Objective: The study objective was to investigate the effect of cigarette smoking on the severity of pain, swelling and trismus on male after the surgical removal of impacted lower third molar. Material and Methods: This prospective comparative study was conducted for 150 male in two groups of patients, smokers and non-smokers. Each group consisted of 75 patients; smoking patient were the ones who smoke more than twenty cigarettes per day for more than one year of continuous smoking. Postoperative pain was evaluated using a visual analog scale (VAS) and the degree of swelling was evaluated through facial reference points’ variation. The presence of trismus was analyzed through measurement of the interincisal distance (IID).Result: Clinical and radiographic examinations were carried out. Data regarding the age, gender, angulations type, depth and width of impactions were evaluated and analyzedThe severity of pain, swelling and trismus on the 1st, 2nd , 5th and 7thday postoperatively was estimated. In both groups the pain and trismus were reported to be in peak level during the first post-operative day while post-operative swelling reaches its peak level in the second postoperative day.Conclusion: Cigarettes smoking do not have any significant relationship with the severity of pain, swelling and trismus after surgical removal of lower third molar on male gender. Key words:Cigarettes smoking, pain, swelling, trismus, impacted lower third molars. It has been scientifically and medically proven that smoking is the cause of a verity of different crucial, deadly illnesses and diseases ,2 among The surgical removal of impacted lower third molar is the daily procedure that is performed by oral and maxi-llofacial surgeons  which inAlthough many articles -17 have To the knowledge of the author there are no studies which discuss the effect of smoking on pain, swelling and trismus after the surgical removal of impacted lower third molar.Thus, this study aims to investigate the clinical significance of smoking on the severity of pain, swelling and trismus in different postoperative times.- Study Design and Sample: This prospective cohort study was obtained from the patients referred for management of impacted third molars to the Oral and Maxillofacial Surgery department, College of Dentistry, SIUST University, from November 1, 2008 to October1, 2010. Ethics Committee of the University has approved this research protocol. A total of 164 participants  were selected. All the patients have been informed by an informed consent.The inclusion criteria for these prospective studies were healthy men patients, without medication, older than 18 years, who completed the questionnaire and agreed to follow the postoperative instructions. Of the 164 patients, 9 were excluded from the study for not completing the questionnaire correctly, 3 for not following the postoperative instructions and 2 complain from post-operative dry socket.Patients diagnosed with one impacted mandibular third molars that need surgical extraction under local anesthesia were included in this study. They were not given any preoperative medications. They were divided in two groups: smokers and nonsmokers. The smoking group consisted of 75 patients who used to smoke more than twenty cigarettes per day for more than one year of continuous smoking and their ages range from 20-27 with the mean 24.56 ± 2.97 at the time of operation while nonsmoking group consisted of 75 patients who never smoked before with age range from 19-25 with the mean 22.48 ±3.12at the time of operation. All patients were routinely examined using conventional panoramic radiographs. The data relating to each patient in each group were recorded which included age, Winter’s classification and Pell and Gregory classification for the position of the impacted mandibular third molars , in addi- Surgical Procedure:The surgical procedure was similar in all cases and was operated by the same oral surgeon, with the protocol that included using 1.8 mL of 2% lidocaine hydrochloride with 1:80,000 adrenaline solutions. The time of injection and the time of surgery started were noted; All teeth were removed from a buccal approach using triangular flap. Bone surrounding the third molar was removed with a round bur in a hand piece using a copious amount of saline irrigation. In the majority of cases, the third molar was split using a tungsten fissure bur and a straight elevator as the routine technique. The tooth was divided with burs before elevation. The alveolus was inspected and curetted for granulation tissue followed by irrigation with saline. The flaps were sutured with a 4-0 silk suture.The time of completion the surgical procedure was noted.Postoperative instructions and prescribed drugs were explained to the patients, the smoking patient was instructed to stop smoking for first eight hours after the operation. For the first 5 postoperative days all patients were given antibiotics (amoxicillin 500 mg every 8 hours), and acetaminophen 500 mg 4 times daily for 3 days postoperatively. And a mouth rinse (0.2% chlorhexidinedigluconate) was started form the second day, every 12 hours for 5 days. The suture material was removed after one week. All surgical details were noted in a pre-made questionnaire.- Post-Surgical Assessment.For each patient the severity of postoperative pain, swelling and trismus on the 1st, 2nd, 5th and 7thday postoperatively was estimated . A singlPostoperative pain was assessed by a 10 mm visual analogue scale(VAS) with the end points marked as “no pain” and “worst pain ever experienced”. Absence of pain was scored as 0. If pain was present the patient was asked to select a field from 1 mm to 10 mm. For each patient, the appropriate score was recorded in the ques-tionnaire by one operator.Two distances were considered to evaluate the facial measurements of swelling, that is the distance from the corner of the mouth to the ear lobe and the outer canthus of the eye to the angle of the mandible measured by a thread which was then transferred to a ruler, the difference between the postoperative and preoperative measu-rements was calculated to measure the swelling area, it was (cm2).Trismus was assessed by measuring the differences in mouth opening .The difference between the postoperative and preoperative measurements was calculated to measure the trismus (mm).- Statistical analysis :Statistics were calculated using the SPSS for Windows  statistical software package. A multivariate repeated measure ANOVA was used to describe changes in the three primary outcomes  over time. The model included age, gender, ostectomy and surgery time (in minutes), class of tooth impaction, mandibular relationship, and occlusal plan as independent predictive variables .The cross table technique was applied for assessment of the variables  of two groups: smokers and non-smokers. Probability less than 0.05 was considered statistically significant.A total of 150 from 164 patients have included in the study analysis. The average duration of the surgery on the smoking group was 26.37 ± 13.5minutes ; on the nonsmokers group, it was 27.44 ± 11.65 minutes with the range (11-48 minutes).The mesioangular impaction according to the Winter classification was the most common types of impaction in both groups 38 (50.6 %) in smokers and 41 (54.6%) in nonsmoking patients while the IIB impaction type according to Pell and Gregory classification was the most common types of impaction in both groups 18 (24%) in smokers and 15 (20%)in nonsmoking patients. Both groups did not differ in age, position, or angulations.Although the severity of pain, swelling measurement and trismus of smoking group were more in all mean measurements than the nonsmoking group, at the end of the present study, the statistical analysis of resulting data confirms that there are no statistical significant differences between the two groups with regard to post-operative pain, swelling and trismus on males .It is certain that there is a paucity of evidence that tobacco usage produces a significant degree of local and systemic negative effects on the morphological and functional aspects of the microcirculation  and deleIt has been shown that chronic cigarette smoking regulates the expression of inflammatory process  and fromThe strengths points of this study were the consistency of only one surgeon and one gender that were males only. The other unique point is that the smoking group was with a history of smoking more than twenty cigarettes per day for more than one year of continuous smoking. Only one limitation is present in this study which is related to the study design, which did not include other types of tobacco smoking like cigar and shisha.It has been reported that nicotine increases the pain threshold and tolerance rating of men, but has no effect on the pain rating of women . In the In all postoperative times, there was no statistic significant correlation between both groups in regarding the severity of pain registered on VAS and this observation also mentioned in two previous studied ,25.The resulting data in all postoperative times also showed that cigarette smoking did not have any significant importance on the postoperative swelling and trismus and this finding came in line with other studies ,25,26 ,eStudies have shown that pain, swelling and trismus following lower third molar removal are influenced by various factors other than smoking such as the difficulty of the surgical procedure involved  and the According to the findings demonstrated in the present research, it can be observed that cigarette smoking does not seem to have any statistically significant relationship on the severity of pain, swelling and trismus after surgical removal of lower third molar on males.Further trials need to be conducted with using larger sample sizes from both gender and other types of tobacco smoking, such as cigar and shish, need to be conducted.


Chronic pain after prosthetic inguinal hernioplasty is one of the most important current issues in the current literature debate. Mechanisms related to pain development are only partially known. Influence of age as well as other factors is still unclear. The aim of this work was to evaluate whether development of chronic pain after open prosthetic plug and mesh inguinal hernioplasty is influenced by age.2-test.Analysis was retrospectively conducted, dividing our cohort of patients  who had undergone prosthetic open plug&mesh inguinal hernioplasty from Jannuary 1994 to May 2012, following only the age criterion (cut-off 65 yrs.), into two groups . All patients were routinely submitted to a postoperative questionnaire. Complications such as analgesic assumption were registered in both groups. Pain intensity was classified following the Visual Analogic Scale (VAS). Incidence of chronic pain, discomfort, and numbness, was assessed in both groups. Statistical significance was assessed by Xp>0.05). Incidence of other postoperative symptoms such as discomfort or numbness were slightly prevalent on young patients (respectively p = 0.0286 and p = 0.01), while for hyperesthesia and sensation of foreign body no statistically significant difference of incidence between groups was observed.Only 0.2% of patients suffered from a recurrence in our cohort. Postoperative chronic pain was observed in Gr. A in 0.12% of patients vs Gr.B 0.09% (Real chronic pain after inguinal hernioplasty is a rare clinical entity. Other causes of chronic pain should be accurately researched and excluded. In young patients psychological factors seem to show a slight influence. There was no influence of age on chronic postoperative pain incidence after inguinal hernioplasty. Chronic pain after prosthetic inguinal hernia repair is considered to be one of the unsolved problems after prosthetic inguinal hernioplsty ,2. Its iFrom January 1994 to May 2012, in our unit, 2902 patients were submitted to an open prosthetic inguinal hernioplasty for primary inguinal hernia following our previously described plug and mesh procedure ,7. Most All patients were preoperatively informed about the procedure, anesthesia, intraoperative feelings or sensation during surgical manipulation and postoperative care as previously described ,9. We diComorbidities of both groups are summarized in table Groups were evaluated for incidence of postoperative (defined as up to 12 postoperative day) and delayed (chronic) pain after inguinal hernioplasty as well as other sensations/complains such as referred numbness, discomfort, hyperestesia, sensation of foreign body.The operation was conducted under local, spinal and general anesthesia in Group A respectively in 98.8%,0 and 1.2% of patients, while in Group B in 97.5%,1% and 1.5%. No statistically significant differences regarding distribution of patients in local general and spinal anesthesia were found between the 2 groups Table .2-test for significance (p < 0.05).Patients were asked about pain intensity on postoperative recovery and during follow-up checks by using a Visual Analogic Scale (VAS). Then we followed-up the patients for the about 2 weeks after the operation, by collecting data about daily activities, referred pain during the daily activities, type of pain, duration of pain, assumption of painkillers. Pain intensity when present was classified following the Visual Analogic Scale (VAS) of Glasgow ranging from 0-10, as previously used in other reports . All patWe had a total of 6 recurrences (0.2%) in our cohort: 4 really inguinal hernia recurrences and 2 pseudo-recurrences as 2 becoming symptomatic after hernioplasty (misdiagnosed hernias).In group A 57.2% of patients used analgesia during recovery and 36.9 at home while in group B respectively 48.2 and 34.3%.p = 0.0286 and 0.01). Table After one year In group A no more pts referred light pain in both groups, rarely they referred mild pain VAS 4-7) without differences between young and old patients, so like for strong chronic pain (VAS 8-10). Minor symptoms like discomfort and numbness showed a slight prevalence on Gr.A in front of Gr.B after one year  referred a progressive relief/reduction of symptoms not hesitating to begin with legal proceedings, were treated conservatively without any exploration of the groin but with local infiltration of local anesthetic drugs.During recovery in group A early postoperative pain till 2 weeks, was more often observed than in group B: 17.1% vs 14.1% 36 Table . Also foChronic pain after inguinal hernioplasty can be defined as a persistent pain in operated groin region, lasting from 6 months after reoperation until at least one year, following EHS guidelines definition ,16. Of cThe incidence in world literature is estimated between 1-31%  patients tend to refer pain tolerance until disappearance or relief of symptoms . Thus inultima ratio" of treatment and has been effective in many series [Treatment methods in literature range from local drug infiltration using desametasone or steroid-like drugs to anesthetics such as bupivacain . Radiofry series -44, eveny series -48. In oIn conclusion our data show that age is not a risk factor to developing chronic inguinal pain after hernioplasty. Real chronic pain is to be considered a rare entity. Unfortunately a heterogeneous group of other sensations more frequently affects patients after prosthetic inguinal hernioplasty, not really affecting daily activities and quality of life. Other causes of chronic pain should be carefully excluded before defining symptoms as chronic pain after hernioplasty.extrema ratio" of treatment.Even if pain in younger patients has the same incidence as in older patients, in younger patients it is less well tolerated and they are prone to a greater analgesic assumption, additionally early postoperative pain in younger patient is more frequent. In the elderly all other sensations are better tolerated. A precise surgical technique, with systematic identification and preservation of inguinal region nerves, should be considered an important factor to prevent chronic pain. A conservative treatment, in many cases, is possible, surgical re-exploration of the groin with total neurectomy of all three nerves should be carefully considered as „VAS ; MRI (Magnetic Resonance Imaging); EHS (European Hernia Society); TENS .The Authors have no conflict of interests. The Authors received no financial support for the present study.MD:designed the study, co-collected data, wrote the paper, made literature research, gave final approval of the version to be published. GB: co-wrote the paper and co-made literature research, gave final approval of the version to be published. AG: collected and interpreted data, gave final approval of the version to be published. AB: co-collected data and draft tables, gave final approval of the version to be published. FB: made finale revisions, gave final style to the paper, gave final approval of the version to be published. AD: conception and co-designed of the study, made revisions, gave final style to the paper, gave final approval of the version to be published.MD: Assistant Professor of Surgery at University of Catania. GB: Associate Professor of Surgery at University of Catania. AG: Resident in General Surgery at University of Catania. AB: Associate Professor of Surgery at University of Catania. FB: Full Professor of Surgery at University of Catania. AD: Full Professor of Surgery at University of Catania.


The comorbidity index is a predictor of mortality in dialysis patients but there are few reports for predicting elderly dialysis mortality and national population-based cost studies on elderly dialysis. The aim of this study was to evaluate the long-term mortality of incident elderly dialysis patients using the Deyo - Charlson comorbidity index (CCI) and to assess the inpatient and outpatient visits along with non-dialysis costs.>75 years) receiving hemodialysis for more than 90 days between Jan 1, 1998, and dec 31, 2007, were included. Baseline comorbidities were determined one year prior to the first dialysis day according to ICD-9 CM codes. Survival time, mortality rate, hospitalization time, outpatient visit frequency, and costs were calculated for different age and CCI groups.Data were obtained from catastrophic illness registration of the Taiwan National Health Insurance Research Database. Incident elderly dialysis patients (age p < 0.001) and CCI patients (p < 0.001). Death rates increased with both increasing age and CCI score. High comorbidity incident hemodialysis and elderly patients were found to have increased length of hospital stay and total hospitalization costs.In 10,759 incident elderly hemodialysis patients, hazard ratios for all-cause mortality were significantly increased in the different age groups  patients. The demand for dialysis for elderly patients is increasing worldwide as a result of population aging  and age-For elderly ESRD patients, prompt renal replacement therapy is costly and does not necessarily extend survival ,11. PrevInternational Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) format, date of diagnosis, date of death, date of hemodialysis, date of every clinic visit, prescriptions, expenditure amounts, and outpatient/ inpatient claims for the beneficiaries with catastrophic illnesses during the period 1998–2007.We conducted a nationwide cohort using data from all elderly ESRD patients receiving hemodialysis in Taiwan’s National Health Insurance Research Database (NHIRD). The NHIRD has been previously described in detail . The NHIUsing the Registry for Catastrophic Illness Patient Database, we selected all patients diagnosed with ESRD defined as those who had catastrophic illness registration cards for ESRD (ICD-9 CM code 585) and who began hemodialysis more than 90 days prior to renal replacement therapy during the period of Jan 1, 1998, to Dec 31, 2007. The NHIRD began collecting statistics in 1997; however, our study cohort included data starting with 1998 to allow for a one-year wash-out period. In addition, we extended the observation time to 2008 in this cohort study. We included individuals older than 75 years of age who started hemodialysis in index days and excluded patients who received renal transplantation either before or after hemodialysis (n = 4).<3, 4-6, 7-9, >10. Hazard ratios of hemodialysis patient mortality in the four comorbidity index groups and different age groups were analyzed. Median survival years between >85 and < 85 years of age were evaluated in the different CCI group.The CCI was calculated to define the existing comorbidities using all diagnosis codes for the year prior to the index date on all inpatients and outpatients. Follow-up began on the index date and continued until death or the end of the study period if the patient was living . The CCI is defined by Charlson et al  and the Taiwan’s NHI is a government-run, single-payer NHI scheme financed by a combination of premiums and taxes. It compensates public and private delivery systems predominantly through a fee-for-service basis. The NHI program allows patient freedom of choice when seeking medical care and uses cost-sharing strategies to reduce unnecessary services. An insured patient would incur additional cost in the form of payment for services not covered by the NHI as well as user fees and co-payments for NHI-covered services. User fees are levied for contact with the provider, whereas co-payments vary according to the type of provider. Co-payments are most expensive for outpatient care at medical centers and least expensive for clinics . The medData were summarized using proportions and mean values (±standard deviation) as appropriate. The association between the CCI or age groups and mortality was assessed using the Cox proportional hazards model and adjusting for age and the CCI, Kaplan–Meier estimates with log-rank tests were used to show survival in the follow-up. In the mortality analyses, the patients were followed until event (death) or censoring (lost to follow-up or end of the follow-up period), whichever occurred first. Analyses were performed using the SAS statistical package software . All statistical tests were 2-sided with p<0.05 considered statistically significant.>75 years of age) with ESRD. Patients’ clinical characteristics and CCI scores are listed in The study population used for these analyses was representative of the Taiwan hemodialysis population and consisted of 10,759 incident elderly patients (age p = 0.197). With regard to CCI scores, mortality increased steadily with increased comorbidity for both unadjusted and adjusted models. Compared to the lowest comorbidity group (CCI <3), fully adjusted models of CCI 4-6, CCI 7-9, and CCI >10 displayed hazard ratios for mortality of 1.39 (95% CI 1.31-1.49), 1.83 (95% CI 1.71-1.95), and 2.64 (95% CI 2.43-2.87), respectively . For patients 80-84 years old, the adjusted hazard ratio (aHR) was 1.37 , at age 85 to 89 years, the aHR was 1.81 . Patients older than 90 years of age displayed an aHR value of 2.27  . Survivaectively .> 10 and elderly patients 85-89 years old with CCI > 10  Group publication, the majority of costs were allocated to dialysis treatment and transportation (70%), hospitalizations 12%) and medication (12%) . The cos% and medThe present study using the NHI database has three strong points. First, it included a large number of patients free of selection bias because more than 99% of patients meeting study criteria were included in the database. Second, the nationwide database is comprehensive and unlikely to miss many hospital admissions and costs. Third, mortality data are also expected to be accurate. However, this study has several limitations. First, laboratory data and measurements of physical function were not available from the NHIRD. Although these clinical parameters may influence the mortality rate, the CCI still performed better than age, diabetes, cardiovascular disease, or albumin . Second,In conclusion, age and CCI scoring are useful for predicting long-term mortality in incident elderly hemodialysis patients. Increased length of hospital stay, low survival rate, and increased utilization of national health insurance was observed in higher comorbidity index elderly dialysis patients. These findings help to clarify the risks and benefits of hemodialysis in elderly patient populations and are informative for dialysis decision-making process. Conservative treatment might be considered for ESRD patients with high comorbidities and low survival rates.Figure S1Cumulative prevalence of comorbid conditions in incident elderly end-stage renal disease patients before hemodialysis initiation.(TIF)Click here for additional data file.


While pain is frequently associated with unipolar depression, few studies have investigated the link between pain and bipolar depression. In the present study we estimated the prevalence and characteristics of pain among patients with bipolar depression treated by psychiatrists in their regular clinical practice. The study was designed to identify factors associated with the manifestation of pain in these patients.Patients diagnosed with bipolar disorder (n=121) were selected to participate in a cross-sectional study in which DSM-IV-TR criteria were employed to identify depressive episodes. The patients were asked to describe any pain experienced during the study, and in the 6 weeks beforehand, by means of a Visual Analogical Scale (VAS).Over half of the bipolar depressed patients , and 2/3 of the female experienced concomitant pain. The pain was of moderate to severe intensity and prolonged duration, and it occurred at multiple sites, significantly limiting the patient’s everyday activities. The most important factors associated with the presence of pain were older age, sleep disorders and delayed diagnosis of bipolar disorder.Chronic pain is common in bipolar depressed patients, and it is related to sleep disorders and delayed diagnosis of their disorder. More attention should be paid to study the presence of pain in bipolar depressed patients, in order to achieve more accurate diagnoses and to provide better treatment options. The link between unipolar depressive disorder and pain has been investigated extensively in a number of epidemiological ,2, cliniDespite the association demonstrated between depression and pain, little is known about the relationship between pain and bipolar depression (BD), or its therapeutic consequences. A link between BD and pain has been proposed and indeed, BD is associated with an increased prevalence of migraine . Indeed,i.e., neuropathic pain). However, while valproate, carbamazepine and lamotrigine in particular were thought to be useful to treat mania and bipolar depression, and in preventing relapses [Better understanding the relationship between BD and pain is also vital to control the potentially risky pharmacological side-effects when treating pain in bipolar depressed patients. For example, chronic pain is frequently treated with antidepressants ,14 whichrelapses , these drelapses . Likewisrelapses .In relation to pain treatment, some analgesic opioids and other classical analgesics have been shown to have an important mood-altering effects on BD patients, increasing the risk of mania -23. In pChronic pain has recently been linked with an increased risk of suicide among individuals with mental disorders . Given tThe aim of the present study was to evaluate the prevalence and characteristics of pain experienced by bipolar depressed patients treated by psychiatrists in their regular clinical practice, and to identify possible factors associated with the presence of pain in these patients.Diagnostic and Statistical Manual of Mental Disorders Fourth Edition Text Revision (DS-IV-TR) criteria. In this study, 121 patients diagnosed with bipolar disorder currently suffering a depressive episode, and who were mentally and physically able to participate in the study, were analyzed. All the patients provided written informed consent before their inclusion in the study. Moreover, the study was carried out in accordance with the Helsinki Declaration, and the standard working procedures and protocols were approved by the Clinical Research Ethics Committee at the Clinic Hospital in Barcelona, ensuring adherence to the norms of good clinical practice.Subjects were selected from among the participants in a multi-centre, cross-sectional study carried out on a representative sample of Mental Health Care Centres in Spain published elsewhere . The samInterviews were performed at psychiatric out-patient centres and depression was confirmed on the basis of the diagnostic criteria of the DSM-IV-TR. The presence of anhedonia, loss of energy, sleep disorders, depressive mood, diminished concentration, change of body weight/appetite, feelings of guilt, psychomotor changes and suicidal ideation were assessed by the psychiatrist, and the intensity of depression was determined using the 17-item Hamilton Depression Scale validated in Spanish . A MaierThe patients’ socio-demographic variables were recorded , and these patients were questioned about the presence of pain at the time of the study and during the preceding 6 weeks. In cases where pain was experienced, the intensity, duration and location of the pain were recorded. To ensure the clear-cut presence of painful symptoms, only patients with pain intensity over 40 on the Visual Analogue Scale (VAS) were considered . PatienThe interference of pain with the patients’ everyday activities in the week prior to the study was also assessed using a VAS, with a score of 0 representing no interference and 100 representing total incapacity. The data collection forms were further monitored centrally to check and correct any missing data or inconsistencies when possible.In the descriptive analysis, the absolute frequency, mean, median and the dispersion measurements were calculated for the qualitative and quantitative variables. The prevalence (± 95% CI) of pain was calculated, and the crude and adjusted odds ratios (ORs) were used to analyze the factors associated with pain. For this purpose, a logistic regression model was drawn up in which the outcome variable was the presence or absence of pain, including the following variables in the model: gender, age, marital status, Hamilton scale score, Maier subscale score, bipolar disorder with/without late bipolar diagnosis (previous diagnosis of other type of depression), and specific symptoms of depression . A subset of the variables that best predicted the presence or absence of pain was selected using the Hosmer-Lemeshow test to identify the best model. Some interaction terms were also introduced into the model.The average age of the 121 participants was 50.7 years (SD 12.3), of whom 62.2% were female, 75.2% had completed primary or secondary education and 52.9% lived with their partner , and in patients between 40 and 59 years of age , although these differences were not significant. The characteristics of the pain experienced are shown in Table The prevalence of pain in the patients with BD was 51.2% . There was a tendency for this prevalence to be higher in the female population  was related to a delay in the accurate diagnosis of bipolar disorder . InteresIt was recently suggested that inter-episode REM sleep, slow-wave sleep and stage 2 sleep are correlated with a predisposition to manic and depressive symptoms , and cerOne limitation of the present study was the small size of the sample, and the fact that some factors associated to pain (OR > 1) were of borderline statistical significance. Likewise, the cross-sectional nature of the survey does not allow us to obtain information regarding the direction of the causality between pain and BD. Therefore, we can only speculate as to how the proposed association between pain and BD is established. It has been suggested that certain pain conditions, like migraine , share aIn summary, we found a high prevalence of moderate to severe intensity pain in bipolar patients, which is persistent and significantly affects the patients’ ability to carry out everyday activities. We propose that greater attention should be paid to the presence of pain in bipolar patients, as well as to other factors that could influence their clinical development, such as sleep disorders and the presence of other forms of depression.VAS: Visual analogical scale; BD: Bipolar depression; SSRIs: Selective serotonergic reuptake inhibitors; DS-IV-TR: Diagnostic and statistical manual of mental disorders fourth edition text revision; ORs: Odds ratios.The authors declare that they have no competing interests.FI, GPA and MJA performed the literature searches and wrote the first draft. DM undertook the statistical analysis and wrote the first draft. FI, AOL, CJA and MJA designed, planned and coordinated the study. All the authors contributed to and have approved the final version of the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/13/112/prepub


Pain is common in gastroenterology. This review aims at giving an overview of pain mechanisms, clinical features, and treatment options in oesophageal disorders. The oesophagus has sensory receptors specific for different stimuli. Painful stimuli are encoded by nociceptors and communicated via afferent nerves to the central nervous system. The pain stimulus is further processed and modulated in specific pain centres in the brain, which may undergo plastic alterations. Hence, tissue inflammation and long-term exposure to pain can cause sensitisation and hypersensitivity. Oesophageal sensitivity can be evaluated ,for example, with the oesophageal multimodal probe. Treatment should target the cause of the patient's symptoms. In gastro-oesophageal reflux diseases, proton pump inhibitors are the primary treatment option, surgery being reserved for patients with severe disease resistant to drug therapy. Functional oesophageal disorders are treated with analgesics, antidepressants, and psychological therapy. Lifestyle changes are another option with less documentation. Pain and gastrointestinal (GI) discomfort are the leading symptoms in the multitude of oesophageal disorders. In oesophageal disorders, this review aims to (1) give an overview of the mechanisms underlying abnormal pain processing, (2) describe the clinical features of the most relevant entities, and (3) give a summary of currently recommended treatments. Pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” . Generalpolymodal) and respond to different stimuli being, for example, mechanical, chemical, and ischemic . . 18]. The fact that each segment in the spinal cord receives afferent fibres from visceral as well as somatic structures causes another phenomenon known as referred pain. Although simplified, referred pain originates due to convergence between visceral and somatic fibres on the same second order  neuron (for details see ). Since The oesophagus is dually innervated by vagal and spinal nerves . Most afThe enteric nervous system (ENS) is present in most of the GI tract including the oesophagus. It is closely related to the central nervous system (CNS) and the autonomic nervous system. The ENS is a local minibrain with reflexes and a library of information for different patterns of gut behaviour  25]. Th. Th25]. From the spinal cord, pain transmits to the brain through several distinct pathways . Most afThe pain system has several inherent mechanisms whereby inflowing pain signals can be modulated. The multiple complex pathways involved in this modulation comprise both spinal and supraspinal regions. In particular, connections between these sites, commonly referred to as the descending modulatory pain pathways, play a central role , 35. PaiPeripheral nociceptor sensitisation underlies the hyperalgesia that develops immediately around an injury site. Analogous to mechanisms documented in the cutaneous system, oesophageal afferent fibres may become sensitised by endogenous chemicals. This results in an increase in their responsiveness to a given stimulus and/or an increase in the spontaneous activity [activity . In contactivity , 38. Upoactivity . Furtheractivity , 41. In activity , 42, 43.Enhanced spinal input from, for example, oesophageal inflammation can activate intracellular signalling cascades within the spinal dorsal horn neurons. This results in an increased synaptic efficacy and is known as central sensitisation . Deep paViscero-visceral hyperalgesia is a complex form of hypersensitivity probably explained by more than one mechanism. Since this phenomenon takes place between visceral organs which share their central afferent termination, it is plausible that central sensitisation play an important role . Animal Viscero-visceral hyperalgesia may explain the epidemiological findings that several clinical conditions with organic diseases show evidence of increased pain from other organs . This waMost information of visceral pain physiology comes from animal studies. However, human experimental pain models have been extensively used in visceral pain studies to elucidate the sensory properties of the gut, that is, the effects of age, gender, and menstrual cycle on pain as well as differences in the sensitivity of several parts of visceral hollow organs –60. ModeIn most experimental studies, assessment of pain has relied on indirect measurements of self-reported pain. These subjective measurements have been improved with the use of validated psychophysical scales like the visual analogue scale, the McGill pain questionnaire, and the Gracely pain scale . As oppoAlthough PET and fMRI possess a high spatial resolution (millimetres), they are hampered by a poor temporal resolution (seconds). Thus, the retrieved brain response using these methods corresponds to rather late events that may be related to arousal and attention rather than pain. On the contrary, evoked brain potentials detect neuronal activity in real time with a very high temporal resolution (milliseconds). Using this technique, the sequential brain activity following electrical stimulation of the oesophagus was determined in a study from our group . FurtherThe clinical picture of oesophageal disorders depends on the pathophysiology responsible for their development. In some diseases, for example ERD, excess oesophageal acid exposure is thought to be the main pathophysiological factor underlying their development . Hence, GORD is defined as chronic mucosal damage or typical symptoms of reflux disease, which reduce quality of life, combined with the retrograde reflux of gastric contents into the oesophagus . The typUsually, GORD is divided into ERD and NERD. When classified according to endoscopy, 24-hour pH profile and symptom-reflux association indices, recent studies have revealed that up to 70% of the GORD patients have NERD. However, the quality of life impairment in patients with NERD is comparable to that in patients with ERD . Since tConclusively, in many patients the exact cause of symptoms remains unclear. Some patients will, however, fulfil the definition of functional oesophageal disorders, see next section.  Midline chest pain or discomfort that is not of burning quality, absence of evidence that gastrooesophageal reflux is the cause of the symptom, and absence of histopathology-based oesophageal motility disorders. The criteria must be fulfilled for the last 6 months with symptom onset at least 3 months prior to diagnosis [According to the Rome III criteria, FCP is defined asiagnosis . AnotherThe prevalence of FCP is much debated, and few studies have used the Rome III criteria. With widely varying criteria, the prevalence has been estimated anywhere between 2  and 46% Formerly, oesophageal hypersensitivity to otherwise physiological stimuli was considered a likely origin for FCP. Hence, the disorder has been termed “irritable oesophagus” or “acid-hypersensitive oesophagus” –73. NowaBarrett's oesophagus (BO) is a metaplastic condition in the oesophagus, in which the squamous epithelium is replaced with columnar epithelium, so far considered to arise due to excess gastro-oesophageal reflux . FurtherPatients with BO are most likely hyposensitive to oesophageal stimuli, but the power of evidence for the hyposensitivity is variable between the different stimulus modalities . SeveralSeveral indications exist that patients with BO have an impaired ability to clear refluxed acid from the oesophagus. An excess acid exposure on 24-hour pH measurement has previously been shown in BO compared to both healthy controls and other GORD patients , 115. ExOverall, PPIs are the most effective acid-suppressive drugs available and are the drug of choice for GORD . SymptomA meta-analysis by Khan et al. including 35.978 patients with erosive oesophagitis found PPIs to be roughly 4 times as effective as placebo and twice as effective as histamine 2 receptor antagonists in healing erosive oesophagitis . Also, tA probably important factor influencing the response to PPI treatment in NERD patients is the degree of distal oesophageal acid exposure measured with 24-hour oesophageal pH. A close relationship was shown between long acid exposure time and the response to PPIs in a large clinical trial .Doubling the dose of PPI using a standard dose twice daily is used in certain cases. In the treatment of ERD, this is supported by reasonable evidence with a NNT of 25 for the doubling of dose . HoweverWhen considering which PPI to use, price and degree of symptoms must be taken into consideration. The potency of the different PPIs is somewhat varying, but the overall efficacy is good. A meta-analysis by Kirchheiner et al. including 57 clinical studies  found reWhen it comes to histamine 2 receptor antagonists, several studies have found these to be superior to placebo (but inferior to PPIs) in healing reflux oesophagitis, including the above-mentioned meta-analysis , 122. ThConclusively, the primary choice of acid suppressive treatment in patients who fulfil the criteria for GORD, regardless of other characteristics, should be a PPI of any choice in the standard dose. This said, those who have normal oesophageal mucosa on endoscopy (NERD) and especially those with negative 24-hour pH (FCP and FH patients according to the previous definitions) benefit less from acid-suppressive treatment than ERD patients. However, they most likely still have a better response to PPIs than to placebo , 92, 121Surgical treatment of reflux is more effective than medical treatment of reflux and pain. The primary surgical method is Nissen fundoplication, in which the gastric fundus is wrapped around the oesophagus to create an artificial valve to support the insufficient upper oesophageal sphincter. A meta-analysis including 1232 patients showed improvement in quality of life, GORD-related symptoms, and 24-hour pH up to 1 year after an operation with Nissen fundoplication compared to medical treatment with PPIs . HoweverB) agonists, metabotropic glutamate receptor antagonists and cannabinoid receptor 1 agonists, which, hence, can be used to treat reflux and associated chest pain. So far, only GABAB agonists have proven clinically valuable, whereas the two latter still await clinical studies [B agonist, acts on the central level and has been shown to reduce the rate of transient lower oesophageal sphincter relaxations and increase lower oesophageal sphincter basal tone. Besides, it has proven effective on clinical parameters such as oesophageal acid exposure, nonacid reflux, bile reflux, and symptom improvement [B agonist is lesogaberan, which has a theoretical effect similar to baclofen, but acts primarily in the periphery. So far, lesogaberan has only been investigated in one clinical study in GORD patients, which found significant reduction on the number of transient lower oesophageal sphincter relaxations and reflux episodes and side effects on placebo level [Transient lower oesophageal sphincter relaxations have been shown to be a major contributor to acidic and nonacidic gastro-oesophageal reflux, especially in NERD patients , 127. Serovement , 129. Anbo level . The evidence supporting a beneficial effect of lifestyle interventions for the treatment of oesophageal pain disorders is sparse. A comprehensive review by Kaltenbach et al. found weight loss and head of bed elevation to be the only certain factors to improve the course of GORD . Both weWeight loss has been found to have a probable positive effect on GORD , 132. HoFCP should not be treated as such before a thorough evaluation has excluded other causes of the patient's symptoms. If a diagnosis of a functional oesophageal disorder is established, the approach to the patient should be based on treatment of symptoms. Patients with heartburn and negative acid exposure have greater anxiety and somatisation scores than those with verified reflux . This meWhen it comes to pharmacological treatment, conventional pain treatment is only one option. Here, the principle of the analgesic ladder applies . This meOther drugs with effect on FCP are tricyclic antidepressants and selective serotonin reuptake inhibitors, which have been demonstrated effective on functional GI disorders including FCP in controlled trials , 138. DrIn summary, when approaching a patient with reflux symptoms suspected for GORD, the general strategy is to start with a short course (e.g. 4 weeks) of PPI in the standard dose as a diagnostic test. This has been shown to be the most cost-effective and time-saving approach with a good sensitivity as well as specificity in diagnosing NERD , 140. IfDisorders of the oesophagus show heterogeneous characteristics in relation to the pathogenesis and symptoms and therefore also require an appropriate investigation and a treatment adjusted to the findings. Methods like the multimodal model for oesophageal pain characterisation have been developed to supplement the conventional investigations such as oesophageal 24-hour pH and impedance measurement and manometry. Furthermore, neurophysiological assessment such as PET, fMRI, and analysis of evoked brain potentials can potentially contribute to the clinical evaluation of these complex disorders in the future. Treatment should be directed against the cause of the disease. When for example, gastro-oesophageal reflux is the cause of symptoms, the recommended treatment is acid suppression with primarily PPIs and in rare cases surgery. Handling of functional oesophageal disorders should include acid suppression and analgesics but also consider anti-depressants and psychological assessment and treatment. Lifestyle changes as treatment of oesophageal disorders can also be tried but should be directed according to the individual effect on symptoms in each patient.


Insufficient control of post-thoracotomy pain can produce breathing dysfunction and long term staying in neonatal intensive care unit (NICU). It can increase the incidence of pulmonary complications such as atelectasis, pneumonia and respiratory failure. The aim of this study was to determine the analgesic effect of continuous extrapleural nerve block, using ropivacaine, in neonates younger than 7 days old with esophageal atersia (EA) and the incidence of atelectasis and duration of hospitalization in NICU.For this purpose, from February 2007 till January 2009 in Mofid children’s hospital, 68 neonates under 7 days old whom were candidate for thoracotomy due to esophageal atresia were, randomly divided into two groups in a controlled clinical trial. The cases received extrapleural infusion of ropivacaine 0.5% (0.1 mL/kg/h for 48 h) and controls received acetaminophen 20 mg/kg three times a day via the rectal route. Hemodynamically unstable patients and those who suffered from hospital infections were excluded from the study. After the surgery, all patients had spontaneous breathing without endotracheal tube and stable hemodynamic in NICU. Pain level was determined for each neonate, based on the neonatal infant pain scale (NIPS) grading. The incidence of atelectasis in the first 48 h after operation and throughout the NICU staying were also determined.Results showed that there were no significant difference in the mean age, sex proportions and mean weight between the two groups. The mean pain score in the group received ropivacaine (1.9 ± 0.7) was significantly less than the control group (5.2 ± 0.6) (p < 0.001).Five percent of cases (n = 1) and 100% of the control group (n=20) had pain scores equal or greater than 3 (p < 0.001). The incidence of atelectasis among cases was less than the control group . Duration of hospitalization in the case group (12 ± 5.6 days) had no significant difference from the control group (13.6 ± 4.8 days) (p = 0.3)In conclusion, the results showed that continuous extrapleural infusion of ropivacaine reduces the pain noticeably and atelectasis relatively, after thoracotomy in neonates younger than 7 days suffering from EA, compared to the acetaminophen group. Pain is an unpleasant physical or spiritual sense due to stimulation of specific nerve endings. Pain threshold in infants is low and there is a negative relationship between pain threshold and age . IncomplMoreover, long term hospitalization may have a role in increasing the incidence and severity of pulmonary complication, such as pneumonia or respiratory failure by incomplete control of pain . Systemic procedures for pain control have significant side effects and little efficacy in pain control . RopivacIn this survey, we compared the analgesic effect of extrapleural infusion of ropivacaine to rectal acetaminophen in less than 7 days old neonates after esophageal atresia surgeries, in Mofid children’s hospital, as the primary outcome and studied the incidence of atelectasis and duration of hospitalization in NICU as the secondary outcome. In order to evaluate the efficacy of analgesic properties and incidence of atelectasis after EA and duration of NICU staying in less than 7 days old neonates, a randomized controlled trial was preformed in Mofid children hospital from February 2007 till January 2009. In this survey, 68 neonates younger than 7 days, whom were candidate for EA repair, selected and after confirmation by the research committee and obtaining written consents from the neonates’ parents about participation in the survey, the patients were randomly divided into two groups. This study was then conducted as a controlled clinical trial, with 34 patients placed in the case group and 34 patients in the control group. All neonates had esophageal atresia and thoracotomy. Furthermore, all the neonates with major congenital heart disease were excluded from this study. The patients in case group received extrapleural infusion of ropivacaine (0.1 mL/kg/h) for 48 h and the control group received acetaminophen (20 mg/kg) three times a day rectally, for the same period of time. Hemodynamically unstable patients and those who suffered from hospital infection were excluded from the study. In the data form of every neonate, according to patient’s evidence and paraclinical laboratory tests, all the information regarding the neonate’s age (days), sex, pain score (according to NIPS) and atelectasis during 48 h after surgery and duration of NICU stay were noted. All patients had spontaneous breathing after operation. In the case group, after performing the operation and while the neonates were anesthetized, a feeding tube  inserted by the surgeon into the extrapleural space, next to pleura and intercostal nerves. Then, 10 mL vials of ropivacaine  were diluted by normal saline to a concentration of 0.5%, and infused as 0.1 mL/kg/h for 48 h. The pain scale was used based on the NIPS score, and contained parameters of crying, facial expression, breathing patterns, legs and arms movements and state of arousal  between the two groups in terms of the mean age, sex and weight proportions. In the case group, the average age was 2.6 ± 0.6 days and in the control group the average age was 2.6 ± 0.7. In the case group, 18 patients were male and 16 were female and in the control group, 17 were male and 17 female. In the case group the mean weight was 3834 ± 359 g and in the control group it was 2715 ± 637 g. There was no significant difference between the weight of both groups (p < 0.05). The mean pain score in the group received ropivacaine (1.91 ± 0.7) was significantly (p < 0.05) less than the control group (5.53 ± 0.72).In our analysis, the mean pain score in the patients whom received ropivacaine was significantly less than the patients which had rectal acetaminophen (p < 0.001). In terms of the description of pain, based on the pain score , the numThe chi-square test showed that the atelectasis proportion in the case group was significantly different from control group . Duration of hospitalization in NICU of the case group was 12 ± 5.6 days and in the control group was 13.6 ± 4.8 days. The statistical analysis showed that there was no significant difference in the duration of hospitalization between the two groups (p > 0.05). By performing our survey, we concluded that analgesia by extrapleural ropivacaine after EA operation in neonates has considerable effects compared to rectal administration of acetaminophen. Moreover, extrapleural ropivacaine, compared to rectal acetaminophen, resulted in a relative decrease in the incidence of atelectasis. By matching some factors such as age, sex and weight in our survey, it was found that the effects of these variables had been omitted well, and since the only obvious difference between the two groups was due to the type of analgesia, it is predicted that differences were due to the effect of extrapleural ropivacaine infusion. In the Meyer’s survey, pain scores and the amount of opioids consumed, revealed that pain was controlled adequately after surgery . In the Marret studied on paravertebral ropivacaine, but Meyer and our survey focused on intercostal extrapleural blocks . Randa aIt should be stated that we did not assess the need for additional analgesia, as an indicator of effective analgesia. However, pain scores in the case group certified effective analgesia after thoracotomy. Another point in our survey is the similarity between the duration of hospitalization in both groups, which in contrast to previous studies, especially on bupivacaine. It should be said that a number of interfering agents play role in hospitalization, such as antibiotic therapy, type of NICU protocols and associated anomalies. Therefore, we could not exactly detect the role of ropivacaine in the duration of hospitalization, and expect that through further studies, the confining bias would be omitted. Furthermore, the need for additional analgesia should be studied. Finally, we think that the most important limitation in our survey was awareness of the nurses who evaluated pain scores and unfortunately, we had no way to resolve this problem. In conclusion, it could be said that extrapleural infusion of ropivacaine after esophageal atresia repair in neonates is more appropriate for decreasing the level of pain and atelectasis than rectal administration of acetaminophen. Even though we did not encounter any side effects using this technique, however, it is proposed that further researches should be carried out in order to confirm the results of our survey.


World Journal of Surgery titled “Efficacy of cholestyramine ointment in the reduction of postoperative pain and pain during defecation after open hemorrhoidectomy: results of a prospective, single-center, randomized, double-blind, placebo-controlled trial”. Hemorrhoidal disease is still a common disorder, and one for which surgery is one of the most common treatment methods. Because of the rich innervation of the anal canal, postoperative pain is still the most significant problem, both for the patient and for the surgeon. Postoperative pain requires opiate use, prolongs the hospital stay, and affects the patient’s comfort. In their recent study, Ala et al. used cholestyramine ointment to reduce the pain after hemorrhoidectomy. They aimed to block the irritation and inflammation in the anal canal caused by bile acids found in stool. The use of cholestyramine ointment after hemorrhoidectomy was first investigated in their study [I read with interest the study by Ala and colleagues  publisheir study , in whicThe toxic and inflammatory effects of bile acids and bile salts are well recognized. These factors cause skin irritation after ileostomy, bile fistula, and ileoanal anastomosis. The preventive effects of cholestyramine ointment on skin irritation caused by bile acids have been demonstrated , 3. Ala Moreover, in similar study by Ala and colleagues  they use


Based on the conducted anatomic studies at our institutions as well as clinical experience with migraine surgery, we have refined our onobotulinumtoxin A (BOTOX®) injection techniques. Pain management physicians are in unique position to be able to not only treat migraine patient, but also to be able to collaborate with neurologists and peripheral nerve surgeons in identifying the migraine trigger sites prior to surgical deactivation. The constellation of migraine symptoms that aid in identifying the migraine trigger sites, the potential pathophysiology of each trigger site, the effective methods of botulinumtoxin and nerve block injection for diagnostic and treatment purposes, as well as the pitfalls and potential complications, will be addressed and discussed in this paper. Migraine headaches (MH) represent a significant cause of morbidity, not only for the prevalence of the disorder, but for the economic burden and the decrease in quality of life. There has been increasing interest and several large-scale studies on the use of onobotulinumtoxin A (BOTOX®) for the treatment of MH -8. In 20Surgical deactivation of migraine trigger sites as well as preoperative botulinum toxin injection has been proven effective for the treatment of severe MH -13. BaseThere is a distinction between the work that has been done on onobotulinumtoxin A in the prevention of chronic migraines -8 and thBecause headaches in themselves are common, and many types of headaches can be confused with MH, it is important to establish a diagnosis of MH prior to initiating treatment, either medical or surgical. Diagnostic criteria for migraine headache are outlined by the International Headache Society (IHS). The headaches are typically unilateral, pulsating, and are typically aggravated by physical activity. In addition, MH are associated with nausea and/or vomiting, photophobia, or phonophobia. MH are further subdivided into those with aura (in which the aura develops over five to twenty minutes and last less than one hour) and without aura. MH are further subdivided into episodic and chronic migraines. Although typically distinguished by the number of headache days per month , population studies have shown that patients with chronic migraines have significantly more comorbidities, including depression, anxiety, chronic pain, respiratory disorders, cardiac risk factors, and were less likely to have full-time employment. Buse and coauthors note that these findings are consistent with a more nuanced and complex understanding of the differences between chronic migraines and episodic migraines .Onobotulinumtoxin A is approved by the FDA for use in prevention of headaches in chronic, but not episodic migraines. The Phase III Research Evaluating Migraine Prophylaxis Therapy I (PREEMPT I) trial was designed as a phase 3 study, with a 24-week double-blind, placebo controlled arm followed by an open label arm. The treatment arm consisted of thirty one fixed-site, fixed dose injections in seven anatomic areas, although studies investigators were able to administer 40 u as “follow-the-pain” strategy, in addition to the designed 155 u. The study noted that while there was no difference between onobotulinumtoxin A and placebo for the primary endpoint (headache episodes), reductions in the onobotulinumtoxin A group were found for other measures, including headache and migraine days, cumulative hours of headache, and frequency of moderate/severe headache days . The pooPrior to any intervention, it is critical that a patient be evaluated by a neurologist to confirm the diagnosis of migraine headache, and to identify possible secondary causes of headache, such as medication overuse headache.Migraine pathogenesis is known to be a complex, multifactorial process that involves neuronal hyper excitability during the interictal phase, cortical spreading depression as the basis of aura , 22, dysThe trigger point hypothesis attempts to explain what the initial trigger of trigeminal nerve irritation is. It takes into account that many patients describe the onset of migraine as occurring in a specific area, and that each migraine may have different characteristics depending on the site of onset. Thus, irritation of peripheral nerves by muscular contraction, or by contact points that induce inflammation, is what ‘triggers’ MH.This theory was first proposed by neurologists and later validated after making the clinical observation of alleviation of migraine symptoms in those patients who underwent endoscopic excision of the corrugator muscles and surgical dissection of the supraorbital and supratrochlear nerves during forehead lifts , 31, 32.Studies of onobotulinumtoxin A by neurologists for prevention in chronic migraine have been designed with injection of many anatomic sites . Based oTrigger sites are identified by the anatomic site in which patients report the migraines begin, and not the final location of the migraine which can be present in more than one site. In order to be able to identify this accurately we obtain a thorough history from the patient, and provide the patient with a Migraine Diary Chart (MDC) to fill daily for at least four weeks prior to labeling the offending trigger sites. Since patients often report the general location of the migraines and sometimes do not pay attention to the trigger origin site, this diary is of paramount importance. The injection must be done in the trigger site where the pain originates and not necessarily where the pain ends. In general, there are four potential trigger sites that have relevance to the surgeon today: frontal (Site I), temporal (Site II), occipital (Site IV), and rhinogenic (Site III).Frontal triggers begin in the central and lateral forehead, and the pain has a central and cephalad radiation. At times they are associated with supraorbital and supratrochlear tenderness. The pain is generally described as being “above the eye radiating from outside to in”. In some cases, corrugator supercilii muscle (CSM) hypertrophy may also be present. Patients in general have a more prominent vertical rhytid associated with the more active corrugator muscle, which could correspond to the laterality of the migraines. Direct pressure over the supraorbital and supratrochlear areas may increase or decrease the pain.Temporal triggers are associated with lateral temporal and posterior auricular radiation of pain. Patients may also note temporal muscle ‘tightness.’ Temporomandibular joint pathology should be excluded as the trigger for migraines.Occipital triggers starts with pain in the occipital region and radiate anteriorly. Patients may also complain of retroauricular pain. The specific area where the migraine starts is usually localized based on the anatomical location of the greater occipital nerve and can be identified by direct digital pressure over the location where the nerve pierces the semispinalis capitis muscle. Atmospheric pressure change may also trigger occipital pain, presumably through a change in greater occipital artery vascular tone, which lies in close proximity to the greater occipital nerve .In septal triggers, patients often report an association with the weather and pressure change usually starting during morning hours. They may note rhinitis, halitosis, dental pain, and hyposmia or anosmia. Septal triggers should also be considered if patients have continued complaints despite injection on onobotulinumtoxin A in other trigger sites. The pain is generally described as being “behind the eye from coming from inside to out”. Patient also commonly complain of breathing problems. Treatment with oxymetazoline nasal spray may temporarily halt the progression of pain from this site and serve as a diagnostic adjunct. A computed tomography scan can confirm intranasal pathology, such as contact between the septum and turbinates, and conchae bullosae that can contribute to MH, and often can be addressed surgically .These trigger sites, then, determine the surgical approach. Although surgical intervention for migraine surgery has been described before -41, it hWhile migraine descriptions by patients provide information for trigger site selection, the injection itself is performed based on the anatomy of the trigger sites. Recent anatomical studies have provided increased knowledge about the musculature and nervous anatomy of the trigger sites , 42, 43.et al.  may be involved. Janis et al.  noted foFigure 1). To minimize the volume and possible caudal leakage of the drug causing inadvertent complication of eyelid ptosis, this solution is more concentrated than the ones used for the temporal and occipital regions. A total of 12.5U in 0.25 cc of NS is injected into each corrugator, deeper medially to reflect the anatomy, and more superficial laterally. The needle is inserted from superficial lateral border of the corrugator to the medial deep surface . The injection can be done either while drawing the needle back or advancing it, but we prefer injecting as advancing, which provides more control of the needle. Alternatively, a five-point injection technique can be used . Skin cooling with ice packs before and after injection increases the patient comfort. After injection, gauze is place on the injection site with light pressure. Massage of the site is avoided, as it may cause diffusion which may lead to eyelid ptosis. We do not inject onobotulinumtoxin A into the frontalis muscle at this time, as there is no evidence for an anatomic basis for compression.For injection, we use a 1 cc tuberculin syringe with 0.01 gradations and a long 30 g needle. The CSM is marked during dynamic motion, and areas of hypertrophy are delineated. The muscle itself begins approximately 3mm lateral to middle, and extends 43 mm laterally. It extends 33 mm superiorly from the pupil  , 46. TheFigure 4) . The needle should pierce the temporalis fascia, and 12.5 U in 0.5 cc NS should be injected with a long 30 g needle for a radius of 1.5 cm. Occasionally, patient may experience temporary atrophy of the muscles due to the effects of onobotulinumtoxin, which can appear as “hour glassing” on frontal view.Anatomic studies have shown that the zygomaticofrontal branch of the trigeminal nerve arises 16.9 mm posterolateral to the commissure and 6.5 mm cephalad to the lateral commissure (igure 4) . The tecFigure 6)  , 48.Figure 6. For this the patient is placed in a prone position with hands above the head and the drug is injected deep into the semispinalis capitis and splenius capitis muscles. Nonresponders may have other anatomic causes; one study noted that trapezius fascia and the occipital artery may also play a role in nerve irritation .Onobotulinumtoxin A for primary and secondary triggers CT scan for site IIIDiary for 6 weeksIf no additional triggers, proceed with surgeryIf additional triggers, proceed with injectionsDiary for 6 weeksDecision for surgery; Selected patients will undergo surgery for deactivation of frontal, temporal, retro-bulbar (behind the eyes), or occipital MH either at one setting or as serial surgeries depending on the dominance of a specific trigger site.The summary of the sequence is as follows:This time course may not be feasible for out-of-town patients; however, reliable detection of migraine triggers can still be achieved by using local nerve blocks, (during the onset of migraine only) a single-stage injection of onobotulinumtoxin A into the predominate trigger site, and/or computed tomographic confirmation of intranasal pathology. The above step-wise injection can be an alternative for treatment purposes for reasons of cost saving.New potential trigger sites have come out of anatomic studies , 49. WhiComplications of Onobotulinumtoxin A injections to sites I, II and IV although rare, could include eyelid ptosis, hourglass deformity of the temples, and early fatigue during neck extension and diplopia. Hourglass deformity may improve over time, but can be corrected with artificial fillers or fat injections. Apraclonidine 0.5% eye drops may help with eyelid ptosis. Apraclonidine is an 2-adrenergic agonist, which causes Müller muscles to contract quickly elevating the upper eyelid. By minimizing the amount of onobotulinumtoxin A injected to the necessary amount by correct identification of the trigger sites and other maneuvers described above one can minimize these complications.We use onoboutlinumtoxin as an aid in identifying migraine trigger points. Anatomic variations must be understood so that the onobotulinumtoxin A can be effectively injected at trigger point sites. Knowledge of anatomy for the pain management physicians will provide a more effective, efficient and cost saving way to deliver the Onobotulinumtoxin A for treatment of migraines and craniofacial pain syndromes. This can be done both as a temporary treatment strategy or as a diagnostic tool for trigger sites that can later be decompressed by a migraine surgeon.


Study Design. A randomized, double-blind, active-control trial. Objective. To determine the clinical effectiveness of therapeutic thoracic facet joint nerve blocks with or without steroids in managing chronic mid back and upper back pain. Summary of Background Data. The prevalence of thoracic facet joint pain has been established as 34% to 42%. Multiple therapeutic techniques utilized in managing chronic thoracic pain of facet joint origin include medial branch blocks, radiofrequency neurotomy, and intraarticular injections. Methods. This randomized double-blind active controlled trial was performed in 100 patients with 50 patients in each group who received medial branch blocks with local anesthetic alone or local anesthetic and steroids. Outcome measures included the numeric rating scale (NRS), Oswestry Disability Index (ODI), opioid intake, and work status, at baseline, 3, 6, 12, 18, and 24 months. Results. Significant improvement with significant pain relief and functional status improvement of 50% or more were observed in 80% of the patients in Group I and 84% of the patients in Group II at 2-year followup. Conclusions. Therapeutic medial branch blocks of thoracic facets with or without steroids may provide a management option for chronic function-limiting thoracic pain of facet joint origin.  Leboeuf-Yde et al.  showed t Thoracic pain has been described to originate from multiple structures, including intervertebral discs and facet joints, both of which can be evaluated by proven diagnostic techniques , 19, 21. Significant debate surrounds the appropriate management of spinal pain with diagnostic and therapeutic modalities. The value of controlled local anesthetic blocks has been questioned and vigorously debated , 37–42. Further arguments also surround therapeutic facet joint interventions based on a lack of understanding of placebo control and the criterion standard –48. Howe This report of a double-blind randomized active controlled trial of 100 patients with 2-year results is a continuation of previous reports , 24. ThiThe study was performed based on Consolidated Standards of Reporting Trials (CONSORT) guidelines , with an Study participants were recruited at the interventional pain management practice from consecutive new patients presenting with thoracic pain. One hundred patients were included and randomly assigned to one of 2 groups; either a local anesthetic only group (Group I) or a local anesthetic with steroid group (Group II), with 50 patients in each group. Patients meeting the inclusion criteria were eligible to undergo diagnostic thoracic facet joint nerve blocks. Only patients positive for controlled comparative local anesthetic blocks met the criteria for inclusion for thoracic medial branch blocks. Only patients with nonspecific mid-back or upper back pain without suspected disc herniation, radiculitis, thoracic fracture, stenosis, or intercostal neuritis were included. Further, patients suspected of disc-related pain with radicular symptoms were also excluded, based on radiologic testing and symptomatology involving radicular or chest wall pain. Patients also should have previously received conservative management with physical therapy, chiropractic manipulation exercises, drug therapy, and bed rest, and so forth, but continued to have pain. Further inclusion criteria were a diagnosis of thoracic facet joint pain by means of controlled comparative local anesthetic blocks; patients who were over 18 years of age; patients with a history of chronic function-limiting mid-back or upper back pain of at least 6 months duration; and patients who where competent to understand the study protocol and provide voluntary, written informed consent, and participate in the outcome measurements. A negative or false-positive response to controlled comparative local anesthetic blocks, uncontrollable to heavy opioid use , uncontrolled psychiatric disorders, uncontrolled medical illness, either acute or chronic, or any condition that could interfere with the interpretation of the outcome assessments, such as positioning, women who were pregnant or lactating, and patients with a history or potential for adverse reaction(s) to local anesthetics or steroids were excluded , 24. All patients were provided with the informed consent and protocol approved by the IRB, which described the trial's details, including side effects and the mechanism for withdrawal from the study.Controlled comparative local anesthetic blocks were employed in all patients to diagnose thoracic facet joint pain, in accordance with the modified IASP criteria, with at least 80% pain relief and ability to perform previously painful maneuvers and concordant relief lasting longer with bupivacaine than lidocaine , 7, 50. Diagnostic medial branch blocks were performed either ipsilaterally in patients with unilateral pain or bilaterally in patients with bilateral pain. Each nerve was injected with 0.5 mL of the assigned mixture and the blocks were performed on a minimum of 2 nerves to block a single joint and 3 nerves to block 2 consecutive joints. Following an established diagnosis, patients were enrolled in the study phase. They were then treated with therapeutic medial branch blocks under fluoroscopy in a sterile operating room with an injectate of 1 mL mixture at each level as assigned by grouping. All the blocks utilized a 22 gauge, 2-inch spinal needle. Group I patients received medial branch blocks with injection of bupivacaine 0.25%, whereas Group II participants received medial branch blocks with a mixture of bupivacaine and nonparticulate betamethasone. Nonparticulate betamethasone is a clear solution added to bupivacaine in the amount of 0.15 mg/mL.Patients were followed at 3-month intervals unless otherwise indicated. Thoracic facet joint nerve blocks were repeated based on the response to the prior interventions, specifically, improvement in physical and functional status. Thoracic medial branch blocks were repeated only when the reported pain levels deteriorated to below 50%, with an initial report of significant pain relief of 50% or more after the previous block. The nonresponsive patients receiving other types of treatments after stopping therapeutic lumbar facet joint nerve blocks were considered to be withdrawn from the study.None of the patients received any specific cointerventions such as physical therapy or occupational therapy. However, all patients received the same co-interventions they had been receiving prior to starting the treatment, based on need, either with opioid or nonopioid analgesics and previously directed exercise program. This randomized double-blind active-controlled trial was designed to determine the clinical effectiveness of therapeutic thoracic medial branch blocks of local anesthetic with or without steroids in managing chronic, disabling, thoracic pain of facet joint origin.Outcome measures included the NRS, Oswestry Disability Index (ODI), employment status, and opioid intake, with assessment at 3, 6, 12, 18, and 24 months posttreatment.NRS represented 0 with no pain and 10 with the worst pain imaginable. The ODI was utilized for functional assessment. The accuracy of NRS and ODI has been widely reported –53. Significant improvement was defined as pain relief of at least 50% reduction in the NRS score, and functional status improvement illustrated by at least a 50% reduction in the ODI.We have employed a robust outcome measure in this evaluation rather than mild decreases in pain and functional disability as described in recent evaluations , 54–57. Opioid intake was converted into morphine equivalence  based on Employment data was based on the individual's employability. Patients unemployed or employed on a part-time basis with limited or no employment due to pain were classified as employable; however, patients who chose not to work, were retired, or were homemakers who were not working but not due to pain, were considered as not employable outside. A sample size of 50 patients for each group was determined. There were no randomized trials available to base the calculation of sample size. Previous studies of cervical and lumbar medial branch neurotomies and even epidural injections utilized a smaller number of patients –62. Furt Of the 100 patients, 50 patients were randomly assigned into each group. A computer-generated random allocation sequence generation was utilized.All mixtures appeared to be identical. Patients were randomized and the solutions were prepared appropriately by the operating room nurse assisting with the procedure.After the patients had met the inclusion criteria, one of the 3 nurses assigned as coordinators of the study enrolled and assigned them to their respective groups. All patients were invited to enroll in the study if they met inclusion criteria.The random allocation was not revealed to either the participants or the physician. In addition, all the study patients were mixed with other patients with no specific indication that patients were participating in the study.Patients were unblinded early if they requested to be unblinded or after completing 24 months of the study. Patients were provided with an opportunity to discontinue or withdraw from the study for lack of pain relief or for any other reason. All patients with loss of followup were considered to be withdrawn.t-test, and one-way analysis of variance were used to analyze the data.Chi-squared statistic, Fisher's exact test, paired t-test was used to compare the pre- and posttreatment results of average pain scores, the ODI measurements and combined NRS and ODI scores at baseline versus 3, 6, 12, 18, and 24 months. The t-test was performed for comparison of mean scores between groups. One-way analysis of variance was used for comparison of means among groups.Chi-squared statistic was used to test the differences in proportions. Fisher's exact test was used wherever the expected value was less than 5; a paired An intent-to-treat-analysis was performed on all patients utilizing the last followup data, with application of initial data in the patients who dropped out of the study without further follow-up after the first treatment. Sensitivity analysis was performed utilizing best case, worst case, and last follow-up scores scenarios.Participant flow is illustrated in The recruitment period lasted from April 2003 through August 2009.Demographic characteristics are illustrated in The number of joints was as follows: 3 joints were involved in 23% of the participants, 4 joints were involved in 28% of the participants, 5 joints were involved in 33% of the participants, and 6 joints were involved in 16% of the participants. Bilateral involvement was seen in 68% of the participants.P = 0.0000) for to average pain scores and Oswestry Disability Index.A post hoc analysis indicates that all the mean differences between baseline and with other time point's scores were significant at the 0.05 level.  Employment characteristics are illustrated in There were no serious adverse events reported in the study including infection, pneumothorax, nerve root trauma, or spinal cord trauma.The first randomized, double-blind, active-controlled trial of 100 patients with chronic function-limiting thoracic pain of facet joint origin, using therapeutic thoracic medial branch blocks, showed significant improvement with pain relief and functional status improvement in 80% of the patients in Group I and 84% in Group II at 2-year followup. This study also showed an average number of procedures of 6 over a period of 2 years. Patients experienced 84.7 ± 26.1 weeks of relief in Group I and 88.7 ± 22.1 weeks of relief in Group II. The study illustrated the average relief per procedure as 20.4 ± 20.8 weeks in Group I and 17.4 ± 14.4 in Group II with steroids with relief per procedure from 2 weeks to 2 years. While there was no significant difference in opioid intake or employment characteristics, employment characteristics showed that all the eligible participants were employed at the end of one year and 2 years with one fewer participant in Group I because of retirement. Thus, pain relief and improvement in functional status were significant. Strict criteria were utilized for diagnosing facet joint pain with controlled comparative local anesthetic blocks to avoid the criticism of including patients without facet joint pain in the study. The results of the current study are similar to a previously reported observational study  and 2 pr Criticisms may be included in reference to placebo control. While it is admitted that the lack of placebo control is a drawback, placebo is difficult in any type of neural blockade, apart from the ethical issues, with any interventional techniques. So-called placebo controlled studies have been associated with design flaws, because they lack an understanding of true placebo and do no consider the nocebo effect , 64–68. sensitization [ In the era of comparative effectiveness research (CER) and evidence-based medicine (EBM) and escalating health care costs, active controlled trials are important for providing practice patterns , 74–77. tization , 87, andtization . Furthertization , 54–57, tization , 89.In summary, the results of this study present a real-world example describing patients in a private interventional pain management practice setting, with appropriate selection and judicious use of modalities, with results generalizable to similar settings. However, caution must be exercised in applying these results to the general population unless the same methodology is used for both diagnosis and therapy. The generalizability of the findings of this study might only be feasible if studies are published using large populations in multiple settings.This randomized, double-blind, active-controlled trial report demonstrates that thoracic facet joint pain diagnosed by controlled comparative local anesthetic blocks may be treated with thoracic medial branch blocks of local anesthetics with or without steroids with similar results.


Materials and Methods. A randomized, split-mouth, single-blind study was conducted on 30 patients between 18 and 30 years of age requiring lower third molar extraction. Patients underwent bilateral extractions in a randomized sequence, one extraction being performed under Normast treatment. The Normast treatment involved 2 tablets a day for 15 days. The parameters assessed at each procedure were trismus, swelling, pain, NSAID consumption, postoperative complications, drug tolerability, and safety. The results obtained were processed using repeated measures analysis of variance. Results. Perceived postoperative pain was reportedly significantly milder on Normast treatment than control. The trend of the means differed over time (P < .0001) and between the two extraction groups (P < .0221). On the other hand, for edema and trismus, the trend differed over time for both groups but did not differ between the two groups. Discussion. Our analyses indicate that patients experienced significantly less postoperative pain when they were treated with Normast. Conclusions. Administering Normast improves the postoperative course—in terms of pain—after lower third molar extraction.The aim of this study was to assess the efficacy of Normast 300 mg in reducing swelling and pain after the surgical extraction of impacted lower third molars.  The third molars, and those of the mandible in particular, are the most frequently impacted of all teeth, with an incidence ranging between 9.5% and 39%, depending on the source considered .Impacted third molar extraction is therefore a common procedure in oral and maxillofacial surgery –10, but Most authors prescribe NSAIDs  to prevent and treat postoperative pain and glucocorticoids to control edema and trismus .The aim of the present study was to assess the efficacy of Normast 300 mg in reducing postoperative pain and swelling after surgery to extract impacted lower third molars. Normast was reported to the Italian Ministry of Public Health as a “food product for special medicinal purposes,” based on the European Community standards; the product has no known side effects and is generally well tolerated. The active ingredient is micronized palmitoylethanolamide (300 mg tablets).Palmitoylethanolamide (PEA) has been proposed as a substance capable of modulating mast cell response to inflammation –15 and mPEA is an endogenous endocannabinoid belonging to the N-ACETYL ETHANOLAMINES (NAE) superfamily , 18.PEA is a naturally occurring substance isolated from soy lecithin, egg yolk, and ground peanuts; it is also contained in the lipid fraction of rat brain, liver, and skeletal muscle. The presence of PEA has been documented in the brain and bone marrow of mouse, in dog heart extracts, and in degraded human tissues and peritoneal macrophages. NAEs are also contained in the blood. There is proof of the presence of PEA, and other NAEs, in marine species as well as in mammals .2 receptors [It has been suggested that PEA behaves like an endogenous ligand for the CBeceptors , 18, a seceptors . The liteceptors , by downeceptors , 14, 17.PEA is a compound with documented antinociceptive and anti-inflammatory effects , 18, 20,The effect of PEA on edema is both dose and time dependent . A randomized, split-mouth, single-blind study was conducted on patients referred to the Department of Dentistry at the University of Padua. The study was conducted in accordance with the ethical principles for medical research on human beings established by the 1964 Helsinki protocol.It was not necessary to obtain the approval of the local ethical committee because Normast is not registered as a drug but as a “food product for special medicinal purposes,” and it is already used in other medical specialties. Thirty patients were selected, aged between 18 and 30 years, who needed bilateral lower third molar extractions and who gave their informed consent to enrolment in the study. On medical examination, the third molars had to show no signs of inflammation or tooth decay. Each patient's X-rays had to show that the two lower third molars were identical in position, orientation, depth, and class of impaction according to the Pell and Gregory classification. Patients over 30 years old were ruled out, and so were patients needing monolateral extractions, individuals who had taken part in other clinical studies in the two months prior to enrolment for the present study, patients with systemic diseases and taking chronic pharmacological therapy, and cases thought unlikely to assure the necessary compliance. Patients with known allergies to NSAIDs were also excluded, as were those who could not take such medication for other health-related reasons (gastric disorders).A preoperative clinical examination was conducted on the oral cavity, obtaining an orthopantomography and, where necessary, a CT processed using DentaScan .Before proceeding, the whole procedure was explained to patients in detail and their informed consent was obtained. Patients were also given an explanatory letter for their general practitioner.Each of the 30 patients was scheduled to undergo lower third molar extraction bilaterally, the two extractions being performed in two separate sessions approximately 30 days apart. The surgery was always conducted by the same qualified operator. In each individual, one extraction was completed while, on treatment with Normast, the other being considered as a control; the order of the two extractions was randomly assigned. For the treatment arm, patients had to take Normast at a dose of 2 tablets a day (one in the morning and one in the evening) for a period of 15 days (6 days before surgery and 9 days afterwards). The following parameters were recorded:T0) and on the 3rd and 7th days after surgery (T1 and T2) [trismus: mouth opening range was assessed by measuring the distance between the incisors before surgery (T0) and on the 3rd and 7th days afterwards  [swelling: facial edema was assessed by measuring the distances between the labial commissure and the tragus (following the trend of the cheek), and between the lateral canthus and the gonion, before surgery  10 cm long, where 0 meant no pain and 10 meant the worst pain imaginable ;NSAID consumption in the week after surgery;postoperative complications;drug tolerability and safety: recording any onset of adverse events at the end of the treatment arm.T0, an ad hoc report form was used to record the patient's gender and age, the tooth extracted (3.8 or 4.8), the class and depth of the tooth according to the Pell and Gregory classification, and its orientation according to the Winter classification, the duration of the procedure, the date of starting the Normast treatment, and its duration (for patients in the treatment arm).On the day scheduled for surgery, in addition to collecting information concerning trismus, swelling, and pain perception at T1 (on the 3rd day after surgery), that is, trismus, swelling, and perceived pain, patients were given an ad hoc report form and asked to record these measurements at home; patients received a telephone call to remind them to do so.For the data to record at On the day of their operation, patients were also given a diary and asked to make an accurate note of any NSAIDs used during the postoperative period. T2  were recorded as well as an assessment of healing, postoperative course, and any side effects of the Normast treatment. Patients also returned the previously distributed report forms and diaries on the use of analgesics. On the 7th day after the procedure, patients returned to the outpatients clinic at the Department of Dentistry to have their stitches removed, when the measurements relating to P < .05. The results were processed using repeated measures analysis of variance and were considered significant when Only 26 of the 30 patients enrolled completed the protocol, while 4 dropped out as a result of inadequate compliance: 2 forgot to take Normast for the full 15-day period; one failed to return for the second extraction; one only took Normast for 3 days, then abandoned the drug, reporting the “onset of palpitations lasting 2-3 hours approximately an hour after taking the tablets” (they were apparently taking no other drugs in combination with the Normast treatment).The protocol also involved assessing NSAID intake in the first week postoperatively, but the results proved impossible to analyze statistically because the data were excessively heterogeneous: although patients had been given clear instructions on the type of drug to use, only 4 patients took the prescribed ibuprofen 600 mg for postoperative pain control; the other 22 spontaneously opted for alternative pain control drugs  and at highly variable doses.There were 3 cases of alveolitis, two of which occurred in the same patient; this would seem to have been a patient-related complication rather than a drug-related issue. The findings for postoperative pain, mouth opening range, the distance between the lateral canthus and the gonion, and the distance between the labial commissure and the tragus were assessed by repeated measures analysis of variance using as explanatory variables age, gender, side of mouth, duration of the procedure, time since surgery, and the interaction between the treatment and the time since surgery. All the models were amply significant. The results showed that the means for postoperative pain, mouth opening range, and the distance between the labial commissure and the tragus changed significantly with time, irrespective of the Normast treatment or any of the other explanatory variables.The “duration of the procedure” variable was never statistically significant. P < .0001) and also between the two extraction groups (P < .0221)  see .T0, all the values recorded on the VAS were nil.At T1, the mean VAS recorded by the patients taking Normast was 3.8 ± 3.09 cm, while in the control group it was 5.5 ± 2.42 cm; likewise, at T2, the mean VAS for the group on Normast treatment was lower than in the control group .At P < .0241).The trend of the means differed statistically over time for mouth opening range too, but it did not differ between the two extraction groups see ; there wT0, the mean values were 4.8 ± 0.59 cm and 4.7 ± 0.71 cm for the Normast-treated group and the control group, respectively.At T1, the mean mouth opening range for patients on Normast treatment was 3.6 ± 2.21 cm, as opposed to 3.1 ± 1.18 cm for the control group.At T2, the mean mouth opening range had increased to 4.1 ± 0.89 cm for the treated patients and 4.1 ± 0.93 cm for the controls.At None of the variables were significant for the distance between the lateral canthus and the gonion because of the marked variability of the measurements obtained.T0, the mean distance was 9.6 ± 0.91 cm and 9.6 ± 0.79 cm for the Normast-treated and control groups, respectively.At T1, the distance was 9.6 ± 1.63 cm in the treated group and 9.8 ± 1.46 cm in the control group, and, at T2, the figures were 9.7 ± 1.06 cm and 9.7 ± 0.86 cm, respectively (see At vely see .P < .0058), but not between the two treatment groups.As for the distance between the labial commissure and the tragus, the trend of the mean measurements differed statistically over time  among the patients treated with Normast was 0.5 cm wider than that in the control group. Concerning trismus, the mean mouth opening range on the third postoperative day  and one other patient reported drowsiness after taking Normast. The patient with palpitations associated with the use of Normast reported taking no other drugs at the same time as the Normast treatment. About a week after being excluded from the study, the patient was asked to return to the outpatients clinic at the Department of Dentistry: when further details were obtained, the patient's medical history ultimately proved positive for the use of cannabinoids. There is nothing in the medical literature on any consequences of the joint use of natural or synthetic cannabinoids and PEA, but it may be that the side effects reported by this patient were the consequence of a synergic effect of PEA and tetrahydrocannabinol. According to the literature, patients complain of pain, swelling, and trismus as the main factors negatively influencing their quality of life , 11 afteThe postoperative course is commonly managed by prescribing NSAIDs to control postoperative pain and glucocorticoids for trismus and edema.Our study demonstrated that combining Normast  with the above-mentioned medication significantly reduces perceived pain, as recorded on a VAS, during the week after the surgical procedure.For edema and trismus, on the other hand, our statistical analysis identified no significant differences between the extractions with and without associated Normast treatment.We therefore conclude that, as concerns pain at least, treatment with Normast improves the postoperative course after impacted lower third molar extraction.