, Bayer, Galaxo-Smith-Kline, Janssen-Cilag, and Pfizer. Headache research at the Department of Neurology in Essen is supported by the German Research Council (DFG), the German Ministry of Education and Research (BMBF), and the European Union.MO and ZK conceptualized the experimental design. MO and TH organized the study. TH and VB acquired the data. TH, VB, SN and DH were responsible for the clinical supervision of the test persons. TH, DH, HD and MO analyzed the data. MO conducted the statistical analysis. TH wrote the first draft of the manuscript and interpreted the findings. All authors gave input to the manuscript. All authors read and approved the final manuscript.


Whiplash patients regard cervicogenic headache (CEH) as the most burdensome symptom of their condition. Sufferers experience a significant degree of disability from headache, associated neck pain and disability, and sleep disturbance. Lateral C1/2 joint pulsed radiofrequency (PRF) treatment has been shown to produce significant relief from headache in patients with CEH.The objective of this retrospective questionnaire study of 45 consecutive whiplash patients with CEH who had undergone antero-lateral atlantoaxial joint pulsed radiofrequency treatment (AA PRF) was to evaluate the treatment’s long-term effects on pain-related disability and health-related quality of life.Four questionnaires were sent to all 45 patients who had undergone AA PRF: 1) The short form-36 (SF-36); 2) The neck disability index (NDI); 3) The medical outcome scale-sleep scale (MOS-SS); 4) The headache impact test-6 (HIT-6). All 45 patients received AA PRF under fluoroscopic guidance. PRF treatment was conducted at 45 V with a pulsed frequency of 4 Hz and a pulsed width of 10 ms for 4 minutes .Patients who responded to the procedure reported lower pain scores at 2, 6, and 12 months of follow-up compared to nonresponders. More important, patients reported marked improvements in headache impact (P < 0.01), neck-disability scores (P < 0.01), awakening due to headache (P < 0.01), and sleep problems  on the MOS-SS. Responders to the procedure also reported a significantly higher health-related quality of life in terms of bodily pain (P < 0.05) and health change (P < 0.01) on the SF-36.In light of the inherent limitations of our retrospective study, AA PRF treatment can only be tentatively viewed as a promising treatment modality for whiplash patients with CEH and is subject to validation in future studies. The term cervicogenic headache (CEH) was first coined by Sjaastad et al. in 1983. In 1990 the CHISG criteria  for CEH was issued .The prevalence of CEH had been estimated as high as 4.1% in the general population and as high as 17.5% among patients with severe headaches. For patients with headaches after whiplash, the prevalence is as high as 53%  more than 1 year ago aimed to evaluate its AA PRF’s effects on pain-related disability and health-related quality of life.Institutional review board approval was obtained prior to administering the questionnaire to all patients. This retrospective questionnaire study included 45 consecutive whiplash patients who had undergone lateral C1/2 joint PRF application for CEH in a single pain center in the Netherlands between January 2007 and February 2009. The patients were recruited from a review of the pain center’s procedure records and verified with the individual patient’s medical records. All 45 patients who had fulfilled clinical criteria specified in The technical details of the percutaneous procedure have been described elsewhere . A 22-G,For the analysis of the MOS sleep scale, 90% completion of a section was considered sufficient for analysis. The HIT-6 and NDI scores were excluded if one item was missing. For the SF-36 subscale scores, missing values were substituted with group mean values in accordance with the instructions in the SF-36 manual. All statistics were performed using SPSS (version 16.0 for Windows). Descriptive statistics were generally reported as mean values ± 1 standard deviation (SD) and were analyzed for their degree of skewness or kurtosis. A student’s t-test (continuous variables) and Chi-square test (for dichotomous variables) were used to compare the differences in baseline characteristics and study measures between both groups. Pearson’s correlation coefficients were used to evaluate the correlation between questionnaire scores and their relevant domains. A significance level of P < 0.05 was used for all tests.Thirty-six patients returned their questionnaires within 4 weeks. We attempted to contact the remaining 9 patients. Four patients returned their questionnaires after 2 reminders (88.9%). We were unable to contact 1 patient. One patient agreed to the HIT-6 over the phone but not the rest of the questionnaires. Three patients agreed to the use of retrospective data but not to the questionnaires. Forty patients completed the SF-36 and NDI questionnaires, 39 patients completed the MOS-SS questionnaires, while 41 patients completed the HIT-6 questionnaires. Of the 44 patients who consented to the study, 25 patients self-reported more than 50% pain relief at the time of the survey and were denoted as treatment responders . The remaining 19 patients reported less than 50% pain relief at the time of the survey and were denoted as treatment nonresponders . The responders’ post-AA PRF improvement in pain scores was consistently lower than the scores of the nonresponders at 2, 6, and 12 months . AdditioThe mean questionnaire scores (± SD) of both the responder and the nonresponder group are shown in The lower headache impact scores in the responder group correlated significantly with a decrease in neck disability  as well as with awakening due to headache  in the MOS-SS. The lower neck-disability score in the responder group also correlated significantly with a decrease in sleep problems and awakening due to headache  in the MOS-SS. The perceived improvement in health correlated well with a reduction in the impact of headaches on life , neck disability , and bodily pain .From our retrospective findings, patients with sustained pain relief after AA PRF experienced improvements in headaches’ impact on life, reductions in neck disability, improvements with respect to sleep problems, and an improved overall perception of health within 12 months after treatment. The improvements in headaches’ impact on life were also highly correlated with improvements in neck disability and sleep. The divergent pain scores between the responders and nonresponders at 2, 6, and 12 months after AA PRF were reinforced by a self-reported improvement in general health by the responders. Despite consistently higher scores in all the health-related, quality-of-life domains, we were limited by a relatively small sample size to detect significant improvements in those who responded to AA PRF. We are unable to conclude that the extended duration of pain relief observed in the responder group is entirely a result of antero-lateral C1/2 joint PRF due to inherent limitations in our retrospective study. However, our findings suggest that if whiplash patients with CEH do respond to intra-articular lateral C1/2 joint PRF, they may not only improve in terms of pain scores but also may exhibit positive changes to life burdens, neck-related disability, and perceived health over the long term.An extensive body of research is looking at the mechanisms through which PRF acts. At the time of this writing, most studies point towards an alteration in synaptic transmission in a neuromodulatory-type effect -22. The One of the hypotheses generated from this retrospective study is thus the chrondro-protective mode of action of intra-articular PRF, which may explain the anecdotal observation of pain relief 2 to 4 weeks after PRF in a number of patients. A number of in-vitro studies have shown that chondrocyte proliferation and matrix synthesis are significantly enhanced by pulsed electrical fields , 32-34. The main limitation of our study is the lack of a control group. The retrospective nature of the study and the relatively small sample size also prevent strong conclusions regarding the efficacy of antero-lateral C1/2 PRF for whiplash patients with CEH.As we attempt to prospectively evaluate our results in a formal trial, more studies will be also needed to evaluate other treatment modalities in this multifaceted clinical diagnosis. It seems prudent to adopt an algorithmic approach in the management of such patients, and at the time of this writing, antero-lateral C1/2 joint PRF should be at most be regarded as a potentially viable treatment modality subject to validation in future studies.


Several studies have indicated that pain peaks at 24 to 48 hours after total knee arthroplasty (TKA) surgery. TKA has been associated with disruption in normal sleep patterns, swelling knee, and significant blood loss. However, a satisfactory regime to resolve these mentioned problems has yet to be found.In this study, a total of 420 patients were randomly allocated into two groups and treated with continuous irrigation of either 4000 mL cold saline with 0.5% epinephrine or normal temperature solution. Clinical outcomes including pain scores at rest during postoperative three days, drainage output, analgesic consumption, decreased hemoglobin, sleep quality, and satisfaction rate were analyzed. Mean scores and postoperative change in scores were calculated.P = 0.0016) to 24 hours (P = 0.0004) after TKA. Additional benefits including reduced analgesic consumption, improved satisfaction rate, and sleep quality were observed. In addition, a significant reduction in blood loss reflected by decreased Hb and drainage was found.Visual analog scale (VAS) pain scores in the treatment group were significantly reduced from 4 hours (In this study, irrigation with a cold 0.5% epinephrine solution was a beneficial and cost-effective treatment that decreased acute postoperative VAS pain scores immediately after and 1 day after surgery. Patients reported postoperative improvement in sleep quality and overall satisfaction rate with a decrease in morphine usage. In addition, a reduction of intraoperative blood loss might decrease the blood transfusion rate and related costs. Collectively, irrigation with cold 0.5% epinephrine offers a safe, simple, and effective treatment that might improve recovery and enhance quality of life of patients undergoing TKA. Most patients reported improvements in pain, function, and health-related quality of life (QOL) within 3 to 6 months after surgery.8 The clinical benefits from the use of additives in irrigation solutions, such as antibiotic, detergent, and hypertonic saline, has been previously described.11 Continuous irrigation with certain additives have been shown to reduce bacterial growth in periprosthetic joint infection (PJI).12 Therefore, irrigating the wound during orthopedic surgical procedures, such as TKA, might improve surgical outcomes and reduce perioperative complications at a low cost.Irrigation is necessary during the resection process of TKA to remove bone and soft tissue debris, potential bacteria colony, blood, and heat.13 In addition, cold stimulation could reduce bleeding that is caused by capillary oozing, medullary cavity, and bone bed interface. However, the direct benefits of postoperative cryotherapy are unclear because of the lack of standardization in instruments, frequency, duration, and temperature.2 Few studies have evaluated intraoperative cryotherapy in TKA. Therefore, in this study, we assessed the clinical outcomes in patients undergoing TKA who had received intraoperative chilled irrigation solution containing epinephrine to reduce the perioperative inflammation response. We hypothesized that patients in the treatment group would have less swelling and blood loss, reduced postoperative pain, and an overall higher QOL during hospital admission.Previous studies of postoperative cryotherapy have found a reduction in inflammatory cytokines that changes tissue metabolism by decreasing enzymatic function, inhibiting the stretch reflex, and reducing muscle spasm.A randomized, double-blind, controlled, and single-center study was performed between May 2012 and May 2014 in the orthopedics department of the Chinese PLA General Hospital. Participants undergoing primary, unilateral TKA were placed randomly into either the treatment or control group using computer-generated randomization sequence . Before enrollment, all of the patients gave informed consent and this study was approval by Institutional Review Board and ISRCTN registry (How to recover from TKA with less pain NO.ISRTCN14054997). Sample size estimation was based on detecting the difference in visual analog scale (VAS) pain scores. The estimated number of >150 patients in each group was enough to detect a 20% difference between groups with alpha set at 0.05 and beta 0.1. An additional 10% of total participants were planned in each group to compensate for any unforeseeable loss.In this study, we enrolled a total of 420 patients undergoing primary, unilateral TKA because of degenerative knee joint osteoarthritis. The exclusion criteria in this study were the following: (1) Refuse to participate in this trail, (2) history of severe hypertension or cardiovascular diseases, and (3) Allergies to epinephrine and cold intolerance. During the procedure, all of the patients had intraoperative continuous irrigation. Patients in the treatment group received 4000 mL 4°C cold solution with 0.5% epinephrine and those in the control group were irrigated with 4000 mL of normal saline at normal temperature. Previous studies have recommended the 4000 mL solution as an effective volume for pulse irrigation to remove particles and other debris during cemented TKA. Before surgery, the treatment solution remained 4°C in a nearby refrigerator and was transported by circulating nurse at the appropriate time. Epinephrine was added to the cold solution following preparation of the bone bed. Normal irrigation saline was stored at 21°C to 24°C. After closing the joint capsule, 50 mL of normal saline or cold irrigation solution with 0.5% epinephrine was administered through a drainage tube placed in the knee joint cavity to prolong the effect of the cryotherapy treatment. The drainage tube remained clamped for 4 hours after injection. Acute postoperative pain management for all of the patients included a 48-hour patient-controlled analgesic (PCA) pump and diclofenac sodium  and parecoxib . Following hospital discharge, tramadol was given based on patients’ demand. The thromboprophylaxis protocol was 10 mg rivaroxaban every day.The primary efficacy parameter was based on changes in the pain score using a 100 mm VAS, which ranged from 0 (standing with no pain) to 100 (worst imaginable pain). The VAS score was measured at 4, 8, 12, 16, 20, 24, 36, 48 and 60 hours, respectively, while the patient rested in bed. Patients reported postoperative sleep quality and satisfaction rate using the VAS. Local swelling and inflammation was evaluated by measuring the knee joint girth at 1 cm proximal to the upper border of the patella before surgery, and 48 and 96 hours following the procedure. The Each measurement was performed twice and the mean value was reported. Drainage output was recorded and compared following extraction of the drainage tube after 24 hours. Drainage consisted of mainly blood. The 50 mL of irrigation solution infused perioperatively was subtracted from the total volume of drainage output. Analgesic consumption depended on total doses of morphine used by PCA treatment, weak opioid analgesic, and nonsteroidal antiinflammatory drugs (NSAID) in every 12 hours.The TKA procedure was completed under epidural anesthesia or nerve block by two experienced surgeons. All of the patients were given prophylactic antibiotics (vancomycin or cefotaxime) before the procedure. Cruciate ligament-retaining prosthesis  were provided for all participants in this study. The drainage tube was extracted at 24 hours following surgery. A tourniquet was applied for 30 minutes at 300 mg Hg before the femur osteotomy and after the tibia osteotomy, and released following the closure of the joint capsule.P-value of 0.05. Continuous variables were shown as mean and standard deviation (SD) values. Between-group comparisons of VAS pain scores, knee girth, analgesic consumption, sleep quality, satisfaction rate, and drainage output were completed using the Student t test. Qualitative data was compared using a chi-square test. All values were assumed to have normal distribution. Statistics analysis was performed by SAS Statistical Software 9.1.3.The significance threshold was defined using a The initial 402 participants were randomly allocated in this study according to the exclusion criterion. After 13 patients dropped from the study  a total of 389 patients were analyzed at the end of the study , 8 hours (P = 0.0001), 12 hours (P = 0.0003), 16 hours (P = 0.0001), 20 hours (P = 0.0002), and 24 hours (P = 0.0004)  and 2    Figure .Sleep quality and satisfaction rate were significantly higher in the treatment group than in the control group Table .No adverse events related to our medical intervention, including wound or deep infections, deep venous thrombosis (DVT), were observed throughout the study.In this randomized, double-blind, placebo-controlled and single-center study, we demonstrated that in patients undergoing TKA, an intraoperative application of 4000 mL chilled irrigation solution containing 0.5% epinephrine could improve the overall postoperative recovery. In our opinion, this safe, simple, and cost-effective intervention offers additional pain relief to the standard multimodal analgesic regime and a reduction in blood loss.14 As a result, sleep quality is severely impaired. Postoperative pain usually manifests at the initiation of the inflammatory response.6 Cryotherapy is believed to inhibit the inflammation mechanism caused by an increase in inflammatory cytokines and mediators.13 Traditionally, cryotherapy is applied postoperatively after an elevation in mediators and cytokines have initiated the inflammatory cascade.15 Consequently, the use of cryotherapy at the beginning of inflammatory reaction could reduce cytokines and mediators that induce inflammation. Few studies have investigated the effect of irrigation solution temperature in orthopedic procedures. In one study, cold irrigation did not significantly reduce postoperative pain and swelling in arthroscopic procedure.2 These findings might be because many arthroscopic procedures do not include administration of synovium, thus minimizing the effect on intra-articular inflammation.2 In addition, cold saline was withdrawn from the intra-articular tissues before the onset of the inflammatory response, as most of the irrigation was completed in <30 minutes. The characteristics of arthroscopic procedures are distinct from those of TKA procedures. The synovium, infrapatellar fat pad, and bursa, which are potential sources of pain, are partly or completely resected in TKA. Irrigation is applied after the completed osteotomy, for generally 30 to 40 minutes, and before the inflammatory response has begun. We designed irrigation with a capacity of 4000 mL consisting of 0.5% epinephrine cold and saline. About 50 mL of this was infused into the knee joint cavity after closure of the joint capsule. The use of 4000 mL cold saline is recommended because of its ability for removing particles during cemented TKA.Previous studies have shown that pain peaked at 24 hours following TKA.16 However, it is difficult for postoperative cryotherapy to freeze deep tissues in patients with a high body mass index (BMI) and swollen joints—a prevalent finding among TKA patients. In contrast, intraoperative cold irrigation is not affected by BMI. Cold irrigation solution is able to directly reach tissues in the articular cavity. The anesthetic effect of local cooling is produced by the slowing or elimination of pain signal transmissions.15 Our results revealed that VAS pain scores significantly decreased from 4 to 24 hours postoperatively with less analgesic use required. Swelling at 48 and 96 hours was not improved since it is difficult to maintain an effect for such an extended period from cold solutions. Therefore, continuous cryotherapy from intraoperative to postoperative points may provide a more efficacious option.Local application of cold penetrates to a depth of 4 cm below the skin and induces clinical cyrotherapy.3 In addition, epinephrine also serves as a vasoconstrictor, and thus blood loss in our treatment group was significantly decreased.Cold stimulation is a safe vasoconstrictor and thus achieves a reduction in blood flow, which decreases the local inflammatory response and formation of edema.Despite the limited benefits of pain relief and swelling in our study, the advantage of reduction in blood loss may be more significant and decrease the use and risks of blood transfusions. Symptoms of fatigue and pyrexia because of blood loss, which cam affect sleep quality and functional exercise, were reduced. In this subset of patients, sleep quality and satisfaction rates on the first postoperative night were significantly improved; and as a result, QOL during hospitalization was improved. In light of these possible advantages, our results revealed that irrigation is a safe, simple, effective, and economic treatment that can help realize the maximum benefits of TKA.The prospective, randomized, double-blind, and controlled nature of this study, along with its large sample size, helps provide weight to our findings. This is the first study to focus on the effects of continuous irrigation on TKA results. Several major clinical outcomes of TKA were evaluated. In addition, we devised a 50 mL 0.5% epinephrine cold irrigation solution that was infused into the knee joint cavity by a drainage tube at the completion of suturing the joint capsule tissue to produce a more lasting effect.However, there were several limitations to this study. It is not clear if these findings would remain true if cold irrigation was applied without a tourniquet in place. Additionally, the temperatures of the soft tissues after cold irrigation were not measured. The absence of these statistics may make the results relatively inaccurate. The degree to which the epinephrine solution affected intraoperative blood loss was not quantitatively measured. Furthermore, there seems to be a necessity to investigate whether intraoperative cold irrigation combined with cryotherapy after operation could obtain favorable benefits and be considered by future studies.Irrigation with a cold saline solution containing 0.5% epinephrine may benefit patients after TKA at a low cost. Such an application could significantly decrease postoperative VAS pain scores with reduced morphine consumption, improved sleep quality, and increased patient satisfaction after surgery. Additionally, reduction in blood loss may help decrease blood transfusion rates and their related costs. Collectively, this safe, simple, and effective technique may help recovery and enhance quality of life in patients undergoing TKA.


The Brief Pain Inventory (BPI) was used to measure pain intensity prior to treatment (T0), 2, 4, 6, 8 and 12 weeks  after treatment in a 24-hour period. Analgesic, quality of life (QOL) scores and complications were also recorded. Four patients were excluded as they were lost to follow-up or had incomplete data.89 patients with painful bone metastases secondary to lung cancer were consented and enrolled in this study from June 2013 to May 2015. All patients had failed or refused conventional treatments underwent percutaneous CT-guided 0. At T2, T4, T6, T8 and T12, the score in a 24-hour period decreased to 4.9±1.2 (P<0.01), 3.7±1.3 (P<0.01), 3.4±1.2 (P<0.01), 2.6±0.9 (P<0.01), and 1.4±0.8 (P<0.01) respectively. Comparison of QOL scores showed improvements including sleep, appetite, spiritual state, and fatigue at T2, T4, T6, T8 and T12 when compared to T0. No serious complications or massive bleeding were observed.85 patients with 126 bone metastases from lung cancer were treated. There were significantly lower scores after treatment in the visual analog scale (VAS) and analgesic. The VAS scores for worst pain was 6.3±1.8 at T125I brachytherapy is a safe and effective method for palliation of painful bone metastases from lung cancer after failure or rejection of conventional treatments. Bone was a common site of metastasis for patients with lung cancer, particularly non-small cell lung cancer, approximately 30-40% would appear skeletal metastases . At the 125I brachytherapy [Currently, conventional treatments were defined as bone metastases secondary to lung cancer had received local control therapies , chemotherapy, analgesics and so on) before ytherapy . Palliatytherapy . For focytherapy . For difAlthough a majority of traditional treatments have been used to treat painful bone metastases, the results can be disappointing . Recent 125I seed implantation was an acceptable and useful minimally invasive therapy for primary lung tumor or metastatic lymph node resulting in a high local control rate making it an alternate approach for achieving remission [125I brachytherapy for the palliation of painful bone metastases from lung cancer after failure or rejection of conventional treatments has not been reported. The purpose of this study is to report such data in patients with skeletal metastases secondary to lung cancer.Previous studies had shown that emission , 14. HowThe patient, tumor, and brachytherapy characteristics were delineated in Table 2, T4, T6, T8 and T12, the score in a 24-hour period decreased to 4.9±1.2, 3.7±1.3, 3.4±1.2, 2.6±0.9, and 1.4±0.8 respectively. Similarity, the score for average pain were 4.6±1.5, 3.5±1.2, 2.6±0.9, 2.1±0.7, 1.4±1.1 and 0.9±0.5 in a 24-hour period at T0, T2 (p<0.01), T4 (p<0.01), T6 (p<0.01), T8 (p<0.01) and T12 (p<0.01) respectively. The relief from pain was significantly improved from T0 to T12, whereas there was no significant difference in scores between T0 and T2 (P=0.27). The mean morphine equivalent 24-hour doses of 136.2±33.9mg at T0 and 109.4±29.8mg(p=0.57), 96.8±22.1mg(p=0.32), 108.4±27.2mg(p=0.64), 76.3±19.8mg(p=0.80), 39±6.8 mg(p=0.87) in the first 24 hours following T2, T4, T6, T8, T12 were not significantly different.The effectiveness of pain palliation is summarized in Table 4(p<0.01), T6(p<0.01), T8(p<0.01), T12(p<0.01) than T0, whereas there was no significant difference in scores between T0 and T2 (P=0.32) , spiritual state(p=0.33), and fatigue(p=0.28) categories  at 2 weeks on CT or PET-CT image and the range of tumor necrosis was gradually increasing with the follow-up prolonged. In addition, patients treated with 125I brachytherapy did not experience increased pain.All local bone tumors afterSeveral complications related to the procedure occurred during or after brachytherapy Table . Small vUp to 30 % of patients with lung cancer have bone metastases, and half of these develop intractable pain . The etiConventional therapies for painful bone metastases included systemic and local interventions. Chemotherapy and analgesic were systemically administered in select patients for palliation, but the effectiveness was variable , 19, 20.125I brachytherapy did not experience increased pain. A second advantage is providing complete irradiation to the local tumor, while it provided a lower dose to normal adjacent tissue.Previously, multiple minimally invasive image-guided ablation strategies have been studied as treatments for painful bone metastases , 24. Cry125I brachytherapy was an effective, accurate method for palliation of painful bone metastases. We found that the scores for worst pain were 6.3±1.8 before brachytherapy, and 4.9±1.2, 3.7±1.3, 3.4±1.2, 2.6±0.9, and 1.4±0.8 at 2, 4, 6, 8 and 12 weeks respectively, the symptom of pain was decreased obviously from T2 to T12. These corresponding results further illustrated that 125I brachytherapy for palliation of painful bone metastases painful bone metastases was significant and feasible.In this study, we demonstrated that 125I brachytherapy was effective at improving QOL. Comparison of QOL scores, the quality of sleep, appetite, spiritual state, fatigue and KPS at T2, T4, T6, T8 and T12 were all significantly better than at T0. We found that the treatment of pain was valuable, because the bone metastases were the only evidence of recurrence since lung cancer was controlled. Particularly encouraging were outcomes in five patients who were alive without pain or recurrence after125I brachytherapy. For these patients, 125I brachytherapy had been a curative treatment thus far.Another significant finding in this study was that 125I brachytherapy for pain palliation depended on the accurate placement of radioactive seeds within a known volume of tumor [125I seed dropped off with distance, our study showed that TPS can help peripheral tumor doses reach the MPD of 100-140 Gy and ensure that more than 95% of the tumor get 100% prescription dose [125I brachytherapy was safe and effective.The success ofof tumor . Americaof tumor . Becauseion dose . Thus, t125I brachytherapy. Thus, the next research is to explore the responses and sensibility about different pathology sub-types of lung cancer metastases for 125I brachytherapy. Last, responses to the pain score and QOL rating systems were provided by patients who were not previously familiar with these surveys introducing subjectivity into their assessments.The main limitations of this study were small sample size and a short duration of follow up. Also, a control group consisting of patients treated with EBRT or chemotherapy should be needed, further comparison and longer follow-up were desired for future analysis. Although pathology sub-types of lung cancer metastases with the 85 patients were clarified, it is not clear which pathology sub-type of metastasis is more sensitive to 125I seed implantation is a safe, effective, and accurate treatment for patients with painful bone metastases from lung cancer, who had failed or refused conventional therapies. Both QOL and pain palliation are achieved by this locoregional approach to skeletal metastases. Studies, in larger cohorts, can help substantiate this claim and may help broaden application of this therapy to primary bone tumors.In conclusion, CT-guided 125I brachytherapy After excluding patients lost to follow-up or for whom data was missing (n=4), data for the remaining 85 patients with 126 treated metastases was analyzed.The study was approved by the ethics committees at Sun Yat-sen University Cancer Center. Between June 2013 and May 2015, a total of 89 lung cancer patients with painful bone metastases  were recruited and consented for participation in this study. Most patients had previously pain management to bone metastases with external beam radiation therapy(EBRT), chemotherapy, analgesics, or patients had refused therapies, but the remission of pain was unsatisfied. These patients underwent CT-guided 125I brachytherapy with CT-imaging; (i) Absence of impending fracture; (j) No severe cardiopulmonary dysfunction.All enrolled patients met the following criteria: (a) Bone metastases from lung cancer were histologically or cytologically proven with imaging concordance; (b) Score of ≥4 worst pain over the past 24 hours according to BPI-Short Form; (c) Failure or refusal of conventional treatments ; (d) The number of bone lesions ≤3 with the size of each lesion ≤6cm; (e) Expected survival time ≥3 months; (f) Karnofsky performance status of ≥70; (g) Absence of coagulopathy ; (h) Ability to tolerate 125I seed  was 6711–1985, with a diameter of 0.8 mm, and a length of 4.5 mm. The central source of the particles was a 125I radionuclide silver rod, with a diameter of 0.5 mm, and a length of 3.0 mm. The matched peripheral dose was 110–140 Gy, and the average energy was 27–32 KeV. Each deposit had an initial activity of 0.8 mCi and a half-life of 59.6 days, release of continuous low-dose γ-ray and soft X-ray  after decaying into the organization. The 125I seeds had effective anti-tumor activity at a radius of 1.7 cm. Within 8–10 months, 93–97% of the brachytherapy dose was delivered.The type of each implanted 125I brachytherapy, 5mm axial enhanced CT images were obtained in all patients , planned target volume (PTV) and surrounding vital organs  was sought in every CT slice. PTV is defined as a 1.5 cm of expansion external to the GTV. The prescribed dose was averaged 120 Gy (range 100-140 Gy). Based on three orthogonal diameters within the target tumor and a prescribed matched peripheral dose (MPD) of averaging 120 Gy, TPS generated a dose-volume histogram (DVH), isodose curves of different percentages, and calculated the position of brachytherapy applicator, dose and number of implanted seeds Figure . The PTV125I seeds according to TPS , an 18 G spinal needle  reached the farthest tumor edge, but was kept at approximately or less than 5 mm of the border Figure . A turntS Figure . If a le0, T2, T4, T6, T8 and T12, respectively. The worst pain, least pain, and average pain scores from 0 to 10  were recorded. Relief of pain through the use of pain treatments or medications were scored on a 0–100 % scale in 24 hours . To further evaluate the results, pain scores of 0–3 were categorized as mild; 4–6, as moderate; and 7–10, as severe pain. The percentage distribution of patients whose worst pain score decreased in each category was compared during various periods.A dynamic enhanced CT and clinical hematological examination  were performed every two weeks for the first two months, then once every month after 2 months. Each patient was asked to answer relative questions with respect to the lesion that was to be treated by interview or telephone. we assessed pain intensity using the BPI-Short Form  and personal analgesic use in a 24-hour period at T0, T2, T4, T6, T8 and T12 by using a five-point categoric scale , similarly, KPS also was recorded. The changes in scores during these intervals, indicating recovery of QOL, were calculated and analyzed.Quality-of-life factors including sleep, appetite, spiritual state, and fatigue were rated by patients at T125I seed implantation underwent cardiac monitoring. All postoperative symptoms and complatations were recorded in detail, including a small amount of subcutaneous hemorrhage, local skin reaction, minor displacement of radioactive seeds, fever, granulocytopenia, pathologic fracture, hydropneumothorax, radiation pneumonia and massive bleeding. We calculated the percentage of various complications in order to further evaluated the safety of 125I seed implantation.Those patients who underwent percutaneous 0. Scores for QOL factors were compared using the same methods. The percentage distribution of patients in each pain category during each interal was analyzed with the Cochran-Mantel- Haenszel x2 test. A P value of less than 0.05 was considered an indicator of a statistically significant difference.The statistical software package SPSS version 10.0 was used for statistical analyses. Brachytherapy effectiveness was assessed by comparing the mean pain scores and the percentage distribution of patients reporting scores in each pain category  for each time period. The mean pain scores differences among various treatment periods were analyzed by paired t tests supplemented with repeated-measures analysis of variance (ANOVA), comparing them with scores at T


Some patients refer to pre-banding orthodontic separation as a painfulorthodontic procedure. Low-level laser therapy (LLLT) has been reported to havelocal analgesic effect.  The aim of this single-blind study was to investigate the perception of paincaused by orthodontic elastomeric separators with and without a single LLLTapplication (6J).  The sample comprised 79 individuals aged between 13 and 34 years old atorthodontic treatment onset. Elastomeric separators were placed in first maxillarymolars at mesial and distal surfaces and kept in place for three days. Thevolunteers scored pain intensity on a visual analogue scale (VAS) after 6 and 12hours, and after the first, second and third days. One third of patients receivedlaser applications, whereas another third received placebo applications and theremaining ones were controls. Applications were performed in a split-mouth design.Thus, three groups  were assessed.  No differences were found among groups considering pain perception in all periodsobserved.  The use of a single-dose of LLLT did not cause significant reduction inorthodontic pain perception. Overall pain perception due to orthodontic separatorplacement varied widely and was usually mild. It has been reported that 28% oforthodontic patients consider discontinuing treatment due to fear of pain, while 39% ofthem claim it is the worst feature of orthodontic appliances.,-It has been observed that, due to being mild to moderate and often transient pain,In light of the above, the aim of this study was to assess pain perception associatedwith elastomeric separators with and without a single application of 808-nm LLLT.This study was approved by Universidade Estadual de Maringá Institutional Review Board(0315.0.093.000-09) and all volunteers and legal guardians signed an informed consentform.Sample size calculation was performed with a confidence level of 95%, 5-mm margin oferror, 8.1 mm standard deviation, and an infinite population.The following inclusion criteria were applied: complete permanent dentition in themaxillary arch, except for third molars, and good systemic health. Patients who hadundergone prior oral LLLT; those who presented with systemic problems, such as diabetesor metabolic diseases, which may interfere in the inflammatory process; pregnant orlactating patients; those who were using painkillers or anti-inflammatory medicationsand/or presented with clear signs of periodontal disease, such as bleeding or signs ofinflammation  were excluded from the study.,The initial sample comprised 100 patients and all of them had the following maxillaryteeth separated with elastomeric separators : betweenthe second premolar and first molar , and between the first molarand second molar .Patients were randomly divided into four initial groups in which maxillary molars onboth sides received elastomeric separators. Each group was approached differently, asfollows: Group 1, LLLT applied on the left side and placebo on the right side (blind)(SOLce); Group 2, LLLT applied on the left side and control on the right side (aware)(SOLci); Group 3, control on the right side and placebo on the left side (blind) (SOce);Group 4, control on both sides (aware) (SOci). The term "blind" refers to the fact thatpatients were not aware of the procedure (placebo).In the group "orthodontic separation with laser application (blind)" (SOLce), LLLT wasapplied immediately after elastomeric separators placement in the maxillary left firstmolars. On the right side, placebo applications were performed, with the LLLT deviceproducing beeps without firing the laser. Since the infrared laser used is not visibleand protection glasses were on, patients could not detect any differences between thetwo applications.In the group "orthodontic separation with laser application (aware)" (SOLci), lasertherapy was performed only on the left side, as in group 1; but this time, patients wereaware that the laser would be applied on one side, only. On the other side, no placeboapplications were performed.In the group "orthodontic separation (blind)" (SOce), recorded as group 3, no LLLT wasapplied. However, on the left side, placebo applications were performed as previouslydescribed. Patients did not receive laser applications on the other side. Thus, thepsychological factor was assessed in terms of what extent to which it interferes in thepain process, inducing the patient into thinking that the side supposedly treated withsome sort of therapy would hurt less.In the group "orthodontic separation (aware)" (SOci), recorded as group 4, thevolunteers received neither placebo nor laser applications, thus fully characterizing itas the control group.Twenty-one subjects dropped out of the study or provided incorrect data: five of themreported severe pain ; and sixteen lacked complete data in one of the study periods (three fromthe SOce group and 13 from the SOci group). Therefore, final data distribution (n = 79)was as follows: SOLce (n = 23), SOLci (n = 25), SOce (n = 21) and SOci (n = 10).Considering the sample in terms of the sides assessed (n = 158), distribution was asfollows: laser = 30.37% (n = 48), placebo = 27.48% (n = 44), control = 41.77% (n =66).Applications were performed with a Whitening Lase II device  which has two laser probes with distinct functions: a smaller laserprobe for LLLT and a curved laser probe for teeth bleaching. The laser therapy probe ininfrared mode (AsGaAl) was used.A standard guide was used for all patients  based on the average size (13 mm) of thebuccal roots of the maxillary first molar.2, as recommended bythe manufacturer , thereby totalingapproximately 6 J of energy per tooth (1 x 60 s x 100 mW).The probe of the deviceremained in contact with the gingival tissue during applications. Elastomeric separatorswere placed and laser applications performed by the same previously trained andcalibrated operator.The wavelength used was 808 nm, with a fluency of 80 J/cmSubsequently, all patients were instructed to rate their level of spontaneous pain on avisual analogue scale (VAS). Initial scores were assigned as soon as the patient arrivedat the office and before any procedure was carried out. This initial score made itpossible to judge whether or not the patient already felt some pain, which was notrelated to the separation procedure, in the teeth involved in the study. Afterseparation, patients' pain levels were recorded 6 hours, 12 hours and 1, 2 and 3 daysfollowing separation. The scores assigned by the patient on the visual analogue scaleswere measured with a caliper . A zero score, located on the left sideof the scale, suggested no pain; while a 100 (100 mm) score, at the right end of thescale, suggested maximum pain. The center of the scale corresponded to a score equal to50 and suggested moderate pain. This information was provided to the subjects beforethey started assigning scores on their dental history cards, which patients tookhome.st and 3rd). Pain perception was assessed by analysis ofvariance (ANOVA) for repeated measures. Mauchly's sphericity test was also applied and,whenever violated, technical corrections were performed by Greenhouse-Geisser test.Statistical significance was set at 5% and analyses were carried out by means of SPSSversion 15.0.Data were tested for normality of distribution by means of the Shapiro-Wilk test. Shouldnormal distribution not be found, data were presented using median and their quartiles(1Patients' mean age was 23.4 ± 6.3 years for group SOLce (9 men and 14 women); 22.3 ± 4.1years for group SOLci (8 men and 17 women); 23 ± 4.7 years for group SOce (6 men and 15women) and 25.5 ± 7.8 years for group SOci (1 man and 9 women) .Data frequency distribution for age and sex was performed in a similar manner (p >0.05), confirming the homogeneity of the sample. Female patients were predominant onlyin the control group . This fap = 0.16)between left and right sides in all periods compared across all groups  did not report any pain over all evaluated periods; and only15.18% (n = 12) reported pain levels equal to or greater than 40 in at least one of theassessment periods. No statistical difference was found (l groups . Althougl groups  and 3.p= 0.32) in terms of pain level , such as COX-2 selective inhibitor, are still the best choice to reduce painduring orthodontic treatment, despite potential side effects.Since patients generally perceive pain as mild and transient, an analgesic regimenshould only be adopted for less tolerant patients. However, should such regimen provenecessary, a single application of LLLT does not seem to provide a fully effectiveprotocol for this purpose.A single application (6 J) of LLLT (808 nm) did not produce significant effects on theperception of pain caused by orthodontic separation.Overall, pain arising from the use of orthodontic pre-banding elastomeric separators waslow and transient, and discomfort was reported as relevant only by a minority ofpatients (18% in this study).