Preoperative decongestion with Moffett's solution is routine practice in sinonasal procedures providing an ideal operative field. Anecdotally, it is related to postoperative throat pain, yet a quantitative relationship has not been established. We compare the incidence and severity of postoperative throat pain after application of Moffett's solution against Cophenylcaine decongestion. A total of thirty patients from two consultants were recruited. The intervention arm (twenty) was decongested with Moffett's solution and the control arm (ten) with Cophenylcaine. The primary outcome was self-reported postoperative throat pain as measured by visual analogue scale (VAS) at 2 hours, 4 hours, 6 hours, and next morning. There was a significantly higher VAS for throat pain in patients decongested with Moffett's solution in the early postoperative period . Moffett's solution is associated with a greater severity of transient postoperative throat pain compared to topical Cophenylcaine. We recommend further studies to identify means to minimise this side effect.ACTRN12619000772145. This paper has been registered with the Australian and New Zealand Clinical Trials Registry under the registration number:  Moffett's solution is commonly used as a topical decongestant and local anaesthetic in sinonasal surgery. It is a combination of cocaine, adrenaline, bicarbonate, and 0.9% sodium chloride, which was first described by Major A. J. Moffett of the Royal Army Medical Corps in 1941 , 3. ThisIn his 1941 paper “Postural Instillation”, Moffett described his method of instilling the solution via a syringe and a “Clarke's needle”, in which the patient's head is rotated through various positions to coat all of the mucosal surfaces . In 2003Anecdotally, rhinologists from our unit and others have noted that significant postoperative throat pain is a common side effect of Moffett's solution use. However, this is underreported in the literature. To the best of our knowledge, there are no studies in the literature which assess the relationship between Moffett's solution and throat pain except one UK survey of otolaryngologists in 2010 which reported only four individual cases of throat pain from 159 otolaryngologists . We hypoThis multicentre prospective observational study was conducted at a Tertiary University Hospital in Sydney, Australia , in 2018.The study was approved by the Western Sydney Local Health District Human Research Ethics Committee (WSLHD HREC) as a low and negligible risk project (reference number: LNR/17/WMEAD/568). The WSLHD HREC is accredited by the New South Wales Ministry of Health to provide ethical and scientific review to conduct research within the NSW public health system. The study operates in accordance with the National Health and Medical Research Council's National Statement on Ethical Conduct in Human Research and the CPMP/ICH Note for guidance on Good Clinical Practice and the international guidelines for observational studies .A consecutive series of patients undergoing routine sinonasal surgery  requiring nasal preparation were included in the study. Patients with a history of previous sinonasal surgery were excluded from the study. Patients were recruited following informed consent.The treatment arms in this study were based on current practice by the two senior surgeons. Patients in the intervention arm (Moffett's solution) received topically applied Moffett's solution preoperatively via the MADgic™ atomiser . The solution consisted of a mixture of 2mL of 10% cocaine solution (200mg), 1mL of 1:1000 adrenaline, 2mL of sodium bicarbonate, and 5mL of 0.9% sodium chloride solution, 10mL in total with 5mL applied to each side. Patients in the control arm received Cophenylcaine Forte™ topical nasal spray , consisting of 5% lignocaine hydrochloride  and 0.5% phenylephrine hydrochloride  delivered using the provided atomised spray nozzle, five sprays per side (100 microlitre per spray). In both arms, the solution was applied following the induction of general anaesthesia, prior to surgery. The patients were blinded to the agent used, whereas the investigators applying the solution and recording the results were not.The primary outcome for this study was throat pain measured by the patient recording a point on a 100mm visual analogue scale (VAS) for pain between 0mm (no pain) and 100mm (worst pain possible). Scores were recorded at 2 hours, 4 hours, and 6 hours postoperatively and the next morning . Each mePotential confounding factors that may have contributed to throat pain, such as type of airway ventilation device  and whether a throat pack was used, were also recorded. Stata Statistical Software: Release 14, College Station, TX: StataCorp LP.) and a p value < 0.05 was considered statistically significant. Continuous, parametric variables were presented as means with standard deviations, while categorical variables were presented as percentages. Comparison of VAS scores was performed using a Student's unpaired t-test. Comparison of potential airway confounders between groups was performed using Fisher's exact test.Statistical analysis was performed using Stata version 14.0 , mostly without a throat pack . In termThere were statistically significant differences in the VAS scores at 2 hours postoperatively  and at 4 hours  . HoweverNo systemic side effects of either Moffett's solution or Cophenylcaine were observed in the duration of this study. Procedures included various combinations of functional endoscopic sinus surgery (FESS), septoplasty, and inferior turbinoplasty.α1 and α2 adrenoeceptors in nasal vasculature. By contrast, Cophenylcaine (phenylephrine and oxymetazoline) acts only on α1 adrenoreceptors. α1 adrenoreceptors chiefly innervate the arterial system and α2 adrenoreceptors chiefly innervate the venous system. Although the surgical conditions created using Moffett's solution and Cophenylcaine have not previously been directly compared in the literature, Moffett's solution has a theoretical advantage over Cophenylcaine [Moffett's solution remains a popular choice for the preparation of the surgical field in sinonasal surgery due to its efficacy and safety in achieving profound decongestion . It decrnylcaine . In the The present study found that the use of Moffett's solution in sinonasal surgery causes a statistically significant increase in throat pain when compared to its alternative, Cophenylcaine, in the postoperative period for up to four hours. Although throat pain has been reported in the literature as a minor side effect of Moffett's solution, to our knowledge, this is the first and only study to examine this specific relationship in detail .α1 adrenergic receptors when stimulated are responsible for arterial vasoconstriction, decreasing flow to capillary networks, while the stimulation of α2 adrenergic receptors decreases flow to venous sinusoids, thus causing decongestion [Cocaine, or scientifically benzoylmethylecgonine, is an ester. When applied topically, it exerts its vasoconstrictive and analgesic effects via two different pathways. Its vasoconstrictive property is affected indirectly by presynaptic blockade of catecholamine reuptake, thereby increasing stimulation of the presynaptic adrenergic receptor , 15. α1 ngestion . When adngestion , 18. CocThroat pain is the second most common minor side effect of Moffett's solution after transient tachycardia . AnecdotA number of anaesthetic confounding factors could potentially also lead to the complaint of throat pain postoperatively, including the choice of airway , the use of throat packs, and trauma related to securing the airway. However, in this study, subgroup analysis demonstrated that the two arms had statistically similar rates of endotracheal intubation and throat pack use.We postulate that the passage of excess Moffett's solution through the nasopharynx results in prolonged pooling in the oropharynx, causing profound and prolonged decongestion of the oropharyngeal mucosa, resulting in temporary superficial ischaemic changes, thereby leading to the complaint of postoperative throat pain. We hypothesise that pain in the nose following Moffett's solution administration is not seen as the solution and is only in transient contact with nasal mucosa before being either absorbed or passing through to the oropharynx. The effect may also be diminished by the rich vascular supply of the nose, compared to the oropharynx, which reduces the likelihood of ischaemic pain. However, we emphasize that this is the author's speculation and further research may be required to determine the true cause of postoperative throat pain in this context.Such postapplication pooling in the oropharynx could potentially be prevented by various methods, such as the use of a reduced volume of solution, use of nebulised solution instead of sprayed solution, use of a postnasal balloon to prevent posterior passage, and immediate suctioning of excess solution from the oropharynx. Based on the results of this study, we propose that further studies to assess such methods are warranted.The current study has several limitations. Firstly, this pilot study is a small cohort study and the patients were not randomised. As a result, the investigators applying the solution and those recording the results were not blinded. As the two groups of patients underwent surgery under two different surgeons, there is a potential for the surgeons' approach to contribute to the observed results. As the patients received various combinations of septoplasty, turbinoplasty, and FESS, there is a potential for the differences in procedures to contribute to the observed results. The duration of the procedures was not analysed in the present study and may also play a role in postoperative throat pain. In this study, there was a high usage of ETT compared to laryngeal mask. Although results were similar in both forms of airway, the study was not sufficiently powered to compare these two groups. Lastly, postoperative throat pain was a self-reported outcome measure. This is subject to various factors affecting the patients' perception and tolerance of pain.Moffett's solution is an efficacious, safe, and commonly used agent in preparing the surgical field for sinonasal surgery. This study is the first to show a statistically significant increase in throat pain up to 4 hours after the use of Moffett's solution in sinonasal surgery when compared to an alternative, Cophenylcaine. Based on these results, the authors propose that future studies designed to investigate methods of preventing postoperative throat pain associated with Moffett's solution are warranted.


Na1.1) contributes to the processing of neuropathic pain, and that Slack activators, when injected into mice, ameliorate pain-related hypersensitivity. However, whether Slack activation might reduce neuropathic pain in humans remains elusive. Here, we evaluated the tolerability and analgesic efficacy of loxapine, a first-generation antipsychotic drug and Slack activator, in neuropathic pain patients. We aimed to treat 12 patients with chronic chemotherapy-induced, treatment-refractory neuropathic pain  in a monocentric, open label, proof-of-principle study. Patients received loxapine orally as add-on analgesic in a dose-escalating manner  depending on tolerability and analgesic efficacy. Patient-reported outcomes of pain intensity and/or relief were recorded daily. After enrolling four patients, this study was prematurely terminated due to adverse events typically occurring with first-generation antipsychotic drugs that were reported by all patients. In two patients receiving loxapine for at least two treatment episodes, a clinically relevant analgesic effect was found at a daily dose of 20–30 mg of loxapine. Another two patients tolerated loxapine only for a few days. Together, our data further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy. However, loxapine is no valid treatment option for painful polyneuropathy due to profound dopamine and histamine receptor-related side effects.Neuropathic pain is a debilitating and commonly treatment-refractory condition requiring novel therapeutic options. Accumulating preclinical studies indicate that the potassium channel Slack (Kwww.ClinicalTrials.gov, identifier NCT02820519.Clinical Trial Registration:  Neuropathic pain is caused by a lesion or disease of the somatosensory system that can arise from a diverse group of pathological conditions . The pre+) channels are the most populous and diverse class of neuronal ion channels, and they are increasingly recognized as potential targets for pain therapy  is a K+ channel that is highly expressed in nociceptive sensory neurons. Recent preclinical studies suggest that Slack controls the sensory input in chronic pain states , serotonin receptors (5-HT2A and 5-HT2C), histamine receptors (H1), and lower-affinity antagonism of other receptors [(https://pdsp.unc.edu/databases/kidb.php)]. Although classified as a typical antipsychotic, loxapine has atypical characteristics such as a high 5-HT2/D2 receptor ratio  and was approved by an independent ethics committee  and the Federal Institute for Drugs and Medical Devices  prior to subject screening and enrollment. The study was conducted in conformity with the ethical standards according to the Declaration of Helsinki and Good Clinical Practice guidelines. Participants were compensated for travel expenses and received 50 € for completion of the 8-week trial, but there were no other financial incentives to participate. Written informed consent was obtained from all participants before initiating study-related procedures.We enrolled outpatients  with chemotherapy-induced neuropathic pain (including mixed pain), present on a daily basis for at least 3 months and refractory to at least one analgesic compound, and baseline neuropathic pain intensity ≥4 on an 11-point numerical rating scale . Exclusion criteria were as follows: Parkinson’s disease, movement disorders  associated with antipsychotics, neuroleptic malignant syndrome, other syndromes associated with antipsychotics, severe hypotension with a syncope in history, glaucoma, urinary retention, epilepsy or other seizure disorders in history, severe dementia, dementia-related psychosis in history, breast cancer in medical history, malignancies with a life expectancy of less than 6 months, other severe and life-threatening diseases, known drug or alcohol abuse, concomitant intake of antipsychotics, dopamine agonists , alpha-receptor blocking compounds or compounds with a known potential for QT interval prolongation, pregnancy or lactation period, pre- or perimenopausal females with ineffective contraception, participation in other interventional studies (current or within the last 3 months), and close affiliation with the investigational site.In this study, it was planned to treat 12 subjects with loxapine in a dose-escalating manner during four 14-day treatment episodes. Loxapine capsules 10 mg  were used as investigational medicinal product (IMP) and self-administered on an outpatient basis as add-on treatment to the subject’s usual care . The loxapine dosage for the first episode (days 1–14) was 10 mg b.i.d., dosages for episodes 2, 3, and 4 were defined by taking into account tolerability and analgesic efficacy of the former episode. In case of an acceptable tolerability and if a clinically relevant analgesic efficacy was not reached, loxapine dosage was increased . In case of an acceptable tolerability and if a clinically relevant analgesic efficacy was achieved, the dosage of loxapine was not changed. In case of clinically relevant (serious) adverse events [(S)AEs], loxapine dosage was reduced or the treatment was interrupted or stopped .Subjects underwent examinations at the study center during the screening visit (days −6 to −3), at the beginning of each treatment episode , at the end of the last treatment episode (day 57), and at the follow-up visit (days 60 to 68).Baseline neuropathic pain intensity was assessed using an 11-point NRS during the screening visit, at day −2, day −1, day 0, and during hospital visit at day 1 (prior to the first IMP intake), and was defined as the median of these five values. After the first IMP intake, a daily assessment of neuropathic pain using the 11-point NRS, of adverse events, and of analgesic co-medication were conducted by the patients and documented in a diary. A clinically relevant analgesic effect was defined for a particular treatment episode if pain was reduced by at least 30% or two scale units comparing baseline neuropathic pain intensity and the median NRS values of the last 5 days of the respective treatment episode .Additional procedures in the study center included assessment of the painDETECT questionnaire , a patieThis pilot study was primarily designed as a safety study evaluating the tolerability of loxapine in non-psychiatric patients. Hence, the primary endpoint was initially defined as the first occurrence of a (serious) adverse event leading to dose reduction or withdrawal of loxapine (“event”). Secondary endpoints were related to tolerability and analgesic efficacy of loxapine. A total number of 12 subjects was initially calculated by a biostatistician. However, the planned statistical analysis was not feasible due to the premature termination of the study and small number of subjects enrolled. Therefore, purely descriptive analysis and graphical presentation were used to elucidate within-subject drug effects and overall findings. All adverse events were coded according to the Medical Dictionary for Regulatory Activities (MedDRA) in its most current version. Severity of adverse events was assessed based on investigator’s decision as “mild”, “moderate”, or “severe”.Between June 2016 and April 2017, six patients provided informed consent and were screened for eligibility. Two patients could not be included in the study due to pain not fulfilling the inclusion criteria or due to the presence of an exclusion criterion (cachexia). Out of the four subjects receiving IMP (Table 1), two subjects conducted all pre-specified study visits whereas two subjects were not willing to conduct all planned study visits according to the protocol Figure 1The four subjects receiving IMP  were aged between 56 and 79 years, had received cytotoxic anticancer drugs suspicious to induce neuropathic pain, and suffered from chronic pain for 1.2–14 years prior to the study Table 1.In subject #1, actual analgesic treatment during the screening visit was ibuprofen, which was continued during the study. The painDETECT total score was 21 at day 1, indicating the likely presence of neuropathic pain. The subject tolerated 20 mg/day of loxapine during the first treatment episode. Because pain intensity at day 15 was comparable to baseline values Table 2.Subject #2 was treated with pregabalin at the screening visit and during the study. Neuropathic pain was likely existent at day 1 as suggested by a PainDETECT total score of 20. After the intake of loxapine 20 mg/day during the first treatment episode, the subject reported clinically relevant analgesia at day 15 . No changes in pain scores were found between baseline and day 4 .In subject #4, analgesic treatment at the screening visit included ibuprofen, morphine, pregabalin, and quetiapine, an atypical antipsychotic drug with potentially analgesic properties . QuetiapAdverse events occurred in all subjects receiving loxapine Table 2.The SF-12v2 and HADS-D results for the two patients receiving loxapine for at least two treatment episodes are presented in In this pilot study, we assessed the effects of loxapine, an antipsychotic drug with off-target activity on Slack channels, in patients suffering from refractory neuropathic pain after chemotherapy. The study was prematurely terminated because antipsychotic-related adverse events occurred in all subjects. Hence, we conclude that loxapine is no valid treatment option for this type of painful neuropathy. Nevertheless, the analgesic effects of loxapine observed in this study in combination with results from preclinical studies further support the hypothesis that Slack activation might be a novel strategy for neuropathic pain therapy in the future if novel compounds with improved pharmacological profile are available.Based on reports that Parkinsonian-like symptoms are not usually observed at clinically effective antipsychotic doses  and thatThe SF-12v2 scores suggest that the analgesic effect of loxapine in subject #1 and #2 was irrespective of mental and physical health problems that may at least in part have resulted from loxapine intake. The HADS-D scores indicate that subject #1 was emotionally rather stable, while subject #2 was emotionally instable. In particular, the anxiety data  of subject #2 suggest that other life events, and not loxapine, induced changes in emotional states. It also needs to be taken into consideration that subject #2 was treated with pregabalin, which has anxiolytic effects. Together, the SF-12v2 and HADS-D data indicate that subject #1 and #2 strongly differed from each other with respect to mental and emotional health. It can thus be concluded that loxapine had analgesic effects in two subjects with highly differential characteristics in psychological health.N-desalkylquetiapine through partial 5-HT1A agonism and inhibition of the norepinephrine reuptake transporter  was found in a dose-escalating study evaluating pregabalin in patients with neuropathic pain . As statThe datasets generated for this study are available on request to the corresponding author.This single-center, dose-escalating, out-patient, open, proof-of-principle study was conducted at the Helios University Hospital Wuppertal, Wuppertal, Germany. The study was registered at clinicaltrials.gov (NCT02820519) and was approved by the institutional ethics committee of Witten/Herdecke University (F-183/2014) and the Federal Institute for Drugs and Medical Devices . The study was conducted according to the Declaration of Helsinki and Good Clinical Practice guidelines. Participants were compensated for travel expenses and received 50 € for completion of the 8-week trial, but there were no other financial incentives to participate. Written informed consent was obtained from all participants before initiating study-related procedures.SS and AS designed the study and wrote the manuscript. All authors contributed substantially to acquisition, analysis, and interpretation of data; discussed the results; and commented on the manuscript.This study was supported by an internal research funding of the Witten/Herdecke University, Witten, Germany. The investigational compound was provided in parts free of charge by Lannett Company Inc., Philadelphia, USA.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Emerging evidence show that patients with chronic pancreatitis (CP) and abdominal pain have structural and functional alterations in the central nervous system. The aim was to investigate cerebral metabolic signatures in CP and the associations to various risk factors/clinical characteristics and patient outcomes.Magnetic resonance spectroscopy was used to measure brain metabolites in the anterior cingulate cortex (ACC), insula, prefrontal cortex and the parietal region in patients with CP and healthy controls. Subgroup analyses based on disease characteristics  were performed. Finally, relations to abdominal pain symptoms and quality of life scores were explored.p = .045) and reduced parietal N-acetylaspartate/creatine (NAA/cre) levels . Patients with alcoholic etiology of CP had significant lower levels of parietal NAA/cre as compared to patients without alcoholic etiology and healthy controls (p < .006). Patients with a high level of ACC glu/cre reported more severe abdominal pain than their counterparts with a low level of ACC glu/cre .Thirty-one patients with CP (mean age 58.5 ± 9.2 years) and 23 healthy controls (54.6 ± 7.8 years) were included. Compared to healthy controls, patients had increased glutamate/creatine (glu/cre) levels in the ACC (1.24 ± 0.17 vs. 1.13 ± 0.21, Cerebral spectroscopy revealed novel and complementary information on central pain mechanisms and alcohol mediated toxic effects in patients with CP. Our data suggest that cingulate glutamate levels associate with the patients clinical pain symptoms, while parietal NAA levels more likely associate with an alcoholic etiology of CP. •Patients with chronic pancreatitis have altered brain metabolites.•Increased cingulate glutamate levels associate with clinical pain symptoms.•N-acetylaspartate levels likely relate to alcoholic etiology.Decreased parietal  Chronic abdominal pain is the hallmark symptom of CP and, in addition to changes in the pancreas and peripheral nerves, the chronic pain syndrome has been associated with an abnormal central pain processing and structural brain abnormalities . No publN-acetylaspartate (NAA) recognized as a marker of neuronal functionality and density, creatine (cre) involved in neuronal energy metabolism, glutamate (glu) that is a neurotransmitter, myo-inositol (mI) that is a glial marker, and choline containing compounds associated with membrane turnover  to assess brain metabolites in patients with CP as compared to healthy controls in areas involved in pain processing  and in the parietal region, 2) to compare brain metabolite levels in subgroups with different disease characteristics , and finally 3) to explore associations between altered brain metabolites in pain related areas and patient outcome .22.1Thirty-five patients with both painful and non-painful CP and 23 healthy controls were included in this cross-sectional study. The study was conducted at Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology and Department of Radiology, Aalborg University Hospital, Denmark. All subjects were screened by a medical doctor before enrollment. Patients were included if they had a CP diagnosis based on the Mayo Clinic diagnostic criteria  and excl2.2The electronic medical records were reviewed to obtain information on pharmacological treatment, diabetes status, and demographic characteristics including gender, age, etiology and duration of CP.2.3Magnetic resonance spectroscopy measurements were obtained using a 3 T GE scanner . A standard eight-channel head coil was used and the head was fixed using foam pads. Single voxel PRESS (Point RESolved Spectroscopy) spectroscopy were acquired (TR/TE = 2000/30 ms) and total number of scans was 128  in four different voxels of interests (VOIs), see example in A radiologist reviewed all scans for major structural changes within the VOIs. Potential scanner drift was monitored with a PRESS spectroscopy sequence of a phantom on each day.LCModel (Version 6.3) was utilized for post-processing . Water s2.4Patient outcome measurements  were assessed using Brief Pain Inventory (BPI) short form  and the 2.5t-tests or chi-squared tests. Only brain metabolites that were significant different between patients and healthy controls were investigated for further analyses regarding disease characteristics and patient outcomes.Differences of clinical characteristics and brain metabolite levels between patients and healthy controls were assessed using appropriate independent-sample Patient subgroups were stratified based on their 1) etiology of CP , 2) diabetes status (no/yes), and 3) current opioid treatment (no/yes). One-way ANCOVAs were conducted to analyze differences between patient subgroups and healthy controls controlling for age as covariate.U test. This was only explored in pain related areas that revealed changed metabolites.Patient reported outcomes  were compared between patients with high and low glu/cre levels (stratified on the median metabolite level) using Mann-Whitney's p < .05 was considered significant. Statistical analyses were performed in IBM SPSS Statistics .Data are presented as mean ± standard deviation unless otherwise indicated and 3p ≥ .11). No significant differences in SNR or FWHM were found between spectra from the two groups in any of the four VOIs .Of the 35 patients considered for analysis, two patients were excluded due to poor MRI scan quality and two patients were excluded due to active alcohol abuse . Hence, thirty-one patients (mean age 58.5 ± 9.2 years) and 23 healthy controls (mean age 54.6 ± 7.8 years) were included for the final analysis. Spectroscopy data in the parietal region were for technical/logistic reasons only obtained from twenty-five patients. Demographics, clinical characteristics and brain metabolite levels are presented in 3.1p = .045) and reduced NAA/cre levels in the parietal region (p = .027) compared to healthy controls. Thus, subsequent subgroup analyses  was found. As seen in n = 14) compared to patients with non-alcoholic etiology (n = 11) (p = .006) and healthy controls (n = 23) (p = .005). No differences were seen between patients without alcoholic etiology and healthy controls (p = .63). Furthermore, no differences were demonstrated in the subgroup analyses of parietal NAA/cre of diabetes  and opioid treatment . Finally, increased ACC glu/cre levels for patients were not associated with presence of alcoholic etiology of CP, diabetes or opioid treatment .Focusing on ACC glu/cre and parietal NAA/cre levels, a significant association between alcoholic etiology and NAA/cre levels in the parietal region  and felt worse pain (within the last 24 h) as compared to patients with lowest glu/cre (p = .046). Patients with high glu/cre had a trend towards decreased quality of life within the emotional functioning domain (p = .076). No significant differences were seen for other pain scores or quality of life domains .Patient reported BPI pain and quality of life scores for high and low metabolites levels of ACC glu/cre are presented in 4N-acetylaspartate, which associated with an alcoholic etiology of CP.In this study, magnetic resonance spectroscopy measurements were obtained from four brain areas in patients with chronic pancreatitis and healthy controls. Patients had increased levels of the excitatory neurotransmitter glutamate in the anterior cingulate cortex, which was associated with the clinical pain symptoms. Furthermore, as a marker of neuronal functionality patients had decreased white matter parietal 4.1Increased glutamate levels in the ACC in patients with CP is a very relevant finding, since glutamate is an excitatory neurotransmitter which has previously been shown to be elevated in the ACC of patients with chronic pain . A previOne-third of the patients in our study were using opioids, which potentially could influence the measured metabolite levels. Especially, decreased levels of ACC glu/cre have been shown during acute morphine and oxycodone treatment . Thus, tPrevious electroencephalography studies suggested that patients with CP and abdominal pain symptoms have abnormal cerebral pain processing  includin4.2Previous studies in acute pain models and in chronic pain patients have revealed decreased NAA/cre levels in the ACC . In our Our data could support a theory that general structural brain changes and decrease of NAA could be more related to alcohol exposure (and other related co-factors), while functional brain alternations and regional glutamate changes are more related to pain mechanisms and the patients' clinical functioning.4.3Magnetic resonance spectroscopy measurements were obtained from predefined VOIs based on the literature, but other areas might also be relevant to investigate. As this was an explorative study, the significance level was not corrected for the number of VOIs or metabolites tested. Due to the relatively small number of subjects in the subgroup analyses, caution must be applied when interpreting the subgroup comparisons. Future studies should include more subjects or a study design to investigate specific subgroups including a more advanced multivariate statistical analysis. Finally, in this study, a few patients had incomplete data sets due to different reasons , and as several of the associations between the glutamate level and patient outcome pointed in a meaningful direction without being significant, it may indicate that more subjects will be needed in future studies to provide enough statistical power.5Brain metabolites were altered in patients with chronic pancreatitis. High level of glutamate in the anterior cingulate cortex was linked to increased perceived pain, which may indicate a hyperexcitatbility state of the anterior cingulate cortex in painful chronic pancreatitis. On the other hand, decreased levels of parietal NAA are likely more related to the general impact of alcohol on the brain and not chronic pancreatitis per se. A combination of structural, functional and metabolic brain assessments should be considered to further explore the multi-faceted role of the brain in patients with painful chronic pancreatitis.Obel Family Foundation. The foundation had no further role in study design, in the collection, analysis and interpretation of data, in the writing the manuscript or in the decision to submit the paper for publication.This study was supported by the TMH, JM, JBF acquired data; TMH, JM, SSO, AMD, JBF were involved in the study concept and design; TMH, JM, SSO, JBF analyzed the data; All co-authors were involved in interpretation of the data and critical revision of the manuscript.The authors declare that there is no duality of interest associated with this manuscript.


The PRESTO study of non-invasive vagus nerve stimulation  featured key primary and secondary end points recommended by the International Headache Society to provide Class I evidence that for patients with an episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. Here, we examined additional data from PRESTO to provide further insights into the practical utility of nVNS by evaluating its ability to consistently deliver clinically meaningful improvements in pain intensity while reducing the need for rescue medication.Patients recorded pain intensity for treated migraine attacks on a 4-point scale. Data were examined to compare nVNS and sham with regard to the percentage of patients who benefited by at least 1 point in pain intensity. We also assessed the percentage of attacks that required rescue medication and pain-free rates stratified by pain intensity at treatment initiation.n = 120) vs sham (n = 123) reported a ≥ 1-point decrease in pain intensity at 30 min , 60 min , and 120 min  after the first attack. Similar significant results were seen when assessing the benefit in all attacks. The proportion of patients who did not require rescue medication was significantly higher with nVNS than with sham for the first attack  and all attacks . When initial pain intensity was mild, the percentage of patients with no pain after treatment was significantly higher with nVNS than with sham at 60 min  and 120 min .A significantly higher percentage of patients who used acute nVNS treatment (This post hoc analysis demonstrated that acute nVNS treatment quickly and consistently reduced pain intensity while decreasing rescue medication use. These clinical benefits provide guidance in the optimal use of nVNS in everyday practice, which can potentially reduce use of acute pharmacologic medications and their associated adverse events.NCT02686034.ClinicalTrials.gov identifier:  PRospectivE Study of nVNS for the acute Treatment Of migraine (PRESTO), nVNS was superior to sham for the majority of end points including pain freedom, pain relief, and ≥ 50% responder rates at various time points [Non-invasive vagus nerve stimulation  Fig.  is a safe points . Adversee points . The PREIn this post hoc analysis, we provide further insight into the practical utility of acute nVNS treatment through the reporting of clinically relevant end points that extend beyond the traditional key end points recommended for pivotal clinical trials by the International Headache Society (IHS) . The objThe methods for the prospective, double-blind, randomized, sham-controlled, multicenter PRESTO study were previously reported  [International Classification of Headache Disorders, 3rd edition criteria (ICHD-3) [Patients were 18 to 75 years of age and had a previous diagnosis of migraine with or without aura according to the (ICHD-3) . Key excWithin 20 min of migraine pain onset, patients self-administered two bilateral 120-s stimulations   was measured at 30, 60, and 120 min after the first treated attack of the double-blind and open-label periods. Rescue medication use and pain-free rates at 30, 60, and 120 min stratified by initial pain intensity were evaluated for the first treated attack of both periods. Similar analyses were performed for all attacks for both periods.The percentage of patients with a ≥ 1-point reduction in pain intensity on a 4-point scale  population, defined as patients who treated at least one migraine attack in the double-blind period. Proportions of patients with pain reductions of ≥1 point and proportions of patients who did not use rescue medication were estimated for the first attack using logistic regression models adjusted for baseline pain score, preventive medication use, and presence of aura. P-values for comparisons between the nVNS and sham groups were from the covariate-adjusted logistic regression models. Pain-free rates for the first attack were presented as proportion and 95% exact binomial confidence interval (CI). P-values for comparison of pain-free rates for the first attack between the nVNS and sham groups in the double-blind period were from the chi-square test or Fisher exact test, as appropriate. To estimate proportions of all attacks that achieved ≥1-point pain reductions and proportions of all attacks not requiring rescue medication, generalized linear mixed-effects regression models adjusted for baseline pain score, preventive medication use, and presence of aura were used. Odds ratios and 95% CIs for comparisons of rates between the nVNS and sham groups for all attacks were from the covariate-adjusted generalized linear mixed-effects regression models; P-values were from resulting F tests. To estimate pain-free rates for all attacks, unadjusted generalized linear mixed-effects regression models were used; P-values comparing nVNS with sham were from resulting F tests. All data were analyzed using SAS® 9.4 .All analyses were evaluated in the n = 122) and sham (n = 126) groups. The ITT population consisted of 120 patients randomized to receive nVNS and 123 patients randomized to receive sham. Patients were < 50 years of age at migraine onset, with a frequency of 3 to 8 attacks per month. Demographic and baseline characteristics were similar between the nVNS and sham groups. More patients in the nVNS group than in the sham group initiated treatment when attack intensity was severe . A total of 238 patients  completed the open-label period.Full details on patient disposition, demographics, and baseline characteristics in the PRESTO study were reported previously . A totalP = 0.020), 60 min , and 120 min . For all treated attacks  and 120 min .Acute nVNS treatment provided clinically meaningful and significant benefits vs sham in the double-blind period. For the first treated attack Fig. , percentcks Fig. , signifiP = 0.013) and for all attacks    and at 120 min    Fig. . When al37) Fig. . When th01) Fig. . The staTherapeutic benefits observed in the nVNS group at 120 min during the double-blind period  were sustained in the 4-week open-label period during which all patients received nVNS (Table Treatment with nVNS consistently led to clinically relevant reductions in pain while reducing the need for rescue medication for the first and all attacks. The ability of nVNS to offer measurable pain relief for patients without increasing their exposure to pharmacologic adverse events or medication overuse provides a practical rationale for its early use as an acute treatment . PatientFindings from mechanistic studies further support the initiation of nVNS treatment as early as possible to facilitate greater reductions in pain , 23. EarMigraine may share common mechanistic pathways and latent causes with comorbid pain disorders such as fibromyalgia, chronic pelvic pain, and myofascial pain syndromes , 27. ConPost hoc analyses of clinical trials can be criticized for the use of less-rigorous methods or nonrepresentative subsets of a larger population –33. We pA limiting factor of the PRESTO trial was that the sham device, which delivered an appreciable electrical signal, appears to have had some level of vagal activation . The desnVNS is a practical treatment option with considerable clinical utility in the acute treatment of migraine. The likelihood that nVNS will quickly reduce pain by at least 1 point and decrease the use of rescue medication highlights its favorable risk-benefit profile , 9. SignThese data highlight clinically important benefits of nVNS as an acute treatment of migraine. nVNS decreased pain by at least 1 point while reducing rescue medication use in most migraine attacks. Unlike most pharmacologic options, nVNS has the flexibility to be used alone or as adjunctive therapy for multiple attacks without risk of pharmacologic interactions and adverse events. These benefits, along with its convenience and ease of use, make nVNS an appealing practical option for the acute treatment of migraine.


Three main activity patterns have been distinguished in describing chronic pain . However, their influence on patient outcomes remains a question of debate. This observational study aimed to measure the associations between the avoidance, pacing, and persistence (labelled overdoing) scales of the Patterns of Activity Measure–Pain (POAM-P), self-reported outcomes , and observational outcomes .We conducted an observational study with cross-sectional and longitudinal analyses. The data were collected prospectively before and after treatment, which was a 5-week functional rehabilitation including vocational aspects. In addition to self-reported and observational outcomes, patients were asked if they thought they would be able to return to work at 6 months. Analyses were conducted with treatment effect sizes, correlations, and multiple regression models.In this sample (891 patients), we found on average small to moderate improvements for pain-interference and observational outcomes (Cohen’s d: 0.37 to 0.64). According to the multivariable models, overdoing was associated with most of the beneficial psychosocial and observational outcomes . Avoidance was related to negative psychosocial outcomes before treatment . Pacing, which had moderate correlation with avoidance (r = 0.46), was not associated with most of the outcomes. The feeling that the goal of returning to work was attainable was associated with lower avoidance scores .The overdoing POAM-P scale probably measures a task-contingent persistence, which appears appropriate in the setting of this study. Persistent behavior was indeed related to small or moderate positive biopsychosocial outcomes, before and after treatment. Moreover feeling able to return to work was related to lower avoidance. Further studies should test the efficacy of motivational strategies that may promote functional task-contingent persistence and reduce avoidance of painful tasks. Behavioral factors influence the development and perpetuation of musculoskeletal pain. Three main activity patterns have been described in patients with chronic pain: avoidance, pacing, and persistence. AvoidanObservational studies were conducted to study the association among these patterns and clinical outcomes. Avoidance has been the most studied and has consistently been associated with poor physical and psychological functioning and increase in pain, 10, 11.To date, no theoretical models can explain all these different patterns. The Fear-Avoidance Model is the mRecently, in a contextual-functional approach, Mc Cracken proposedWe aimed to describe how the 3 activity patterns are related to pain-interference, depressive symptomatology, functional ability, and to measurements of walking, lifting test, and physical fitness, in a functional rehabilitation program including vocational aspects for patients with chronic pain. Activity patterns were assessed by using the Patterns of Activity Measure—Pain (POAM-P) developed by Cane and receWe conducted a single-center observational study with cross-sectional and longitudinal analyses in a Swiss rehabilitation hospital . We measured pretreatment and posttreatment relationships between pain behaviors , and self-reported (questionnaires) and observational (performance-based measures) outcomes. The study was approved by the Local Medical Ethics Committee, Canton Wallis (CCVEM 034/12) and conducted in accordance with the Declaration of Helsinki. All patients read and signed an informed consent form. The STROBE checklist  and the Participants were referred from all of the French-speaking counties of Switzerland, which includes urban and industrial city centers or more rural regions. The inclusion period was between October 2013 and June 2016. Patients of working age (18–65 years old) were sent to the functional multidisciplinary rehabilitation program by general practitioners, surgeons, or insurance medical advisors when they presented with chronic pain (for more than 3 months), functional impairments, and inability to return to work after orthopedic trauma injuries following work, traffic, sport, or leisure accidents. Health The aim of the therapeutic program was to manage pain, and to improve function, activity, and participation including return to work , using a multidisciplinary biopsychosocial approach according to the recommended practice for patients with chronic pain . This prThe following data were available from the medical chart: age, gender, marital status (yes vs no), education (≤ 9 years compulsory schooling vs > 9 years), professional qualification (yes vs no), severity of the injury (Abbreviated Injury Score (AIS): minor, Activity patterns: Avoidance, pacing, and persistence were assessed at entry by using the Patterns of Activity Measure—Pain (POAM-P) developed by Cane[d by Cane and reced by Cane. Unlike d by Cane, 34, 35.Pain severity and Pain-interference: To assess these 2 parameters we used the Brief Pain Inventory (BPI) questionnaire[tionnaire, dividedtionnaire. Accorditionnaire, functioPain-related fears: We used the TAMPA scale of Kinesiophobia  to assess pain-related fears (fears of movement and re-injury), Higher scores indicate more pain-related-fears and were consistently related to higher pain and disability levels[ty levels.Catastrophizing thoughts: We used the Pain Catastrophizing Scale [nt: 0.91) to invesAnxious and depressive symptomatology: We used the Hospital Anxiety and Depression Scale . Higher scores indicate greater anxious or depressive symptomatology, and a cut-off point of 8/21 is generally accepted for anxiety or depression symptoms[ symptoms.Functional Ability: Functional ability represents a person's belief in his or her capability to perform a task/skill successfully[cessfully. Questiocessfully  of the Baecke Physical Activity Questionnaire (BPAQ)[re (BPAQ) was usedAll questionnaires used were the validated French versions, 46–52.Performance-based measures: At entry and discharge, patients performed the 3 following observational measures: 1. The 6-minute walk test (6MWT)[st (6MWT), a reliast (6MWT). Particist (6MWT), a commost (6MWT). After ast (6MWT). PerformData collection and bias: To minimize the measurement bias, questionnaires and outcomes at entry were collected before starting the therapeutic program. Records were collected electronically with a digital pen. The performance-based measures were done under the supervision of highly experienced physiotherapists, familiar with the tests through regular training and clear instructions. Questionnaires as well as physical tests were administered in the 2–3 days following entry, and the 2–3 days before discharge. Therapeutic teams were unaware of the pattern activity scores.Self-reported evaluations , questions about the possibility of resuming work, and observational performance-based measures  were assessed upon entry. Before discharge, we investigated the evolution of the scores of the self-reported and observational measures following the rehabilitation protocol.t tests or ANOVA, as appropriate. Correlations between POAM-P scores and other continuous variables were also computed. Following Evans[Descriptive statistics were expressed as mean and standard deviation for continuous variables, and as count and percentage for categorical ones. Influence of socio-demographic characteristics on POAM-P scores were assessed by means of ing Evans, the strAssociations between the self-reported and observational outcomes and the 3 subscales of the POAM-P were assessed by the mean of linear regression models. Associations between the possibility of resuming work and the 3 subscales of the POAM-P were assessed by the mean of logistic regression models. These associations were adjusted for age, gender, pain severity at admission, trauma localization, and education level, which could be potential confounding factors. At discharge, associations were also adjusted with the outcome baseline values as proposed by Senn , and witIt has been demonstrated  that patAll statistical analyses were performed with Stata 15.0 . The limit for statistical significance was set as usual at p<0.05.During the study period , 891 patHigher avoidance scores were found in cases of minor injuries (AIS 1), work-related injuries, a lower level of education, non-native speakers, and male patients. Higher scores of pacing were found in non-native speakers, a lower level of education, and stable partnership, whereas higher scores of overdoing were found in female patients, serious injuries (AIS ≥ 3), native speakers, non-occupational injury, and patients with more than 9 years of compulsory schooling. Lower avoidance scores were related to the self-perceived ability to return to work. All these differences were statistically significant . Effect All correlations are presented in According to the multivariable regression models , a higheThe avoidance score was significantly lower if the self-perceived ability of work resumption was viewed as attainable. For each 1 point difference in the avoidance score (0–40 points) the adjusted Odds Ratio was 0.97 (p = 0.024). No association was found with the pacing or overdoing scores .Considering the total sample , differeRegarding the relationships between activity patterns and improvements during the rehabilitation stay, overdoing was associated with pain-interference and depressive symptom reductions, functional ability improvement, as well as better walking and lifting performances (β coefficient between 0.10 to 0.13), the higher the overdoing score the higher the improvement . No otheThe same analyses as presented above were computed on complete-case data. No noteworthy differences were observed compared to multiple imputation analyses in multivariable regression models . When meThis study included a large cohort of patients with musculoskeletal chronic pain undergoing functional and vocational rehabilitation, and for the total sample we found on average small to moderate improvements for the different outcomes. Our results on treatment effects are similar to previous studies . RegardiAs expected, before rehabilitation, overdoing was positively related to functional ability and physical performances and negatively related to depressive symptomatology. However we failed to demonstrate a relationship with pain-interference. At discharge, overdoing was also positively related to improvements with all self-reported and observational measures, except for physical fitness (SRT).Regarding avoidance and in accordance with our hypotheses a positive relationship was observed with pain-interference and depressive symptomatology before rehabilitation, whereas functional ability was negatively related. Interestingly no relationship was found with physical performance. The small association between avoidance and pain-interference shows that they are 2 distinct contructs. At discharge, there were no self-reported or observational measures significantly related to the avoidance pattern. Our assumptions concerning the ability to resume work were partially confirmed here. Indeed the avoidance score was negatively related to the perceived ability to resume work, while no relationship was found with the 2 other patterns.Few relationships were found for the pacing pattern. Before rehabilitation, pacing was negatively related to depressive symptomatology and lower walking performance. At discharge, pacing was not associated with any changes from baseline.Others significant results, pointed towards moderate correlations between the avoidance and pacing POAM-P scores. A lower level of education was also significantly associated with higher avoidance and pacing scores, as well as lower overdoing scores. We found similar associations with the non-native speakers. However, the positive significant association found between minor injuries and avoidance score seems to be the result of probable selection bias; patients who combine less severe injuries with higher avoidance are most likely to be referred to rehabilitation.The strength of this study relies on its large sample of patients and measurement of several self-reported and observational outcomes. Furthermore, we collected longitudinal data for the association of baseline behavior with the changes in outcomes. Our study enlarges the existing body of literature, which mainly focuses on patients with nonspecific pain syndrome with many years of pain history. Most of our patients were in a professional reintegration program with a 1-year average pain duration, and the functional and vocational setting of our project may shed a new light on the possible relationships between patients’ goals and activity patterns. Self-regulation and motivational theories, indeed, postulate that behaviors should be studied for their relationship with identity and valued goals. In the Results on the overdoing behavior may simply due to the operationalization of this behavior in the POAM-P questionnaire. Kindermans has conducted a factor analysis on 4 questionnaires assessing activity patterns, including the POAM-P. She fouRegarding personal factors, models like that of Self-Discrepancy, seemed pertinent if considering the function of activity behaviors as an attempt to restore or to protect personal identity. Self-discrepancies with the fear- self (the self one fears to become) was positively related to avoidance behavior. However, the expected positive relationship between persistence and the ideal or ought self was not fully confirmed , 20. A pThe possible role of education remains largely unexplored. McCracken found a significant lower education level in the avoiders, compared to the medium cyclers (patients with high persistence level and medium pacing and avoidance). We alsoOur other findings on the avoidant pattern are in accordance with a relevant body of literature, patients adopting this behavior showing consistently poorer outcomes. HoweverIn our sample, pacing was not associated with the baseline or post-treatment outcomes, with the exception of a negative relationship with depressive symptoms and weaker walking performance at baseline. In his original study, Cane foAll associations found in this study were small to moderate. However, because of the rather large number of factors associated with outcomes in this population, a single factor cannot show a large association. The magFirst, the unusual fact that the sample was mainly composed of men may reduce the generalization of the results. Second, due to the real-world clinical setting, we were unable to control for the potentially different therapeutic advice provided by all the members of the healthcare teams about pain, behavior, and physical activity. Indeed, caregivers’ beliefs may also influence patient outcomes. We alsoIn this study, conducted in a functional and vocational rehabilitation program with patients with chronic musculoskeletal pain, overdoing which appears to be linked to a task-contingent form of persistence, was mosS1 File(PDF)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


To compare gabapentin extended-release, a gastro-retentive formulation, in relieving postamputation pain among gabapentin-experienced and gabapentin-naïve patients.Open-labeled pilot study.Sixteen patients with postamputation pain (8 patients in the gabapentin-experienced and 8 patients in the gabapentin-naïve groups).Patients were started on gabapentin extended-release and were followed up for 8 weeks. Patients reported their pain severity during rest and movement using a numeric rating scale (NRS), interference of pain with daily activities using the modified brief pain inventory (MBPI) questionnaire, and treatment satisfaction using the treatment satisfaction questionnaire for medication (TSQM).p < 0.01) after 8 weeks of therapy among gabapentin-experienced (81.25 ± 16.42%) and gabapentin-naïve groups (85 ± 17.73%) when compared to baseline for gabapentin-experienced (31.25 ± 29%) and gabapentin-naïve groups (36.25 ± 34.2%), respectively. Gabapentin-experienced and gabapentin-naïve groups had no significant difference in global satisfaction from treatment (79.14 ± 10.47 and 83.3 ± 20.82), convenience of treatment (73.78 ± 19.04 and 90.44 ± 11.66), effectiveness of treatment (72.6 ± 10.1 and 79.73 ± 11.6). The only statistically significant difference among gabapentin-experienced and gabapentin-naïve groups was found in adverse event tolerability .Patients from both gabapentin-experienced and gabapentin-naïve groups achieved a significant and sustainable pain relief over the course of therapy. The pain scores at rest decreased in both gabapentin-experienced and gabapentin-naïve groups from 5.88 ± 1.36 and 4.88 ± 2.95 to 1.88 ± 0.99 and 1.38 ± 1.51, respectively. An average percent of pain relief with gabapentin extended-release was noted to be significant (Once-daily dosing of gabapentin-extended release showed significant improvement in pain severity and functional status, with no difference found between gabapentin-experienced versus gabapentin-naïve patients. Postamputation pain (PAP) is defined as pain developing after a surgical amputation of a body part, which persists for several months after amputation and for which other causes of pain have been ruled out . PAP is Since PAP is considered to be a neuropathic pain, there is a special interest in using gabapentin for prevention and treatment of pain . However®, Kansas) use in patients experiencing PAP, which was defined as pain after amputation persisting for more than 6 months  and IND exemption was obtained from Food and Drug Administration (FDA). This was an open-labeled, single intervention study determining the efficacy and safety of gabapentin ER  recommendations, we used multiple endpoints in our trial, including an 11-point numeric rating scale (NRS) for pain intensity at rest and during movement which scores pain between 0 and 10 . InterfeAll the patients participating in the study were started on a once-daily dose of gabapentin ER using a titrating regimen, recommended by the United States Food and Drug Administration (FDA) for the treatment of postherpetic neuralgia . Patientt-test for independent samples for continuous data. The one-way repeated measure analysis of variance (ANOVA) test was used to compare the mean differences in pain at rest and pain during movement with time, with statistical significance set at the 5% level. An independent samples t-test was run to determine if there were differences in pain interference and pain relief with medication between gabapentin-experienced and gabapentin-naïve groups. The differences in effectiveness, adverse events, convenience, and overall satisfaction between gabapentin-naïve and gabapentin-experienced groups were compared using a t-test for independent samples. Statistical significance was set at the 5% level for all the results. Data analysis was performed using SPSS 23.0 .Descriptive analysis was conducted for the baseline characteristics, i.e., proportion for categorical data and mean with standard deviation for continuous data. The statistical differences in baseline characteristics between the gabapentin-experienced and gabapentin-naïve groups were compared using Pearson’s chi-squared test or Fischer’s exact test for categorical data, and a Eight patients suffering from PAP were recruited to each group of the study according to previous history of gabapentin use. This resulted in 6 males and 2 females being recruited in each group. No statistically significant difference was found in age, BMI, race/ethnicity, amputation site, or for time since amputation between gabapentin-naïve and gabapentin-experienced groups as shown in F = 27.6, p < 0.001, partial η2 = 0.648  = 49.7, p < 0.001, partial η2 = 0.768  and gabapentin-naïve patients at the end of study was , with no statistically significant difference between the groups, MD = −0.55, 95% CI , p = 0.54. Pain relief with medications reported by gabapentin-experienced patients at the end of study was  and gabapentin-naïve patients was , with no statistically significant difference between the groups, MD = 8.5, 95% CI , p = 0.67 (Pain interference reported by gabapentin-experienced patients was (p = 0.67 .p = 0.53) and effectiveness (p = 0.21) between the two groups. Gabapentin-experienced group reported acceptable tolerance of adverse effect at 85.8% as compared to 65.8% in the gabapentin-naïve group, which was a statistically significant difference, p = 0.002. Gabapentin-naïve group scored 83.3% in the overall satisfaction associated with the therapy, compared to 79.1% score in the gabapentin-experienced group, however, there were no significant differences between the two groups, p = 0.62  cyclohexane acetic acid], is a synthetic analog of gamma-aminobutyric acid (GABA), which subsequently inhibits pain neurotransmission, particularly targeting neuropathic pain pathways . SeveralGabapentin ER has been evaluated as both once-daily and twice daily dosing in the past. In our study, we used a once-daily dosage regimen only because previously published literature has not shown any differences in efficacy with either dosing regimen . This haOur results on gabapentin ER adverse effect tolerance were very encouraging. Most common adverse events in our study were dizziness, somnolence, and headache, which are consistent with the previously published literature . Rates oWe showed that gabapentin is safe to use as up to a dose of 1800 mg/day in patients with PAP. We also demonstrated that it is safe to titrate gabapentin to its maintenance dose over a 2-week period in both gabapentin-naïve and gabapentin-experienced patients. For this reason, the FDA recommended dose titrations up to 1800 mg/day, over 2 weeks, at the time of approval of gabapentin ER for postherpetic neuralgia . Once-daOur study also demonstrated that gabapentin ER is effective in relieving PAP. Our study was designed to compare the role of gabapentin ER between gabapentin-naïve and gabapentin-experienced patients; however, we neither had a placebo nor other medication group, which could have served as true control group(s). There is limited literature available comparing gabapentin with placebo in PAP. A noteworthy trial was conducted by Smith et al. comparing gabapentin with placebo in patients with PAP, which did fail to show significant pain relief in patients on gabapentin . HoweverOur study limited the maximum dose of gabapentin ER to 1800 mg/day, which is equivalent to the commonly used dosage of gabapentin IR for the treatment of PAP. However, it is important to determine the maximum dose, which can be used to treat PAP without increasing risks of serious adverse effects. Secondly, we excluded patients with end-stage renal disease because of the known renal metabolism and excretion of gabapentin, which would require a dosage adjustment and because of a potential factor for bias in interpreting the attained results. Although gabapentin ER has been shown to be safe in patients with end-stage renal disease in a previous randomized control trial, further confirmation of the safety of gabapentin ER in this subgroup is needed. Lastly, it is also important to consider doing a long-term follow-up study to assess whether the effects of this medication in this patient population is sustainable over long period of time. Furthermore, costs of gabapentin ER therapy should be considered before deciding its role in the treatment of PAP. We therefore suggest that a detailed analysis of total costs associated with gabapentin therapy be evaluated, which is possibly only done in a large clinical trial aimed at assessing patients over a longer period of time than what has been accomplished to date.We found that a gabapentin ER formulation both alleviates the pain severity and improves the functional status of patients suffering from PAP. Moreover, we did not find any new or unusual adverse events from the use of gabapentin ER. We are extremely optimistic that gabapentin ER may be of great value clinically for patients suffering from PAP.Study was approved by Advocate Healthcare Institutional Review Board.NK and KC designed the study, revised the manuscript, and made the final corrections. NK, AL, and IK collected the data. AL, TA, and IK analyzed the data and interpreted the results. SK and TA wrote the manuscript. All authors approved the final version of the manuscript.Depomed, Inc. provided Gralise medication for the study purpose without any charge to the subjects/subjects’ insurance.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Osteoarthritis (OA) in the thumb carpometacarpal joint (CMCJ) is a prevalent disease which may lead to structural damage, severe pain and functional limitations. Evidence-based treatment recommendations state that all patients with hand OA should be offered non-pharmacological treatment. Surgery should be considered only when other treatment has proven insufficient in relieving pain. The purpose of this study was to investigate prior treatment and characteristics of patients referred to specialist health care surgical consultation due to CMCJ OA. The study includes exploring differences in pain and function between referred and non-referred hand, between men and women, and between patients with and without OA affection of other finger joints than CMCJ.Patients in this cross-sectional study reported prior non-pharmacological treatment for CMCJ OA. Patient demographics, disease and functional variables were assessed based on hand radiographs, patient-reported and observer-based outcome measures. Differences in pain and function between referred and non-referred hand, men and women, and between patients with and without additional affection of finger joints other than CMCJ, were analysed using Paired-samples T-tests, Wilcoxon Signed Rank, or Chi-Square tests.One hundred and eighty patients were included. The mean age was 63 years and 79% were women. Only 21% reported having received non-pharmacological treatment before referral to surgical consultation. The results show a statistically significant worse function for referred hands, women and involvement of additional interphalangeal joints. Most patients reported no pain or mild pain in their referred hand.. The results furthermore show that CMCJ OA negatively affects all aspects of function. Strategies need to be developed to improve OA care, including educating general practitioners in evidence-based treatment recommendations and in the assessment of hand pain, and encourage the routine referral of patients with symptomatic hand OA to occupational therapy before considering surgery.The results of this study show a non-pharmacological treatment gap in OA care. Most patients report no pain or mild pain, and that they had not received non-pharmacological treatment prior to being referred to CMCJ OA surgical consultation Osteoarthritis of the hand (HOA) is a highly prevalent disease that can potentially lead to pain, joint stiffness, reduced pinch and grip strength, impaired activity performance and can have a negative effect on work and quality of life –3. In thThere is currently no cure for OA. Non-pharmacological interventions, which include assistive devices, orthoses, hand exercise and patient education, are recommended as a core treatment for all patients with HOA. Surgery should only be considered for patients with structural abnormalities when other treatment modalities have not been sufficiently effective in relieving pain , 9. ResuThe aim of this study was to investigate prior treatment and characteristics of patients referred to surgical consultation in specialist health care due to CMCJ OA. The study explores differences in pain and function between the referred and non-referred hand, between men and women, and between patients with and without OA affection  of finger joints besides CMCJ.The study had a cross-sectional design, using baseline data from a multicentre randomised controlled trial (RCT)   referrals to CMCJ OA surgical consultation at three hospitals in Norway. The hospitals were the department of orthopaedics, St. Olav’s University Hospital, Trondheim, the department of plastic surgery, Haukeland University Hospital, Bergen and the department of rheumatology and orthopaedics, Haugesund Rheumatism Hospital, Haugesund. Patients unable to speak Norwegian or with cognitive dysfunctions were excluded.Local coordinators at the three hospitals sent information about the study to patients on lists of surgical consultation referrals. Patients interested in participating responded using a pre-stamped envelope or by calling the coordinator. The coordinator then booked a baseline assessment appointment. At the baseline assessment, patients were screened for eligibility, and the written informed consent was collected before further assessment.The International Classification of Functioning, Disability and Health (ICF) model was used to categorise variables . PersonaBody structures Tables , 3 and 4OA affection in IPJ was defined as at minimum one finger joint with clinical nodes plus pain . RadiogrAll body function measurements Tables , 3 and 4Patient reported activity performance and participation Tables  and 4 weNumbers and percentages are reported for categorical variables. Mean and standard deviation (SD) if normally distributed, or median and interquartile range (IQR) if skewed is reported for continuous variables.p-value ≤0.05 was considered statistically significant. The NRS pain score cut off points were 1–4 for mild pain, 5–6 for moderate pain and ≥ 7 for severe pain [The One-Way between groups ANOVA or Kruskal-Wallis test was used to examine differences in continuous variables between study patients referred to the three hospital departments. The Chi-square test was used to compare categorical variables. Body structure and body function differences between the referred and non-referred hand  and left and right hand  were assessed using the Paired-samples T-test if normally distributed, Wilcoxon Signed Rank test if skewed, or Chi-Square test if categorical. In addition to these variables, activity and participation were used when assessing differences between women and men and between different OA phenotypes (isolated CMCJ OA vs. CMCJ OA plus IPJ OA). The dependent variables in these comparisons were the values for the referred hand, or the mean of both hands for those with bilateral referral. Continuous variables were examined using the Independent-samples T-test or Mann-Whitney U test. Categorical variables were assessed using the Chi-square test. A ere pain , 22. Eacn = 101, 56%) were referred for unilateral surgery, 53 (29%) for left hand and 48 (27%) for right hand surgery, whereas 79 (44%) were referred for bilateral surgery. Sixty-three (35%) patients also had OA affection in IPJs in addition to CMCJ OA.One hundred and eighty patients were included in the study Table . The meaThe unilateral referral group had consistently better function in the non-referred hand compared to the referred hand Table , with stThe majority of patients reported no pain 13–16%) or mild pain (46–60%). Median (IQR) pain levels were 3.0 (1 to 4) at rest, 3.0 (2 to 5) following grip strength measurement and 3.5 (2 to 6) following pinch strength measurement (Fig. 3–16% or There were statistically significant more patients with CMCJ subluxation in the left hand than in the right Table  and sublRadiographic severity in the CMCJ was similar in men and women. Women, however, had statistically significant more joints with interphalangeal nodes Table . Women aPatients with CMCJ OA plus IPJ OA had statistically significant more pain, lower grip and pinch grip strength and less joint mobility than those with isolated CMCJ OA. Those with CMCJ OA plus IPJ OA also reported more activity limitations and participation restrictions than patients with isolated CMCJ OA Table .Table 4DAll of the patients in this study were referred to specialist health care surgical consultation due to CMCJ OA. Most of these patients reported no pain or mild pain in the referred hand. Only a minority had received the recommended first-line non-pharmacological treatment, the remainder being referred directly to surgical consultation by their GP. The results furthermore show that unilateral referral patients consistently reported better function in the non-referred hand, and that there were only minor differences between left and right hand in bilateral referral patients. Gender differences include women having poorer scores than men in most aspects of function. Patients with both CMCJ OA and IPJ OA furthermore reported more severe symptoms and functional limitations than those with isolated CMCJ OA.Pain is the predominant symptom that leads patients with OA to contact their GP , and theIn line with studies on hip and knee OA , only a As expected, unilateral referral patients in this study reported consistently worse function in their referred hand, and women had lower hand strength and more functional limitations than men. The gender differences are in line with previous studies of HOA patients , rheumatAlthough results are somewhat ambiguous, previous research has shown that CMCJ OA and IPJ OA functional limitations are comparable  and thatOur findings in general support the hypothesis that there is a treatment gap in OA care , 45. DziThe availability of only referred hand radiographs represents a limitation of this study. This, however, only slightly limited the referred hand/non-referred hand comparison. A further limitation is the cross sectional design, which does not allow cause and effect relationship conclusions to be drawn. It should, however, be kept in mind when comparing pain and function of the referred hand versus non-referred hand, that the patients may also have OA in the non-referred hand. Some patients also had co-existing diseases, which can potentially affect self-reported outcome measurements. The use of analgesics and assistive devices were self-reported. This can have induced a recall bias. The strengths of the study include the large study sample, the thorough clinical and radiographic evaluation combined with patient self-reported data, and that patients were recruited from three different and geographically separate hospitals.. The results further show that CMCJ OA negatively affected all aspects of function, especially in the referred hand, in women, and in those who also had IPJ OA. Strategies need to be developed to improve clinical practice. These include educating GPs in evidence-based treatment recommendations and in the assessment of hand pain, and to routinely refer those with symptomatic HOA to occupational therapy before considering surgery.The results of this study show that there is a non-pharmacological treatment gap preceding surgical consultation in CMCJ OA. Most patients referred to surgical consultation reported no pain or mild pain. They also had not received the recommended non-pharmacological treatment before being referred


Low body mass index (BMI) is suspected of being associated with low transdermal fentanyl (TDF) blood levels and worse pain relief. Clinical pain data to support this claim are lacking.Using a Chronic Pain Registry, we identified 901 cancer patients who received TDF at outpatient pain service clinics of our cancer center from 7/1/2011 to 12/1/2016. Of these, 240 patients had a BMI measure, pain intensity, and pain relief scores documented within 30 days of a TDF order. We examined associations between BMI, TDF dose, Worst and Least pain scores, and pain relief scores using standard statistical tests.P = .073), suggesting that low BMI may independently predict better pain relief in cancer patients. As there were no significant associations between BMI and TDF dose, we find no basis for BMI‐dependent dose modification or avoiding TDF in cachectic and low BMI patients.In cancer patients receiving TDF, low BMI (<18.5) was significantly associated with greater pain relief irrespective of TDF dose and borderline significantly associated with greater percent pain relief after controlling for age, cancer diagnoses, and pain etiology  is suspected of being associated with low transdermal fentanyl (TDF) blood levels and worse pain relief. Of the 240 patients who reported patient‐reported outcomes, whereas on TDF, patients with lowest BMI trended toward better pain relief on the lowest TDF doses. When predicting percent pain relief, we found no basis for avoiding TDF or modifying its dose in cancer patients with low BMI and cachexia. It is also advantageous for patients who forget to take their prescription medications, have dementia or cognitive impairment from brain metastases, as well as for patients for whom there is concern about compliance. Many of these factors are seen in patients with low body weight during treatment  and in advanced cancer patients with high prevalence of weight loss and cachexia.Previously, delivery rate‐adjusted serum fentanyl concentration has been shown to vary widely.Body mass index (BMI) has been suspected of being associated with lower fentanyl blood levels in cachectic patients.In a recent study of 129 cancer pain patients undergoing opioid rotation from strong opioids to TDF, the equianalgesic ratio was not significantly impacted by BMI or serum albumin.2The Institutional Review Board at Memorial Sloan Kettering Cancer Center approved the Patient‐Reported Outcomes (PRO) Pain Registry project that included patients seen in outpatient pain clinics between 7/1/2011 and 12/1/2016.2.1We collected information regarding patient demographics, TDF dose, and BMI from the electronic medical record. Among the PRO, Worst and Least pain intensity scores, and percent pain relief were collected as part of the Brief Pain Inventory.2.2Patients over 18 years old who completed PRO including Worst and Least pain and percentage pain relief within 30 days after receiving TDF prescription and with BMI recorded within 30 days were included in the analysis. As each patient received TDF for at least 30 days prior to completing PRO we assume that the patients had come to steady state.2.3Our primary objective was to evaluate the correlations between BMI, TDF dose, Worst and Least pain, and pain relief.Five BMI categories , described in a recent study of BMI as a prognostic indicator in cancer patients.Four BMI categories  used by Center for Disease Control (CDC).Two different classifications of BMI were used:P values < .05 were considered statistically significant. All computations were carried out in SAS software .Data were summarized first using standard descriptive statistics. Then, associations between categorical variables were examined by chi‐square tests or Fisher exact tests. Kruskal‐Wallis nonparametric one‐way analysis of variance test was used to examine differences in continuous variables between four or five BMI groups. Correlations were assessed using the Spearman correlation coefficient. Linear regression models were applied to estimate the linear associations between predictor variables of BMI categories and TDF dose only and dependent variables. Subsequently, regression models were re‐analyzed adding the covariates of Age, Cancer Diagnosis, and Pain Etiology (cancer pain vs. cancer treatment‐related pain in a patient with cancer in remission) to the regression models with BMI categories and TDF dose. All 3Of 2320 cancer pain patients that took part in the prospective PRO project in pain clinics of a tertiary cancer center between 7/1/2011 and 12/1/2016, 901 patients received TDF. Of these, 240 patients satisfied inclusion criteria of having three measures of interest: a BMI measure, a TDF dose recorded within 30 days of a Worst and a Least pain intensity score, and a percent pain relief score.Of 240 patients included in analysis, 124 were females, 193 self‐reported their race as white, 27 as black, 7 as Other, Asian or Native Indian, and 13 refused to answer. Median age was 60 with interquartile range of 52‐70 and full range from 22 to 98. Cancer diagnoses classified according to the American Cancer Society cancer classification, 2018, American Cancer Society, Inc, Surveillance Research are listed in Table When using BMI classification A,P ≥ .25). Also differences in TDF dose and pain levels were not statistically significant by BMI category. In a regression analysis to predict percent pain relief (Table P = .077). When predicting percent pain relief, the BMI category of <18.5 was significantly associated with greater pain relief irrespective of TDF dose (P = .038) . When predicting Least pain in last 24 hours . The only significant covariate associated with greater least pain was cancer of oral cavity and pharynx (P ≤ .049) controlling for either four or five BMI categories and other covariates.Of the covariates of age, cancer diagnosis, and pain etiology (cancer pain vs. cancer treatment‐related pain in a patient with cancer in remission), the only significant covariate associated with higher fentanyl dose was age under 25  and previously published results of all patients in our Pain Registry,P = .073), suggesting that low BMI may independently predict better pain relief in cancer patients. As there were no significant associations between BMI and TDF dose, we find no basis for BMI‐dependent dose modification or avoiding TDF in cachectic and low BMI patients.Low BMI (<18.5) was significantly associated with greater pain relief irrespective of TDF dose and borderline significantly associated with greater percent pain relief after controlling for age, cancer diagnoses, and pain etiology (The authors have no conflicts of interest to declare.


Background. Temporomandibular joint dysfunction (TMD) is a term that describes problems in the masticatory system, including the temporomandibular joint, the dento-muscular system and the supporting bones. Injection of botulinum toxin, as a noninvasive technique, might be useful in decreasing symptoms such as muscular spasm, dystonia, migraine headaches and TMD. Therefore, the aim of the present study was to evaluate the effect of injection of botulinum toxin on decreasing the symptoms and signs of masticatory muscles in patients with TMD.Methods. A total of 61 patients were consecutively included in the present study in 2016‒2017. All the subjects received a 50-unit injection of Dysport botulinum toxin in the masseter muscles using an extraoral injection technique. The results of the injection were evaluated in terms of pain severity using VAS, clinical evaluations of the joint click through palpation and by determining the inter-incisal distance. The patients underwent follow-up examinations at 1-week, 3-month and 6-month intervals after injection. Data were analyzed with appropriate statistical tests.Results. Comparison of pain severity and articular clicks at different intervals showed decreases in these parameters over time, with significant differences between the time intervals (P<0.05). Comparison of mouth opening at different intervals showed increases in mouth opening over time.Conclusion. The results of the present study showed that injection of botulinum toxin can be used in patients with TMD as a non-invasive treatment modality The clinical manifestations of TMD are very similar to those of chronic low back pain.4 Conventionally, to treat TMD, first noninvasive techniques, including medications  are used, followed by physiotherapy. If the symptoms persist, the second line of treatment includes irrigation of the joint and invasive surgeries to replace the joint, etc. Since great morbidity is associated with surgical procedures, it is necessary to apply all the noninvasive treatment modalities to decrease the symptoms and signs of TMD. None of these treatment modalities are completely effective and even some are associated with untoward complications.5 Therefore, researchers are trying to find novel treatment modalities for TMD.Temporomandibular joint dysfunction (TMD) describes problems in the masticatory system, including TM joint, the dento-muscular system and the supporting bones. The prevalence of this disorder in the adults is around 40‒70% and in children in the deciduous dentition period the prevalence is approximately 16%, with 90% in the mixed dentition period.Clostridium botulinum. It results in the paralysis of nerves by blocking the release of acetylcholine.6 The toxin is a known treatment to remove skin wrinkles and some studies have evaluated the use of this toxin to relieve muscular spasm, dystonia, migraine headaches, blepharospasm, strabismus, spasmodic torticollis, removal of cleft lip scars and the capability to permanently accept botulinum toxin.7 Some studies have reported improvements in the anatomic position of TMJ subsequent to the injection of the toxin into the lateral pterygoid muscles; in addition, the results have shown that the toxin can improve the clinical status of TMJ.9 In addition, a study evaluated the success of the injection of this toxin in the treatment of myofascial pains, including TMD. Studies have shown improvements in pain severity and patients’ psychological status.10 Furthermore, several studies have evaluated the treatment of TMJ dislocations, including the habitual neurologic cases. In a case report by Vazquez et al,11 infiltration of botulinum toxin into the muscle involved resulted in the successful management of the disorder in a conservative manner. However, Ernberg et al12 evaluated the effect of injection of this toxin into the masseter muscle on relieving TMD symptoms and reported a significant difference between the group receiving normal saline solution and the group receiving botulinum toxin. In a review study, Ihde et al13 reported that use of botulinum toxin was effective in treating myofascial pains, including that of TMD.Botulinum toxin is a neurotoxin derived from There is a limited number of studies available on the use of botulinum toxin for the treatment of myofascial pains; in addition, these studies have not elaborated on significant improvements in these conditions. The results of these studies have raised many questions in relation to the role of masticatory muscles in myofascial pain. If muscular problems are accepted as a chief etiologic factor for TMD, only muscular function should be evaluated as a serious etiologic factor for myofascial pains. Therefore, the aim of the present study was to evaluate the effect of injection of botulinum toxin on decreasing the symptoms and signs of masticatory muscles in patients with TMD.In the present clinical trial, 61 patients with TMD were selected consecutively during 2016‒2017 and included in the study based on inclusion and exclusion criteria after signing informed consent forms. All the subjected completed the study procedures with no dropouts. The inclusion criteria consisted of an age range of 18‒50 years and signing an informed consent form.The exclusion criteria consisted of systemic conditions, a history of surgery or trauma in the TMJ area, a history of injection of botulinum toxin in the TMJ area, and a history of physiotherapy with heat in the TMJ area.The diagnoses were based on medical history, an increase in muscular tonicity and muscular spasm, including pain triggers. Therefore, all the patients with a diagnosis of TMD, complaining of pain in masticatory muscles related to TMD were selected. The patients’ severity of pain was recorded based on VAS. To this end, each patient was asked to select a number from zero to ten based on the severity of pain. The presence or absence of articular clicks  was evaluated and recorded by palpating the TMD area during the function of the mandible. The presence or absence of limitation in mouth opening was evaluated and recorded by measuring the inter-incisal distance. All the examinations were carried out by two oral and maxillofacial surgeons who were blinded to the aims of the study (a double-blind design). All the patients underwent a conservative treatment protocol  for 3 months before the interventions in the study. Then 50 units of Dysport botulinum toxin  were injected into the masseter muscle in each patient. An extraoral technique was used in the bulk of the masseter muscle to deposit the toxin at a depth of 1 cm at 3 points. In cases in which the symptoms and signs were bilateral, the injection was carried out bilaterally; otherwise, unilateral injection was carried out. All the patients were followed at 1-week, 1-month, 3-month and 6-month intervals after the injection. VAS was used to evaluate the presence or absence articular clicks by palpation and the amount of mouth opening by measuring the inter-incisal distance during each follow-up visits. All the patients were recommended to continue conservative treatment modalities and refer to the clinic if the symptoms and signs recurred.The protocol of the study was approved by the Ethics Committee of Tabriz University of Medical Sciences under the code TBZMED.REC.1396.1098. No costs were inflicted on the patients. All the patients underwent routine procedures of diagnosis and treatment and were free to leave the study whenever they wished without stating any reasons. Data were analyzed with descriptive statistics  using repeated measures ANOVA and Friedman test with the use of SPSS 20. Statistical significance was set at P<0.05.A total of 33 female subjects (54.1%) and 28 male subjects (45.9%) were included in the present study. The mean age of the subjects was 31.86±6.82 years and 21 (42.6%) and 35 (57.4%) subjects had bilateral and unilateral TMD, respectively.As shown in the Table, before injection 23 subjects (37.7%) (the highest frequency) had a pain severity of 3 and one (1.6%) subject (the lowest frequency) had a pain score of 7 and no subject had a pain score of 1.One week after injection, 27 subjects (44.3%) (the highest frequency) still had a pain score of 3 and no subject had a score of 6 or 7. One month after injection, the severity of pain decreased and 24 subjects (39.3%) had a pain score of 2. At this interval again, no subjects had a pain score of 6 or 7. Three months after injection, 27 subjects (44.3%) (the highest frequency) had a pain score of 1 and no subject had a pain score of 5‒7. Six months after injection, 42 subjects (68.9%) (the majority of the subjects) had a pain score of 1 and the subjects had pain severity up to score 3. The differences in pain severities of the objects at different time intervals after injection were significant based on the results of Friedman test (P<0.001).Normal distribution of data was evaluated with the use of Kolmogorov-Smirnov test in order to compare the extent of mouth opening at different time intervals before and after injection of the toxin. The results of the test showed that data were not distributed normally only at 1-week and 3-month intervals after injection of the toxin (P>0.05).The mean mouth opening was determined at different time intervals and the results are presented in 14 Muscle relaxation might be lost under the influence of various factors, including inadequate concentration of active toxin adjacent to motor end plate, the presence of antibodies against BTX-A, improper regeneration and inadequate medication pool.15TMD-related disorders are usually due to pain in the joints and facial muscles. In relation to arthralgia, there is inflammation in tissues in association with limitations in movements; in addition, there is pain at loading and lack of reflexes during mastication and pain on mouth opening. However, the origin of chronic pain in the facial muscles is still to be elucidated. Furthermore, it is still unknown whether chronic pain in the facial muscles in TMD patients has a relationship with other similar conditions such as fibromyalgia.18 In addition, comparison of pain and articular clicking at different intervals in the present study showed that these variables decreased over time. However, comparison of the extent of mouth opening at different intervals showed an increase in mouth opening over time. In this context, in relation to the severity of pain, approximately 69% of the patients had the least pain severity (a pain score of 1) 6 months after injection and only one subject had a pain score of 3. In addition, 6 months after injection only 6 subjects (9.8%) exhibited articular clicking. A study evaluated the effect of injecting botulinum toxin on resolving TMJ disorders; the results showed improvements in pain severity and the performance of TMJ, consistent with the results of the present study. The study above, too, did not have a control group; however, the follow-up period was shorter and evaluations were carried out before injection and up to 8 weeks after injection.9 In addition, in another study the success of injection of botulinum toxin was evaluated in the treatment of myofascial pains due to TMD. The results showed improvements in pain severity and psychological conditions of patients, consistent with the results of the present study. However, the study had some limitations such as short follow-up period of patients, small sample size and no evaluation of the anatomic status of the articular disk.10The results of the present study and the majority of other studies indicated a higher prevalence of TMD in female patients. Most researchers believe that the difference in gender distribution is due to the higher frequency of medical visits by female subjects. In addition, some researchers believe that it is due to the lower pain tolerance by women. In addition, a study has shown that a higher rate of referral by female subjects to receive treatment for TMD is directly related to sex hormone levels and estrogen.11 infiltration of botulinum toxin into the muscle involved resulted in conservative management of the condition. Some studies have reported improvements in the anatomic position of TMJ after injection of botulinum toxin into the lateral pterygoid muscle, with the results showing that the injection of the toxin might improve the clinical status of TMJ. The results of the study above, too, were consistent with those of the present study; however, the study had some limitations, including short follow-up period of the subjects, small sample size and lack of a control group.8In addition, some studies have evaluated the treatment of dislocation of TMJ in habitual neurologic cases. In a case report by Vazquez et al,12 evaluated the effect of injection of botulinum toxin into the masseter muscle on decreasing the symptoms and signs of TMD. The results showed no significant differences between the two groups, with one receiving normal saline solution and the other one receiving botulinum toxin, which is different from the results of the present study. It should be noted that the study above had a small sample size and with such a small sample size it is not possible to rule out the effect of injection of botulinum toxin. In addition, in the study above samples with TMD were not differentiated from others with other myofascial pains. Therefore, inconstancy in the results is possible.Ernberg et al13 reported that use of botulinum toxin was effective in the treatment of myofascial pains due to TMD. The results of this study were similar to the present study in one-month follow-up. However, in one-week follow-up in the present study, pain decrease was lower compared to the study above.Ihde et alIt might be concluded from the results of the present study that injection of botulinum toxin can be used as an adjunct for the noninvasive treatment of TMD-related disorders. In addition, based on the results of the present study, it is expected that the best results would be achieved in relation to a decrease in pain severity and articular clicking 6 months after injection of the toxin.MAG was responsible for the concept and design of the work, data collection, data analysis and interpretation, drafting the article, critical revision of the article and final approval of the version to be published. JY was responsible for data collection and final approval of the version to be published. AA contributed to data collection, data analysis and interpretation, drafting the article and critical revision of the article. AG contributed to drafting the article, critical revision of the article and final approval of the version to be published. SVD contributed to data analysis and interpretation, drafting the article and critical revision of the article.NoneNot applicable.The authors declare no competing interests with regards to the authorship and/or publication of this article.The protocol of the study was approved by the Ethics Committee of Tabriz University of Medical Sciences under the code TBZMED.REC.1396.1098.