Pain intensity was rated on a 0–10 numerical rating scale (NRS) and pressure pain thresholds (PPT) and mechanical sensitivity mapping were recorded before and after the treatment on day 1 and day 7. Jaw function was assessed by pain free jaw opening, maximum unassisted jaw opening, maximum assisted jaw opening, maximum protrusion and right and left excursion. Data were analyzed with a mixed model analysis of variance (ANOVA). Pain intensity in arthralgia patients decreased over time (P < 0.001) for both types of interventions, however, PBMT caused greater reduction in pain scores than placebo (P = 0.014). For myalgia patients, pain intensity decreased over time (P < 0.001) but without difference between interventions (P = 0.074). PPTs increased in both myalgia (P < 0.001) and TMJ arthralgia patients over time (P < 0.001) but without difference between interventions (P ≥ 0.614). Overall, PBMT was associated with marginally better improvements in range of motion compared to placebo in both myalgia and arthralgia patients. Pain intensity, sensory function and jaw movements improve after both PBMT and placebo treatments in myalgia and arthralgia patients indicating a substantial non-specific effect of PBMT.To evaluate the effect of photobiomodulation therapy (PBMT) on painful temporomandibular disorders (TMD) patients in a randomized, double-blinded, placebo-controlled manner. Participants were divided into a masseter myalgia group (n = 88) and a temporomandibular joint (TMJ) arthralgia group (n = 87) according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). Both groups randomly received PBMT or placebo treatment once a day for 7 consecutive days, one session. The PBMT was applied with a gallium-aluminum-arsenide (GaAlAs) laser (wavelength = 810 nm) at pre-determined points in the masseter muscle (6 J/cm Pain is one of the most common and limiting clinical manifestations of such disorders2. The pathophysiology of pain in TMD patients is still not fully understood, however, peripheral and central sensitization of the trigeminal nociceptive pathways in addition to impairment in endogenous pain modulatory mechanisms influenced by genetic and epigenetic factors, and a wide and multifaceted range of environmental conditions such as for example bruxism, psychosocial distress, mood, sleep patterns etc. are encapsulated in the bio-psycho-social model for chronic pain4. Recent classification schemes have taken the step to include TMD pain as a primary type of chronic pain meaning that pain in itself has become the disease without a clear and identifiable cause whereas the secondary types of (TMD) pain are viewed as painful conditions which are caused by a disease or disorder and therefore represent a symptom rather than a disease6. In this scenario, causal treatment is not an option and palliative and non-invasive treatment modalities should be preferred. Several non-invasive treatment modalities have been used to relieve painful TMD conditions including occlusal splints, ultrasonography, pharmacologic-based therapy7, manipulative therapy8, oral motor exercise9, transcutaneous electrical stimulation, and photobiomodulation therapy (PBMT)10. Studies in specific TMD pain populations are, however, needed before strong recommendations can made.Temporomandibular disorders (TMD) cover a number of clinical conditions affecting the temporomandibular joint (TMJ), masticatory muscles and related structures12. The mechanism of photobiomodulation (PBM) is still debated but may be related to its potential influence on the synthesis, release, and metabolism of countless signaling substances involved in pain and analgesia14. Many prospective clinical trials have been performed to evaluate the efficacy of PBMT17, however, the results have been ambiguous due to the different laser parameters, lack of standardized operation procedures, lack of reliable methodology including placebo control, and small sample sizes. Therefore, more solid evidence is needed to evaluate the therapeutic effect of PBMT in TMD pain patients.PBMT has been widely used as an alternative or complementary treatment for TMD pain due to the non-invasive and safe features related to the low-intensity energy and wavelength characteristics20. The QST technique has the advantage of more objective and accurate evaluation of patients’ somatosensory function. In addition, a mechanical sensitivity mapping technique which has recently been used in the field of headache disorders such as migraine21 and chronic tension-type headache22 has been confirmed to have excellent reliability to demonstrate changes in somatosensory function and mechanical sensitivity in the masseter muscle and TMJ regions23.A standardized quantitative sensory testing (QST) developed by the German Research Network on Neuropathic Pain (DFNS) has been shown to be reliable in the orofacial region and upper and lower limbs24. In addition to these differences in clinical manifestations, the mechanism of TMJ pain and myalgia may also be different24. Since there are different clinical manifestations and potentially different underlying pain mechanisms between TMD myalgia and TMJ arthralgia, studies may need to test the efficacy of interventions in both groups to obtain a better platform for evidenced-based recommendations for management. Therefore, the purpose of this study was to evaluate the effect of PBMT on myalgia and TMJ arthralgia patients by use of QST and pain sensitivity mapping techniques in a randomized, double-blinded, placebo-controlled manner.Patients with TMJ pain often involve disorders of the articular surfaces, articular disk, bilaminar zone, joint capsule and ligaments, manifested as sound, limited mandibular movement and pain in these areas, while patients with muscle disorders often present with pain in the related muscle region, reduction of mandibular mobility and “pulling” sensations such as feeling of fatigue and bracingA total of 175 participants were initially enrolled into the study, 28 of them were excluded due to the exclusion criteria. 147 participants were randomized into 4 groups, while 16 participants dropped out due to personal reasons or inability to cooperate. In total, 100 participants completed all sessions in the study and 31 participants were lost in the follow-up during the study due to personal reasons Fig. ). Eight The relative changes of pressure pain thresholds (PPT) and numerical rating scale (NRS) scores of patients are shown in Fig. For mechanical sensitivity mapping, the changes of the mean NRS values of each grid point in every examination are presented in Fig. The results of analysis regarding jaw function assessment including pain free jaw opening, maximum unassisted jaw opening, maximum assisted jaw opening, maximum protrusion excursion and right and left excursion, COG coordinates and entropy of myalgia patients are shown in Table , the main effects of time were found in the PPTs of the right TMJ, left masseter muscle and right masseter muscle  without significant differences between intervention  or interaction between time and intervention . The PPTs in the left TMJ increased over time , but no significant treatment effect was found between the PBMT and placebo groups , however, the interaction between time and intervention was statistically significant .The relative changes of PPTs and NRS scores of patients are shown in Fig. For mechanical sensitivity mapping, the changes of the mean NRS values of each grid in every examination are shown in Fig. The results of analysis regarding jaw function assessment, COG coordinates and entropy of TMJ arthralgia patients are shown in Table This randomized, placebo-controlled study indicated that both PBM and placebo interventions can reduce the self-reported pain intensity and improve the jaw function in TMD pain patients, but PBM showed marginally better effectiveness in patients with TMJ arthralgia and more advantages in improving jaw movement compared to placebo. Pain sensitivity of TMD patients appears to improve over time following both PBMT and placebo treatment without specific effects or differences between subgroups of TMD pain.32. The hypothesis on PBM effects mainly covers three aspects: modulation of inflammatory processes, alteration of excitation and nerve conduction in peripheral nerves, and release of endogenous endorphins. The effects of PBMT on inflammatory processes include changes in biochemical markers , altered distributions of inflammatory cells, reduced formation of edema, hemorrhage, and necrosis33. The thinly myelinated A-σ and unmyelinated, slow-conducting C fiber distributed under the epidermis form the peripheral nerve endings of nociceptors can be activated by noxious stimuli leading to propagation of action potentials. When the laser energy is absorbed by the skin, these action potentials are believed to be inhibited, causing changes in activation threshold of the nerve fibers and a decrease in the release of pro-inflammatory neuropeptides 34. The increase of serotonin and endorphin levels is a further putative mechanism of pain relief35. Although these putative molecular and biological mechanisms underlying of PBMT is far from complete, it is commonly believed that Cytochrome c Oxidase (CCO) in the mitochondrial respiratory chain serves as the primary photoceptor36. Since the action spectrum of PBMT matches the absorption spectrum of CCO, after absorption of photons by CCO, inhibitory Nitric Oxide (NO) which is non-covalently bound to the heme and Cu centers of CCO and competitively blocks oxygen at a ratio of 1:10 can be dissociated, and the activation of mitochondrial respiration can lead to increase of mitochondrial membrane potential (MMP), cyclic adenosine monophosphate (cAMP), oxygen resumption and ATP production37. NO is known as a vasodilator, which can stimulate the soluble guanylate cyclase to form cyclic-GMP (cGMP) and activates protein kinase G, which leads to reuptake of Ca2+ and opening of calcium-activated potassium channels, causing the relaxation of blood vessels and lymphatic vessels38. The mediated activation of transient receptor potential (TRP) ion-channels is also considered as one of the mechanisms of action of PBM. After laser irradiation, these cation channels will open and depolarize the cell membrane, the increase of intracellular Ca2+ can lead to the release of histamine to promote tissue healing40. Besides that, the lipid peroxidation of cell membranes can also lead to a generation of reactive oxygen species (ROS)41. ROS can activate the transcription factor nuclear factor kappa B (NF-kB), which regulates the expression of genes related cellular functions such as inflammatory-induced response and survival42. The activation of NF-kB can be induced by PBM to enhance gene transcription that leads to cell proliferation and migration, to reduce cell death and enhance neurological function37. Although the evidence for the mechanism of action of PBM is mounting, there continues to be controversies about the clinical effectiveness of PBMT in TMD pain patients due to lack of standardization of laser parameters and operating procedures, as well as lack of high-quality and sufficiently operationalized outcome measures. Therefore, the present study applied reliable and validated QST measures and comprehensive pain mapping techniques to provide more objective and robust evidence to evaluate the therapeutic effect of PBMT stimulation.As a non-invasive and non-pharmacological modality, PBMT has been suggested to be effective in improving mandibular movements and promoting analgesia in TMD pain patients35. In previous studies, it has been shown that lower doses of light are more effective than much higher doses due to a biphasic dose response curve exhibited by PBM44. In clinical practice, multiple PBM treatment protocols are available for TMD patients, after reviewing all available therapeutic regimens, a recent systematic review suggested an evidence-based protocol for clinical PBM administration for these patients45. According to this review, the application of GaAlAs diode laser, wavelength 800–900 nm, 100–500 mW and energy density lower than 10 J/cm2, twice a week for 30 days showed the best results for pain relief and improvement of mandibular movements45. To achieve the same total dose as the recommendation45 and minimize the possibility of spontaneous remission, we modified the treatment application to once a day for 7 consecutive days.The effectiveness of PBM is related to the laser irradiation parameters including wavelength, power, power density, energy density, time and total energy47. For example, simple rating scales like a NRS or VAS  are the most popular way to evaluate the self-reported pain intensity in clinical practice; however, this approach may be an oversimplification of complex biopsychosocial pain problems and possibly result in an underestimation or overestimation of pain46.In many previous studies on PBMT in TMD pain patients the focus has been on jaw movements or self-reported pain intensity, only a few studies have determined changes in patients’ somatosensory function using more objective testing methods19. Pressure algometry delivers both a stable, reliable and quantifiable pressure through a flat base applied to the dermal surface48. The force is generally applied as a gradual increased pressure stimulus by the examiner, and the stimulation is stopped once the test participant presses a button. The value of interest is typically defined as the pressure pain threshold (PPT) which is minimum pressure that the participant report to be consistently just barely painful50. PPT has been shown to be reliable for evaluation of deep pain sensitivity in e.g., the masseter muscle and TMJ regions20. In addition, a pain mapping technique has also been demonstrated to have excellent reliability in assessment of the spatial aspects of mechanical sensitivity in the masseter muscle area and TMJ regions23. This method is considered as a valuable approach for a more comprehensive investigation of the pathology of somatosensory system, and it can provide an overall description of how somatosensory function varies with time or change in sensitivity among multiple test sites51. Therefore, the pain mapping technique, which was performed with a simple quantitative palpometer in this study, is one of the main novelties of this experiment and demonstrated significant changes in deep pain sensitivity across the masseter and TMJ regions following both PBM and placebo interventions while PBM showed more advantage than placebo in TMJ arthralgia patients.Pressure algometry is part of the QST technology and is the most-commonly used method to detect pressure sensitivity and static mechanical allodynia in deep tissues53. The present study found that the jaw movement of PBMT group showed more improvement than those in the placebo group, which is also corroborated by other studies56. The effectiveness of placebo in this study can also be related to the activation of endogenous opioids and neural mechanisms of pain modulation59. Pain modulation is, indeed, influenced by many factors, such as psychological issues, memory of pain experience, hope of health restoration, educational level and professional-patient relationship etc.62. The sham-laser treatment provided in the placebo sessions may have amplified the psychological impact and anticipation of treatment effects in myalgia patients which is reflected in similar expectations scores between PBM and placebo. Furthermore, a good relationship between the professionals and patients in the present experiment may also contribute to the improvement following the placebo intervention. From this perspective, we can consider that although the therapeutic effect of PBMT has been indicated in animal studies64, in human-beings the cognitive aspects of the placebo intervention is as important as the putative biological effects following PBMT in mediating an hypoalgesia effect in TMD pain patients with a sub-diagnosis of myalgia.The present study showed that the self-reported pain intensity in patients with masseter myalgia was decreased and the somatosensory sensitivity was improved (less sensitive) following the intervention with both PBM and placebo, which are consistent with previous studies23. Interestingly, the NRS pain scores decreased, COG coordinates shifted, and entropy values decreased as a reflection of a decrease and more homogenous muscle pain sensitivity following both types of interventions. This finding again questions the specificity of PBMT in patients with myalgia.As for the results of pain mapping in myalgia patients, it was clear that patients showed the highest NRS scores around the middle part of the masseter muscle, while the lowest NRS value was found near bony structures and in the periphery of the masseter muscle consistent with previous studies17, the self-reported pain relief following PBM and placebo were both decreased but with no significant difference between groups. It should also be acknowledged that the present differences between PBM and placebo are small and perhaps without a robust clinical importance. Similar to the findings in myalgia patients, the pain mapping results indicated lower entropy scores following PBMT in TMJ arthralgia suggesting a normalization of the pain sensitivity in the TMJ region. It can be speculated that this effect is mediated by a combination of endogenous pain modulation mechanisms related to a placebo response and a peripheral component related to the putative therapeutic effect of PBMT on peripheral sensitization of the TMJ region. Direct measures of the biological markers in the TMJ would add more information to the understanding of PBMT effects in future studies.In the present study, PBM was found to have some minor advantages compared to placebo in terms of decreases in self-reported pain intensity and increases in maximum unassisted jaw opening as well as improvement in mechanical sensitivity in patients with TMJ arthralgia. However, in Emshoff et al.’s studyFirst, it is important to notice that the standardized operating procedure in the scientific literature about the dose and protocols of PBMT for TMD pain patients has not reached a consensus, however, we followed the best available evidence in terms of stimulation parameters. The present results cannot be extrapolated to all types of PBMT for different types of TMD pain patients. Second, it should also be mentioned that only the immediate effect of PBMT was evaluated in this study and the sample size was relatively small partly because of dropouts during the treatment procedure—a well-known challenge in RCT studies. We recommend that multicenter studies are performed in well-defined TMD patient groups  and with larger sample size and reliable and valid outcome measures including the proposed techniques from this study. Nevertheless, it should also be mentioned that we applied rigorous diagnostic criteria to subtype TMD pain patients and this is the first study to investigate PBMT in both TMJ arthralgia and myalgia patients.A striking finding in the present experiment was that both PBM and placebo interventions were associated with significant improvement over time and with only subtle differences between myalgia and arthralgia patients. PBMT seemed slightly more effective in terms of a decrease in self-reported pain intensity and improvement of the mechanical sensitivity in patients with TMJ arthralgia while PBM was more effective in terms of improvement of jaw movements in patients with masseter myalgia. Overall, these findings suggest that specific pain management should be tailored to the different subtype of TMD pain and that PBMT may involve substantial placebo effects.65 by trained examiners and medical histories were collected. Inclusion criteria were: TMD patients aged from 18 to 60 years old reporting unilateral pain in the masseter muscle or TMJ regions lasting at least 2 weeks without receiving alternative treatments in the past 3 months. The pain intensity assessed on a 0–10 NRS during manual palpation should be ≥ 4. Exclusion criteria were: history of orofacial trauma that affects normal somatosensory function; history of serious or chronic systemic diseases ; use of alcohol or caffeine within 24 h of the test day, and/or any mental disorders.A total of 175 TMD pain patients  were involved into the study from April 20th, 2020 to September 30th, 2020. The patients were recruited from the Department of TMD & Orofacial pain, Affiliated Hospital of Stomatology, Nanjing Medical University, P. R. China. The sample size was calculated a priori based on the detection of a minimum clinically relevant difference of 25% at an α level of 0.05 and 80% power . However, considering an anticipated 25% dropout rate, a total of 131 participants were involved and 100 patients were included for data analysis. All patients were examined and diagnosed with Diagnostic Criteria for Temporomandibular Disorders (DC/TMD)According to the exclusion criteria, 28 patients were excluded, 78 patients  were recruited into the TMJ arthralgia group, and 69 patients  were recruited into the masseter myalgia group Fig. ). PatienA randomized, placebo-controlled, double-blinded clinical trial was conducted by two examiners. Examiner 1 was responsible for the examinations of participants before and after treatment and was blinded to which treatment the patient received, while the examiner 2 completed the randomization and treatment. Participants in both groups were randomly assigned to intervention with PBM or placebo once a day for 7 days. A specialist from the department of orofacial pain and TMD monitored the conditions of the participants during the whole study to take effective measures once the adverse effects occur.23. There were 15 test points . After that, they were required to lie down in the dental chair, and examiner 1 measured the PPT values bilaterally at the center of the masseter muscle and at the hinge axis points of the TMJ regions Fig. b). Pain nts Fig. a) above nts Fig. b). The N35 and the evidence-based protocol for PBM administration45, a gallium-aluminum-arsenide (GaAlAs) laser  (wavelength = 810 nm) was used for PBMT and placebo treatment. The laser application was performed at pre-determined points on their masseter muscle area or TMJ region of their painful site: the masseter muscle  and TMJ region 46. Since the area of the masseter muscle was different in each individual and limited by the size of the laser light spot, every irradiation region of the masseter muscle was irradiated from anterior to posterior with approximately three to four irradiated circles to ensure all the test points were involved and received equal irradiation. The treatment application was once a day for 7 consecutive days. The PBM stimulation was applied in the continuous emission mode and did not have direct contact with the patient’s skin or mucous membrane, and irradiated the treatment site in a circular manner with a special trumpet-shaped handle. The irradiation parameters used were as follows: operating frequency = 10 Hz, laser optical power = 3 W, diameter of light spot = 2 cm, the distance between spot and optical fiber = 3 cm; for masseter muscle: energy density = 6 J/cm2, measurements of the output power in irradiated area = 100 mW, time per region = 20 s, total time = 60 s, for the TMJ area: energy density = 6 J/cm2, measurements of the output power in irradiated area = 100 mW, time per point = 6 s, total time = 30 s. The placebo treatment was done exactly in the same manner as the PBMT at the same points for the same time duration but without power output. During the treatment procedure, both participants and the professional responsible for the treatment were wearing special glasses for eye protection.According to the concept of “Optical window”Pain intensity was assessed by means of a 0–10 NRS where 0 indicates “no pain” and 10 means “the most pain imaginable”. Patients were instructed to rate the present pain intensity, and the NRS score was used to represent the intensity of patients’ pain at the time of evaluation.Jaw movement including pain free jaw opening, maximum unassisted jaw opening, maximum assisted jaw opening, maximum protrusion excursion, left lateral excursion, and right lateral excursion were assessed during each examination per the DC/TMD instructions. The distance between the midline of upper and lower central incisors was measured with a ruler.66. The PPTs were measured bilaterally at the center of the masseter muscle and hinge axis points of the TMJs. Each site was tested for 3 times and the average was calculated and used for the statistical analysis.PPTs were measured by a hand-held electronic pressure algometer  with a probe diameter of 8 mm. The pressure was increased at a rate of 30 kPa/s23.A quantitative mechanical palpometer  was used to perform standardized palpation of the painful masseter muscle and TMJ regions to form a mechanical sensitivity map and analyze the pain intensity at different and multiple test points. The circular metal rod of the palpometer was 10 mm in diameter and made of aluminum. There was a hole at the other end of the palpometer to let the stamp-tapering end pass through. The palpometer was held perpendicularly to the surface skin of the participants with the examiner’s thumb and middle finger. The examiner would detect the tapered end with the index finger as the correct force was applied23. The palpometer with a 1.0-kg pressure force was applied to each of the 15 grid points at the masseter muscle, and a palpometer with 0.5-kg pressure force was applied to the 9 grid points of the TMJ region in a randomized order in accordance with the (DC/TMD) guidelines for manual palpation. All test sites were stimulated for approximately 2 s during each measurement. After each measurement, there was a 10-s interval for the participants to rate the perceived pain intensity of the stimulus on a 0–100 NRS which 0 meant “no pain”, 50 was defined “moderate painful”, and 100 “the most pain imaginable”67. The COG coordinates (x = anterior–posterior direction and y = superior-inferior direction) were defined as: 68. Shannon entropy was also calculated to represent the complexity and diversity of patients’ mechanical sensitivity70.In order to investigate the mechanical sensitivity maps, the superficial part of the masseter muscle was divided into 3 × 5 grids Fig. a) while In order to ensure the baseline was comparable and minimize the impact of patient-related factors such as individual cognitive differences, the way and time of enrollment, the different stages and duration of the disease, all parameters except entropy values, which was presented as the absolute difference (Tn-T0) were otherwise expressed as relative changes from baseline (Day 1-pre) (TN/T0) and logarithmic transformed to normalize the data distribution. Then, the calculated absolute difference and relative change from baseline were used for data analysis. A mixed model analysis of variance (ANOVA) was used to assess the main effects of time (repeated factor), intervention (between group factor) and interactions between factors. A significance level of 5% was applied.All statistical work was performed using the Statistical Package for Social Sciences version 20 . The figures and tables presented in this study were produced by Prism 7.0 software.All procedures performed in studies were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Confirms that informed consent was obtained from all participants and/or their legal guardians. The study was approved by the Nanjing Medical University Research Ethics Committee (PJ2019-005-01), and registered on the WHO international clinical trial registry platform .Confirms informed consent was obtained to publish the information in an online open access publication.Supplementary Figure S1.Supplementary Figure S2a.Supplementary Figure S2b.Supplementary Figure S3.Supplementary Figure S4.Supplementary Figure S5.


Background: Opioids prescribed for the management of chronic noncancer pain are associated with nausea, vomiting, and constipation. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, has demonstrated robust efficacy and was well-tolerated in treating opioid-induced constipation without affecting central analgesia. Our objective was to assess changes in the frequency of treatment-emergent adverse events (TEAEs) after the first or second dose of methylnaltrexone or placebo.Methods: This post hoc analysis pooled data from two randomized, placebo-controlled clinical trials assessing methylnaltrexone for opioid-induced constipation in the outpatient setting. Patients received subcutaneous methylnaltrexone (12 mg once daily or 12 mg once every other day), oral methylnaltrexone , or placebo. TEAEs, opioid withdrawal symptoms, pain intensity, and rescue-free bowel movements (RFBMs) within 4 hours of the first dose  were assessed. Associations between TEAE frequencies and RFBM response were also evaluated.Results: The analysis included 1263 adult patients with chronic noncancer pain. TEAE rates declined from treatment day 1 to 2 . Among methylnaltrexone-treated patients, significantly greater proportions of RFBM responders versus nonresponders reported gastrointestinal TEAEs on day 1. No associations between RFBM response and the frequency of TEAEs were observed in the placebo group. No meaningful changes in opioid withdrawal symptoms or pain intensity were observed.Conclusions: Early-onset TEAEs following methylnaltrexone treatment, particularly gastrointestinal TEAEs, are at least partially due to laxation. Methylnaltrexone treatment effectively relieves opioid-induced constipation without affecting the central analgesic effects of opioids. Preventative measures and common constipation remedies, including lifestyle changes and over-the-counter or prescription laxatives, only provide limited relief from OIC.,,Opioids, despite their potential drawbacks, remain an analgesic mainstay for patients with a number of chronic refractory pain conditions, including appropriate patients with chronic noncancer pain. The use of opioids, even over the short-term, may be associated with gastrointestinal side effects, such as nausea, abdominal pain, vomiting, and constipation.®, Salix Pharmaceuticals, a division of Bausch Health US, LLC, Bridgewater, NJ) is a peripherally acting μ-opioid receptor antagonist that reverses opioid-induced effects in the gastrointestinal tract, such as delayed gastric emptying and prolonged oral-cecal transit time., Pain relief with opioid therapy, however, is maintained during methylnaltrexone treatment because the high polarity and low lipid solubility of the molecule inhibits its passage through the blood-brain barrier, thereby preserving centrally mediated opioid analgesia., Methylnaltrexone is available in subcutaneous and oral formulations, both of which are approved for the treatment of OIC in adults with chronic noncancer pain. Subcutaneous methylnaltrexone is also indicated for the treatment of OIC in patients with advanced illness or pain caused by active cancer.–Methylnaltrexone  within 4 hours of the first study drug dose, were also evaluated.In clinical trials, the majority of treatment-emergent adverse events (TEAEs) that occurred during methylnaltrexone treatment were gastrointestinal in nature .NCT00529087 ,NCT01186770 [Study dates September 1, 2010 – November 8, 2011). Study methodologies for both clinical trials have been previously published.,, Briefly, the studies enrolled adult patients who had chronic noncancer pain for at least two months and OIC for at least 30 days. The presence of OIC was confirmed during screening and defined as fewer than three RFBMs (no laxative use within 24 hours prior to the bowel movement) per week on average and one or more of the following symptoms: hard or lumpy stools, straining during bowel movements, or a sensation of incomplete evacuation after bowel movements. Patients were required to have been receiving an opioid for at least one month, with a daily dose of at least 50-mg oral morphine equivalents for 14 days prior to screening. Patients with a history of clinically significant bowel or rectal disease, chronic constipation, unstable hepatic, renal, pulmonary, cardiovascular, ophthalmologic, neurologic, psychiatric or any other medical condition that might compromise the study or put the patient at risk were excluded from the studies. Each study was approved by independent ethics committees at each participating institution and was conducted in accordance with the International Conference on Harmonisation Guideline for Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent.A post hoc analysis was performed using pooled data from two randomized, double-blind, placebo-controlled clinical trials that evaluated the efficacy and safety of subcutaneous or oral methylnaltrexone for the relief of OIC in patients with chronic, noncancer pain  was permitted if the patient had no bowel movements for three consecutive days. Rescue laxative use was limited to a single dose within a 24-hour period administered 4 hours or more after study drug administration.; three questions were added for the purpose of this study to more accurately reflect withdrawal symptoms in a study population with OIC. The three additional statements regarding symptoms included: I have had trouble sleeping; My appetite has been poor; and I have had diarrhea. Additionally, the original SOWS statement of “I feel like shooting up now” was modified to “I have felt like taking more pain medication”. For the OOWS, clinicians assigned patients a score of 0 or 1 based on the absence or presence of 13 symptoms indicative of opioid withdrawal, with a total possible score of 13. In addition to SOWS and OOWS total scores, each scale was also evaluated without inclusion of cramping as a symptom, because cramping may also be associated with constipation and the process of laxation and, therefore, may confound the assessment of opioid withdrawal symptoms. Evaluations of SOWS and OOWS were performed at 1 hour postdose on day 1 and at weeks 2 and 4 during the double-blind treatment phases of the studies. Maintenance of analgesia was assessed via a pain intensity score reflecting patients’ ratings of the intensity of their pain on a scale from 0 (no pain) to 10 (worst pain possible) at each study visit. Efficacy was measured by the proportion of patients demonstrating a laxation response to treatment, defined for the purpose of this analysis as an RFBM within 4 hours of first study drug dose.Safety and tolerability on treatment days 1 and 2 were evaluated by TEAE rates and severity. Opioid withdrawal symptoms were measured by the patient and by the clinician using the Subjective Opiate Withdrawal Scale (SOWS) and the Objective Opiate Withdrawal Scale (OOWS), respectively. For the SOWS, patients rated their perceived severity of 19 opioid withdrawal symptoms on a scale from 0  to 4 (extremely), with a total possible score of 76. The original SOWS scale has 16 questionsThe analysis population consisted of all randomized patients pooled from both included studies. Demographics and TEAEs were summarized using descriptive statistics. Between-group comparisons in RFBM responders were performed using chi-square tests. Associations between individual TEAEs and the occurrence of an RFBM within 4 hours of the first study drug dose were evaluated using Fisher’s exact test. Changes from baseline in SOWS and OOWS between groups were assessed by analysis of covariance, with treatment as the main effect and the baseline value as a covariate. Statistical calculations compared the all methylnaltrexone group versus placebo. All p-values reported for between-group comparisons used a nominal value of 0.05 to denote statistical significance. There were no corrections for multiplicity performed in these exploratory analyses. Statistical analyses were performed using SAS version 9.4 software.A total of 1263 patients who received at least one dose of study medication were included in the pooled analysis: 900 had been randomized to methylnaltrexone  and 363 had been randomized to placebo. Patients in the subcutaneous methylnaltrexone treatment group were evenly divided between those who received 12 mg once daily (n = 150) and 12 mg every other day (n = 148). Among those in the oral methylnaltrexone treatment group, 201, 202, and 200 patients were randomized to treatment with methylnaltrexone 150 mg, 300 mg, and 450 mg once daily, respectively. Among all patients, 88% completed the double-blind phase. The discontinuation rate ranged from 10.0% to 18.8% depending on the methylnaltrexone dose and route of administration. The most common reasons for discontinuation were TEAEs, patient request, and protocol violations. Patients who discontinued due to TEAEs most commonly reported gastrointestinal complaints, such as abdominal pain, nausea, and vomiting .P>0.05 for all methylnaltrexone vs placebo,Demographic and baseline characteristics were generally well balanced among treatment groups  . All TEAOn treatment day 2, the frequency of abdominal pain had decreased among patients treated with methylnaltrexone, whereas the frequency among patients who received placebo was unchanged. Among patients reporting abdominal pain on treatment day 2, pain severity was characterized as mild-moderate in most of the patients treated with methylnaltrexone  and in all of the patients who received placebo . Two methylnaltrexone-treated patients  reported severe abdominal pain on treatment day 2. Abdominal pain on treatment day 2 led to treatment discontinuation in 0.2% (n = 2) of methylnaltrexone-treated patients; none discontinued treatment in the placebo group due to abdominal pain on treatment day 2. Hyperhidrosis and nausea frequency also markedly decreased from day 1 to day 2 of treatment in methylnaltrexone-treated patients. The frequency of TEAEs reported after the second dose of methylnaltrexone treatment were comparable to or less than those reported after the second dose of placebo .P < 0.0001). In addition, more patients treated with subcutaneous versus oral methylnaltrexone were RFBM responders .The proportion of patients who experienced an RFBM within 4 hours after the first dose of study treatment  was significantly greater among all patients who received methylnaltrexone  compared with placebo , but was not statistically significant at weeks 2 or 4. Similar results were observed for SOWS total scores without cramping , but not at weeks 2 or 4. When cramping was omitted from the OOWS total score, the observed increases from baseline score in the methylnaltrexone treatment group lessened but remained significantly different from placebo at day 1 . The investigators also observed a relationship between abdominal pain and laxation response. In total, 80% of patients in the methylnaltrexone treatment group who experienced abdominal pain on study day 1 had an RFBM within 4 hours of the first study drug dose, whereas 47.2% of patients without abdominal pain on day 1 demonstrated an RFBM response. These data support the hypothesis that, in patients with OIC despite ongoing laxative use, the process of being rapidly induced to a bowel movement is initially accompanied by abdominal pain with the first dose, but once laxation has occurred, subsequent doses are generally not accompanied by such pain.A similar decrease in abdominal pain frequency from the first to second dose of methylnaltrexone was reported in a prior post hoc analysis using data from two randomized, placebo-controlled clinical trials of subcutaneous methylnaltrexone in patients with advanced illness whose laxative therapy response was insufficient (N=288). If the hypothesis that the frequencies of the observed gastrointestinal symptoms are partially due to OIC relief is correct, then a greater rate of RFBM response within 4 hours would naturally be linked to a greater frequency of early-onset gastrointestinal TEAEs consistent with laxation, such as abdominal pain and cramping. Second, the study of oral methylnaltrexone investigated three doses, the lower doses being one third (150 mg) and two thirds (300 mg) of the recommended methylnaltrexone dose (450 mg). As oral methylnaltrexone efficacy has been shown to be dose dependent, the inclusion of lower doses in this analysis may have influenced RFBM response and the frequency of any associated TEAEs. However, when the patients receiving the methylnaltrexone doses that are approved for OIC treatment  were analyzed separately, more patients who were responders than nonresponders reported having abdominal pain on day 1, indicating that treatment with the approved doses may have an effect on efficacy. In addition, when discontinuation rates were assessed for each dose and regimen, overall discontinuation rates and discontinuation rates due to TEAEs were consistent between the approved doses  and the other studied doses , further supporting the safety profile of the approved doses.In the current study, safety and efficacy assessments were generally comparable between the subcutaneous and oral methylnaltrexone formulations, although the frequency of TEAEs after the first dose of study drug and the decrease in TEAE rates from day 1 to treatment day 2 were greater among patients treated with subcutaneous methylnaltrexone. There are intrinsic and study-design related factors that could contribute to this observed difference between formulations. First, patients who received subcutaneous methylnaltrexone had a greater response rate  compared with patients who received oral methylnaltrexone. It has been postulated that the greater initial response rate is due to a faster onset of effect with the subcutaneous formulation, which, unlike the oral formulation, does not require time for absorption. Interestingly, the initial decrease from baseline in SOWS was greatest in the placebo group. The clinical significance of a decrease from baseline in SOWS score is not clear, as it insinuates that a patient had symptoms of opioid withdrawal prior to receiving methylnaltrexone that were lessened by treatment. As pain intensity scores were consistent throughout the 12-week study durations and compromised analgesia typically precedes symptoms of opioid withdrawal in patients with chronic pain,, the clinical significance of the SOWS and OOWS score changes observed in this study are even more questionable. Further studies evaluating and validating the use of the OOWS and SOWS in patients taking opioids for chronic nonmalignant pain without an opioid addiction are needed. However, data from this analysis affirm that neither subcutaneous nor oral methylnaltrexone negatively influences opioid-mediated analgesia. Lack of opioid withdrawal symptoms and maintenance of analgesia are consistent with methylnaltrexone’s pharmacologic profile and lack of effect on centrally mediated analgesia.,Pooled data from the two included clinical trials indicate that methylnaltrexone does not induce symptoms of opioid withdrawal. Scores for SOWS and OOWS showed slight changes after the initial study drug dose but returned to baseline levels by the subsequent assessment and were stable thereafter. Early changes in SOWS and OOWS scores could be partially attributable to changes in gastrointestinal TEAE frequency, as several items in both assessments address gastrointestinal symptoms. However, in the individual published studies, the total numbers of TEAEs did not vary appreciably among dose groups, thus any influence on the TEAE attrition assessment is likely to be minimal. The observation period of both studies was limited: opioid withdrawal symptoms were only reported during the 4-week, double-blind treatment period, and pain intensity over 12 weeks. Longer-term data regarding the impact of methylnaltrexone on these parameters is available from a 48-week, open-label study, in which no indications of opioid withdrawal, loss of opioid-mediated analgesia, or alteration in median morphine equivalent dose were observed during methylnaltrexone treatment.There are limitations that need to be considered when interpreting the findings from this analysis. The designs of the two studies were similar, but not identical, which adds potential confounding factors to the analysis. As mentioned above, the oral methylnaltrexone formulation needs time to be absorbed prior to producing any effects not required by the subcutaneous formulation, which could influence the timing of treatment effects. In addition, individual subcutaneous and oral dose groups were combined for the purposes of this analysis, and oral methylnaltrexone efficacy has been shown to be dose dependent.The attrition of TEAEs after the first dose of methylnaltrexone and the association between gastrointestinal TEAEs and laxation response support the hypothesis that early-onset TEAEs experienced with methylnaltrexone treatment, particularly gastrointestinal TEAEs, are at least partially due to laxation. Treatment with methylnaltrexone was additionally shown to relieve OIC without inducing withdrawal symptoms or compromising analgesia. For patients with chronic pain and OIC, methylnaltrexone offers a well-tolerated and effective treatment option for constipation relief.https://doi.org/10.25934/00007291.Vivli: Attrition of TEAEs: Post Hoc Pooled Analysis,Per the study sponsor’s policy, the datasets generated and/or analyzed for this study are not publicly available. Access to the data is provided to bona fide researchers subject upon submission of a research proposal and signing a Data Use Agreement. Interested researchers can request access to the data at the DOI by creating a free Vivli account and using the ‘Prepare to Request Vivli Study’ button on the ‘Administrative Details’ tab. In the title and several parts of the article (regarding Table 3 in particular), the authors use the term “treatment-emergent adverse events”, yet throughout most of the article they simply use “adverse events.” How was this distinction made?Few statistical analyses are presented in the paper. When describing the results of the Tables, the authors often use terms such as “generally well-balanced”, “comparable”, “modestly lower” and “slightly greater”. When describing discontinuation rates (Table 1), patient baseline characteristics (Table 2), and adverse events (Tables 3 and 4), it would be relevant to use statistical significance to characterize similarities and differences between groups.This post hoc analysis pools the results from two randomized, placebo-controlled clinical trials (n=1263) to examine the effect of subcutaneous or oral methylnaltrexone on adverse events in patients with opioid-induced constipation. All patients had chronic, non-cancer pain. The authors conclude that early-onset adverse events experienced in the methylnaltrexone group may be the result of laxation related to rescue-free bowel movements (RFBM).Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?PartlyIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:chronic pain managementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. There was no distinction in use of “treatment-emergent adverse events” and “adverse events”, this was more for ease of reading. We have revised all instances to “TEAE”. We have added more detail in the baseline demographics section that clarifies P>0.05 for methylnaltrexone vs placebo for all baseline parameters. We did not perform any other statistical analyses. Thank you for giving me the opportunity to review the manuscript. This post hoc analysis study used data from two RCTs evaluating methylnaltrexone for opioid-induced constipation. The study aimed to find an association (if any) between the methylnaltrexone induced adverse effects (AEs) and its clinical effect i.e. Rescue free bowel movements. The results of the study demonstrate a statistically significant association between the AEs and the intended clinical effect i.e. laxation.et al. and Nelson KKet al. who have evaluated the efficacy of methylnaltrexone for opioid-induced constipation. Rather than just citing package insert (reference number 16), it would be prudent to cite references like above when the authors mention the indications of Subcutaneous methylnaltrexone for opioid-induced constipation in advanced illnesses in the introduction part.   However, the authors missed citing key recent work done by Chamberlain BH Overall, a good article using a robust methodology for an outcome of clinical significance.Is the work clearly and accurately presented and does it cite the current literature?PartlyIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Cancer pain, palliative careI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. We have added these references to the introduction.


Spinal cord stimulation is emerging as a minimally invasive technique for treatment of persistent spinal pain syndrome (PSPS).We describe a case series of 25 individuals with PSPS who underwent implantation of a spinal cord stimulator device between 2017 and 2021.p < 0.001). There were twelve patients who consumed pre-operative opioid, and 75% showed reduction of use with a significantly lower average daily dose . There was a significant reduction in the Oswestry Disability Index during postoperative follow-up visits (p < 0.001). There were no major perioperative or long-term complications from the procedure in follow-up.There was a significant reduction in mean visual analog scale pain scores in the immediate postoperative phase,  and had meaningful improvement in quality of life and reduction in opioid consumption. Spinal cord stimulation (SCS) in treatment of chronic, intractable truncal, and axial pain has been conducted for over 50 years . ImproveMedical therapy remains the most common form of treatment for PSPS. However, outcomes with existing pharmacological treatments are poor, with only partial relief of pain in 40–60% of patients . In addiIn our study, we describe a retrospective case series of patients with type 1 PSPS and 2 with axial pain not associated to radicular pain or other pain syndromes like CRPS and persistent radicular pain post spinal surgery and treated with spinal cord stimulation, for which we reviewed postoperative outcomes including the use of prescription opioid analgesics, pain score, and disability score.A total of 25 patients had a trial of spinal cord implantation for axial neck and back pain in our institution between September 2017 and March 2021. The implant trial was conducted by the same senior neurosurgeon, under general anesthesia, and neuromonitoring. Since the coverage was under the universal health system, no further approval was needed before permanent implant once the trial was deemed successful, and to decrease surgical cost, permanent epidural leads were used. Leads were wrapped in subcutaneous pocket and an external connection to the external pulse generator was used. All incisions were closed and covered by a compressive dressing to minimize the risk of infection. Trials were deemed successful in case of an improvement in pain score by >50%. A decrease in pain medication consumption, in addition to improvement in daily activities and sleep, was also taken into consideration. Failure was not only defined by <50% improvement in pain score on VAS, but also by an increase or initiation of opioid consumption. Patient consent was obtained to complete a retrospective chart review. These patients were referred for persistent chronic neck and back pain lasting more than 6 months despite previous spinal surgical status and were refractory to conservative management and deemed ineligible for primary or revision spinal surgery by the specialized team.Potential candidates for SCS device implantation underwent a strict multidisciplinary evaluation including medical and psychological assessments. Our multidisciplinary team consisted of an anesthesia pain physician who works closely with a neuropsychologist, a physiotherapist, a pharmacist, and a pain clinic nurse. All the patients were referred by their family physician for persistent chronic pain lasting more than 6 months despite previous spinal surgical status and were refractory to conservative management and deemed ineligible for primary or revision spinal surgery by the specialized team. Candidates were reviewed on a case-by-case basis in a multidisciplinary meeting that included an anesthesiologist pain physician, a functional neurosurgeon, a neuropsychologist, a pharmacist, and a pain nurse coordinator. An initial assessment was conducted by the pain clinic nurse with detailed medical and surgical history. Pain was evaluated using VAS and ODI questionnaires. Prescription was reviewed by the pain clinic pharmacist. The patients were then evaluated clinically, and axial imaging including MRI and x-ray of the whole spine were reviewed. If they were deemed to be candidate for neuromodulation, a neuropsychological evaluation was conducted. The evaluation looked for depression, anxiety, catastrophizing, and patient expectation. It also helped to eliminate any major underlying psychological and cognitive disorders. Once all evaluations were completed, patients considered fit for neuromodulation therapy were evaluated by the neurosurgeon to assess their operability and to discuss in detail the surgical risks and consent. Age was restricted to patients younger than 80 years old, and contraindications included coagulation disorders, systemic infection, decreased cognitive function, major medical comorbidities that contraindicate surgical intervention , substance abuse disorder, psychological disorder , and inability to manipulate the programmer. Patients who were eligible were offered a 7-to-14 day-trial with an external pulse generator.® DTM, Medtronic®) after identification of good coverage of the painful area and initiation of comfortable level of stimulation. The patients also received education from the neuromodulation team on the programmer and how to navigate between programs.After discussion, clear consent was obtained, and the patients were admitted for implantation. All the cases were conducted under general anesthesia in an operating room under strict sterile condition with neuromonitoring and imaging. The implant procedure was performed by the same senior functional neurosurgeon, and percutaneous permanent leads were favored but surgical leads were used in some cases because of anatomical deformities and previous complex spine surgery history. Since a permanent implant was used, a connection to an external extension was performed to facilitate internalization procedure once the trial is deemed successful. The patients were observed post-surgery overnight in a neurosurgical ward and discharged home the morning after for 7–14 days trial. Before discharge, a programming session was performed and two different programs were set, a tonic and a high frequency program  at least 3 times daily, and occurrence of exacerbations was recorded. They also wrote down a diary of their pain medication consumption, daily activities, and sleep duration and quality. On trial days 3 and 6, a virtual follow-up was completed to decide among internalization, cessation, and a 1-week trial extension. The patients were discharged home on day one post epidural implantation because of the large area of coverage  by the single center covering two Atlantic provinces. Because of the distance and since trials are best evaluated in regular daily patient personal settings, virtual follow-up was adapted. This follow up lasted 15–30 min and conducted by the implanter and the neuromodulation nursing team where a review of the setting used was conducted, and all noted pain scores, activities, and medications were gathered.Patients who had a successful trial were assigned for the internalization procedure. The same company provider for the external pulse generator is chosen for internalization. The procedure was performed under local-assisted anesthesia. Removal of the external extension and pulse generator was conducted, and an internal pulse generator was implanted to the left lower back region at the level of the supero-posterior iliac crest. The successful program from the trial was copied and verified clinically with the patients before discharge. The patients were followed after 2 weeks for wound evaluation and general check-up and then after 3, 6, and 12 months for the first year and on a biennial frequency thereafter. An evaluation with the Oswestry Disability Index (ODI), on the impact of lower back pain was completed in both pre-operative stage and 6 months postoperative follow-up .t-test was conducted for paired pre- and postoperative comparisons.Data were collected by chart review including electronic and patient-reported records of prescriptions from clinical encounters. Opioid prescription data for all the trialed patients were converted to morphine equivalents per day (Meq/D) using standard conversion tables . The datA total of 25 patients who had a spinal cord stimulation trial for persistent axial pain and absent radicular pain despite previous spinal surgical status in our institution between September 2017 and July 2021 were included. Demographics for this group are found in Postoperative mean pain score on the visual analog scale (VAS) was significantly lower in patients with internalized devices at 6 months . Two patAll implanted patients with successful trials had office follow-ups for a minimum of 6 months postoperatively, with a median of 29.8 months of follow-ups (6–40.7 months). When assessed in follow-ups, the patients showed a significant reduction in mean ODI .There were 12 patients who required preoperative opioid analgesics. No patients who were previously opioid-naïve initiated opioid therapy by the 6-month follow-up. Patients assessed at 6-month follow-up had a statistically significant reduction in mean morphine equivalents per day . OverallThree patients developed battery failure where the generator reached its end of life and necessitated early revision. One patient died during the follow-up period because of other medical illnesses.There was no infection observed in the first 6 months despite doing a permanent lead trial. One patient underwent device removal despite major benefit from the stimulation because of development of pulse generator pocket infection 19 months after the initial implantation due to a non-related traumatic injury with wound dehiscence.The low risk of infection could be explained by the surgical closure of all wounds and compressive dressing. In addition, we consider the surgery as spinal clean-type with foreign body use, and prophylactic first generation cephalosporine is used 30 min before the procedure started and was continued for the first 24 h of patient hospitalization.We report a retrospective case series of 25 patients with intractable chronic axial pain without radicular pain treated with spinal cord stimulation. Despite a variable pain etiology, we note improved outcomes following the implantation of a spinal cord stimulator with minimal adverse events including improved patient-reported pain outcomes, reduction in post-surgical opioid consumption, and lack of emergency department visit for pain exacerbations.This has led us to evaluate the benefits of spinal cord stimulation for pain control, which are mostly centered on outcomes reported by the patients and are detected by reductions in their opioid consumption. The reduction in average opioid dose in our study was 37.9 Meq/D, consistent with a 59.4% reduction compared to preoperative doses and similar to previously reported ranges (42.4–64%) , 13. We In 2019, a systematic review concerning the use of neurostimulation devices for treatment of intractable chronic pain conditions affecting the spine/limbs found that, compared to medical therapy, spinal cord stimulation was significantly more likely to relieve pain particularly with newer technology . Some ofIn fact, we noted in our study that over their period of follow-up, which can be, in some cases, >3 years, the patients continued to show a positive impact on quality of life as evidenced by very high reduction in ODI scores.It is important to highlight that advantages of well-controlled pain not only include improvement in the quality of life but also other clinical benefits. In fact, patients who report poorly managed chronic pain may be at a significantly increased risk of cardiovascular diseases . MoreoveThere were 2 patients who failed the initial device trial, giving a failure rate of 8.3%. This is similar to the 7.3% of patients with chronic pain of the trunk or limbs who failed the initial trial period in a recent study . From a This was a retrospective case series with no control group for comparison, and we could not examine our outcomes to control for meaningful confounding factors. Our observations were limited by the small sample size of our cohort due to budget restriction by the universal healthcare system, and reduced number of cases in the last 2 years due to coronavirus-2019 (COVID-19) pandemic restrictions and inability to operate elective cases.Spinal cord stimulation (SCS) has been widely studied, and different indications have emerged over the years. Our review redemonstrates the effectiveness of spinal cord stimulation in treating pain in a varied group of patients with type 1 and type 2 PSPS. This supports the use of spinal cord stimulation as a useful opioid-sparing treatment for management of patients with PSPS during the opioid crisis era. It also shows the importance of pain control with opioid reduction in improving the overall QOL and possible return to work of young active patients previously disabled by their pain. This needs to be investigated more from a cost effective perspective in order to have the therapy more available for patients especially in the universal healthcare system.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.GM and JB prepared the manuscript. AS reviewed and edited. AE did senior editing and provided raw data from patient charts. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The coronavirus disease 2019 (COVID-19) pandemic imposes an unprecedented lifestyle, dominated by social isolation. In this frame, the population to pay the highest price is represented by demented patients. This group faces the highest risk of mortality, in case of severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection, and they experience rapid cognitive deterioration, due to lockdown measures that prevent their disease monitoring. This complex landscape mirrors an enhancement of neuropsychiatric symptoms (NPSs), with agitation, delirium and reduced motor performances, particularly in non-communicative patients. Due to the consistent link between agitation and pain in these patients, the use of antipsychotics, increasing the risk of death during COVID-19, can be avoided or reduced through an adequate pain treatment. The most suitable pain assessment scale, also feasible for e-health implementation, is the Mobilization-Observation-Behaviour-Intensity-Dementia (MOBID-2) pain scale, currently under validation in the Italian real-world context. Here, we report the case of an 85-year-old woman suffering from mild cognitive impairment, subjected to off-label treatment with atypical antipsychotics, in the context of undertreated pain, who died during the pandemic from an extensive brain hemorrhage. This underscores the need for appropriate assessment and treatment of pain in demented patients. The outbreak of coronavirus disease 2019 (COVID-19) imposes novel life rules, dominated by quarantine, social distancing (up to lockdown) and the use of personal protective equipment. The distance and the assistance by mask-wearing, seemingly faceless caregivers, worsen the cognitive and behavioral consciousness and, consequently, affect the most fragile population, i.e., the uncommunicative elderly, suffering from moderate to severe dementia. Currently, some 55 million people suffer from dementia, with 75% demented people some 41 million) being undiagnosed . In fact1 millionsequelae and dementia. In fact, SARS-CoV-2 receptor angiotensin-converting enzyme-2 (ACE-2) is expressed by neuronal and glial cells [The COVID-19 pandemic raises the most serious consequences in the fragile population of the elderly, finding them often affected by cognitive impairment from dementia, named Alzheimer‘s disease, and related dementias (ADRD) . The latal cells . Using 1al cells . The nucal cells ,33, is ial cells ,34. Thisal cells . Furtheral cells , that real cells ,38,39. Tal cells . Moreoveal cells .The evidence that patients suffering from dementia develop an aberrant transmission and modulation of pain , togetheHere, we present the case of an 85-year-old woman, with mild cognitive impairment, who died during the pandemic, due to the lack of accurate pain management in the real-world setting of a Southern Italian health district. The neurologic visit led to the prescription of sertraline and haloperidol, the latter administered during acute attacks. After a fall, causing persistent leg joint pain, the patient was sent for geriatrician evaluation, for worsened cognitive dysfunction and unmanageable agitation. The pain assessment and treatment was delayed because of the health emergency and the agitation was considered so severe as to require institutionalization and off-label treatment with the antipsychotic, quetiapine. Within the first ten days after admittance to the nursing home, the mild cognitive impairment progressed into uncommunicative, rapid cognitive decline, accompanied by intractable agitation and delirium, leading to high dosage benzodiazepines that contributed to exacerbating the confusion. One week later, the patient was not able to recognize her relatives and died from an extensive brain hemorrhage. In fact, she was moved to the emergency room of the referred hospital for suspected stroke, but imaging analysis proved it was a brain hemorrhage that led to her death the following day in the hospital. The patient presented good hematochemistry parameters and she had no other cardiovascular risk factors, apart from treatment with antidepressants, previously. The patient had suffered a previous stroke, earlier than ten years and presented senile atrophy, demonstrated by neuroimaging. Unfortunately, this case confirms that delirium may be associated with an increased risk of hospitalization and mortality . ParticuPain assessment is fundamental to improve the quality of life of patients suffering from dementia and to decrease their mortality risk during the pandemic. One of the barriers most difficult to overcome in dementia is represented by the loss of communication skills that these patients experience, preventing them from pain self-report. Furthermore, the social isolation contributes to the worsening of cognitive impairment, and the delaying of non-urgent medical examinations causes the neglection of the assessment, monitoring and treatment of dementia  and consIn the initial phases, Italy was overwhelmed by the pandemic, with 11.9% of deceased COVID-19 positive patients affected by dementia , afflictThe tight link between COVID-19 and dementia highlights the need for greater attention to pain assessment and treatment during the pandemic. Dementia can be exacerbated by acute respiratory distress syndrome, the neurological sequelae of the infection and, also, the social isolation measures to prevent contagion. In particular, the highest mortality for COVID-19 is registered among patients suffering from dementia that are often diagnosed with the infection because of a worsening of agitation, one of the most challenging behavioural and psychological symptoms of dementia (BPSD), and the occurrence of delirium. Agitation is often a form of help-seeking for underdiagnosed and, consequently, unrelieved pain, in non-communicative demented patients. The assessment and management of chronic pain, often experienced by patients affected by dementia due to age-related comorbidities, is made even more difficult during the pandemic because of lockdowns and delayed specialistic examinations. This complex scenario leads to an increased rate of inappropriate prescriptions of antipsychotics to manage agitation due to undertreated pain, doubling the risk of death from stroke, which can be a complication of COVID-19, in the fragile population of demented patients. Therefore, it is fundamental to avoid the unnecessary and harmful use of antipsychotics and antidepressants; on the other hand, the novel rapid-acting antidepressants are worthy of investigation . This pa


Background and Objectives: Periodontal surgery requires local anesthetic coverage to alleviate patient discomfort. Needles and injections can engender feelings of fear and anxiety in individuals. This study aimed to assess the level of comfort and anxiety in patients during the administration of local anesthesia using needleless jet anesthesia (JA) when compared to a conventional syringe (CS) in periodontal surgery. Method and Materials: 60 sites were designated for injection in a split-mouth design in 30 subjects who required periodontal surgery. Local anesthesia was administered in two appointments scheduled one week apart using either a JA system or a CS. The Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), and Beck’s anxiety inventory were used to report the pain and anxiety levels while injecting local anesthesia. Statistical analysis of the results was performed using the Shapiro–Wilks test and Paired t-test. Results: Patients reported greater comfort with JA. The VAS and VRS values were statistically significant—(p = 0.003) and (p = 0.001), respectively. Patients showed fear and were nervous about receiving a local anesthetic using a CS. A few subjects experienced lingering pain with the CS, whereas greater comfort and no lingering soreness were reported post-operatively at the site of JA administration. Conclusions: This study provides the first comprehensive assessment of using JA for periodontal surgical procedures. Lower pain scores were consistently observed with the use of jet injectors. Patients were at ease and reported lesser anxiety and greater comfort with jet injectors, making it ideally suited for providing local anesthesia in periodontal surgery. Periodontal diseases are a range of inflammatory diseases caused due to bacterial buildup . If leftFrom the patient’s perspective, injection of local anesthetics with a conventional needle syringe is unpleasant and is the source of fear and anxiety. Injections are a crucial factor for premature termination or delay of treatment. There is a documented link between anxiety and fear of pain, as well as the actual feeling of pain. Anxiety and dread leads to stress, which lowers a patient’s pain threshold . NeedlesLiterature reveals several approaches to reduce the uncomfortable sensation during local anesthesia such as administering topical anesthetics before injection , employiNeedle-free jet injections are an easy, painless mode of anesthetic delivery . Their dPrevious studies compared the needleless jet technique to other anesthetic techniques in nonsurgical periodontal treatments revealed that the jet technique has superior efficacy . The neeThe present study was designed as a randomized split-mouth clinical trial aimed to compare and evaluate the level of comfort and anxiety in patients during the administration of local anesthesia using needleless jet anesthesia (JA) when compared to a conventional syringe (CS) in periodontal surgery. The null hypothesis of the study was that the patients’ pain experience was similar in both techniques. The alternate hypothesis was that patients experienced lesser pain in the needleless jet anesthesia technique when compared to the conventional syringe technique.This study was approved by the Institutional review board of Meenakshi Ammal Dental College, Chennai-600095 (MADC/IRB-XXXIII/2020/552), India. The study was conducted following the Helsinki declaration and registered with the clinical trial registration (CTRI/2020/10/028527). The 2010 CONSORT guidelines were followed for this RCT. Written informed consent was obtained from all participants in this study.Patient population: 30 subjects with bilateral periodontal disease or mucogingival deformities who required periodontal surgery were registered after obtaining informed consent. 60 sites were designated for injection.Study design: A single-blinded, randomized control trial with a split-mouth design was used, and the treatment quadrants for each patient were assigned at random using a coin toss procedure.Test site (Group A): 30 sites with periodontal disease or mucogingival deformities which required periodontal surgery were administered with local anesthesia using JA (0.5 mL).Control site (Group B): 30 sites with periodontal disease or mucogingival deformities which required periodontal surgery were administered with local anesthesia using a CS (2 mL).Sample size calculation and power of the study: In this investigation, α was set to 0.05, with a maximum of 52 sites accepting 5% and a study power of 95%. To show a meaningful difference in the primary outcome of this RCT, a sample size of 60 sites in thirty patients in each group was required.Participants are in the age group of 18 to 50 years;Systemically healthy male/female patients;Subjects requiring bi-lateral periodontal surgery.Inclusion criteria:Participants who are allergic to local amide anesthetics;Pregnant and lactating women;Alcoholics and smokers;Patients who used analgesics or medication acting on the central nervous system.Exclusion criteria:Procedure:Patients with bilateral surgical intervention (I/IV quadrant and II/III quadrant) in a split-mouth design were scheduled for two appointments one week apart. In the first appointment, a jet injection was administered at the test site . The locPatients were recalled after one week for the second appointment for treatment at the control site. The control site was injected with local anesthesia using the CS. The CS was loaded with a 2 mL local anesthetic agent  and injected using the buccal infiltration technique.A questionnaire was handed over before and after the local anesthetic injections and experiences both at the test site and the control site. Visual Analogue Scale (VAS) and Verbal Rating Scale (VRS) were used for pain assessment at each appointment. VAS used a 100-mm scale was used to assess pain. The left endpoint was labeled “no pain” while the right endpoint was labeled “worst suffering imaginable . VRS is Beck Anxiety Inventory:The Beck’s anxiety scale is a self-reporting 21-questionnaire format . The patThe statistical analysis was performed using SPSS  software. A parametric test (Shapiro–Wilks test) was used to compare data between groups and non-parametric tests (paired t-test) were used to analyze the Visual Analogue Scale (VAS), Verbal Rating Scale (VRS), and Beck’s anxiety scale values, respectively. The significance level was fixed as 5% (α = 0.05).p = 0.003).The Visual Analogue Scale (VAS) scale for pain was recorded from 0 (no pain) to 100 (extreme pain). The values were lesser for the JA group reported lower scores for pain (52.066 ± 13.617) compared to the CS group. The JA scores depicted mild discomfort. The results were statistically significant (p = 0.001).The Verbal Rating Scale (VRS) scale for pain was lower in the JA group compared to the CS group. Patients reported moderate pain in the JA group, which was lesser than with the CS, which was highly significant (p = 0.003). A verbal rating score of 4 was found for CS compared to JA which had a score of 2. This indicates the patient’s feeling of extreme pain with CS. Both the VAS and the VRS values indicate that the discomfort felt by the JA group was lower than that experienced by the CS group. The higher scores in the CS groups indicate greater discomfort and are statistically significant (p = 0.007), nervous (p = 0.018), and scared (p = 0.002) of CS injection compared to JA. The results were statistically significant. Patients were terrified, or afraid, nervous, and scared of the CS technique far more than the JA. The anxiety scale values revealed that patients were terrified  application over JA as the application of EMLA was less traumatic and had desired anesthetic properties. Patients appear wary of jet anesthetic because of its bulky appearance .Konstantinos Nikolaos et al. compared children’s acceptance and preference between the jet injector and conventional injection technique. Counterintuitively, most children (73.6%) preferred the traditional method to the needleless jet injector . This maTissue toxicity is not a concern when local anesthetics are placed topically on mucous membranes due to the relatively short application duration, fast absorption into the circulation, and strong regenerating capability of the oral mucosa. With every shot of the jet injector, the anesthetic solution is delivered at a depth of 2 to 2.5 mm below the epithelium, and one-tenth of an ml solution is deposited. With the velocity and distance of penetration, the periodontal apparatus  was anesthetized making it hassle-free to perform periodontal surgeries.All forms of periodontal therapy—scaling and root planing, periodontal flap treatment, frenectomy, vestibuloplasty, and root coverage procedures—were carried out using the needleless jet and conventional injection technique. Many of the participants who had a fear of dental treatment requiring administration of local anesthesia with needle and syringe reported that the needleless jet anesthetic technique was more comfortable and would opt for the same for future treatments. Subjects were assessed with Beck’s anxiety inventory and reported that they were more comfortable and felt less terrified of the needleless jet injector.There are a few limitations to JA when compared to the CS. The gun-like shot sound from the JA might exacerbate the anxious patients who are already uncomfortable and afraid at the prospect of an injection. The sound is caused by the recoil spring-like action as the solution is deposited at high pressure. The device might be bulky to hold and operate even though it can be carried around handily. The size and appearance of a JA injector are larger compared to the CS. The sight of a large injector could be apprehensive to patients and alarm them, expanding feelings of dread.Despite these shortcomings, they can be valuable in patients who have needle phobia. With sufficient explanation and counseling to acclimatize the patient, jet injectors could be used widely to treat anxious patients. It eliminates the hassle of sharp needle disposal and accidental punctures in the dental clinic. Unlike other needle-free techniques such as sprays, pills, patches, etc., jet injectors can be used with existing drug preparations and commercially available compositions which are designed for conventional needle-based injections. This brings down the inventory requirements and is cost-saving. The cartridges are sterilized using a disinfecting agent and the CAP is discarded after every use. Jet injectors can serve in various surgical procedures such as periodontal flap therapy, periodontal esthetic procedures, extraction, and root canal treatment. They can be used to deliver various dosages based on the procedure and the intensity of anesthesia required. They are also user-friendly. Jet injectors do not require any specialized training to handle the instrument professionally.This paper is the first comprehensive assessment of the feasibility of using JA for periodontal surgery. The jet injection technique was widely accepted by patients due to the reduced pain on injection and they were less anxious and afraid of receiving an anesthetic injection with the jet injector. Further studies are required to assess the latency time. Clinically, JA provides reliable durable local anesthetic coverage with fewer complications. It is user-friendly, cost-effective with a short learning curve for the professional, and is suited for numerous procedures. In summary, based on our findings, we conclude that needleless jet anesthesia offers superior comfort and acceptance to a conventional syringe.


In several previous studies, Charlson comorbidity index (CCI) score was associated with postoperative complications, mortality, and re-admission. There are few reports about the influence of CCI score on postoperative clinical outcome. The purpose of this study was to investigate the influence of comorbidities as calculated with CCI on postoperative clinical outcomes after PLIF.Three hundred sixty-six patients who underwent an elective primary single-level PLIF were included. Postoperative clinical outcome was evaluated with the Japanese Orthopaedic Association lumbar score (JOA score). The correlation coefficient between the CCI score and postoperative improvement in JOA score was investigated. Patients were divided into three groups according to their CCI score . JOA improvement rate, length of stay (LOS), and direct cost were compared between each group. Postoperative complications were also investigated.r = − 0.20). LOS and direct cost had almost no correlation with CCI score. The JOA improvement rate of group 0 and group 1 was significantly higher than group 2+. LOS and direct cost were also significantly different between group 0 and group 2+. There were 14 postoperative complications. Adverse postoperative complications were equivalently distributed in each group, and not associated with the number of comorbidities.There was a weak negative relationship between CCI score and JOA improvement rate (A higher CCI score leads to a poor postoperative outcome. The recovery rate of patients with two or more comorbidities was significantly higher than in patients without comorbidities. However, the CCI score did not influence LOS and increased direct costs. The surgeon must take into consideration the patient’s comorbidities when planning a surgical intervention in order to achieve a good clinical outcome. Medical technology and spine surgery techniques have progressed rapidly, benefitting patients suffering from spinal disease. The indications for spine surgery have broadened to include the elderly and patients with several medical comorbidities. It is very important to assess the patient’s preoperative general condition and comorbidities to assess surgical safety before making a surgical decision. Campbell et al.  reportedThe Charlson comorbidity index (CCI), first reported in 1987, is a useful method for evaluating medical comorbidities . It is aSeveral reports about CCI and orthopedic spine surgery have been published. Voskuijl et al.  reportedPosterior lumbar interbody fusion (PLIF) is a well-known and common surgical procedure for degenerative lumbar disease. Surgical interbody fusion of the degenerative lumbar spine can improve the patient’s low back or lower leg pain and disability. Evidence supporting good clinical outcomes after PLIF has already been reported –11.Several reports have previously identified a relationship between CCI and spine surgery , 6–8. HoThe aim of this study is to determine if the CCI is a predictor of postoperative outcome after PLIF. In addition, this study seeks to investigate correlations between CCI, operative time, intraoperative blood loss, length of stay (LOS), and direct cost of admission. The idea of this study is based translational orthopedics filling the gap between internal medicine and orthopaedic surgery as same as basic science and clinical science , 13. ThiThis is a clinical retrospective study performed at one institution. Patients who underwent PLIF from 2014 to 2018 were analyzed. Inclusion criteria were all elective single-level primary surgeries. Multilevel surgeries, additional or revision surgeries, and unplanned surgeries were excluded. PLIFs were performed using cages filled with autologous bone from the lamina, spinous process, and facet joints. Posterior instrumentation with pedicle screws was performed in all cases. Drains were removed on postoperative day 3 in all patients. All patients were required to wear a lumbar corset for three months after surgery. All patients were followed as out-patients for at least 1 year.The medical record of these patients was reviewed and information on CCI score, operative time, intraoperative blood loss, Japanese Orthopaedic Association (JOA) lumbar score with a maximum point of 29, JOA improvement rate, postoperative complications, LOS, and direct cost were collected. CCI score was calculated using medical history as reported by the patient, cited in the medical record, or detected during the medical examination. CCI score was divided into three groups for analysis , reflecting the criteria from previous reports . The JOAJOA scores were evaluated based on previous work by Hioki et al. . JOA scoThe correlation coefficient between CCI score and JOA improvement rate was measured. Additionally, the correlation coefficient between CCI score and LOS or direct cost was also calculated.P values less than 0.05 were considered significant.Collected data was analyzed using Excel  and SPSS for Windows Version 25 . Several statistical tests  were used to calculate a correlation coefficient and significant differences. The institutional review board approved this clinical retrospective study .n = 137), group 1 (n = 101), and group 2+ (n = 128). The mean age of all patients was 69 years old. There were 158 males and 208 females. The average follow-up period was 24 months. The mean CCI was 1.3 and diabetes mellitus was the most common comorbidity  . A significant difference was also seen between group 1 and group 2+ (P = 0.009)  Fig. . However09) Fig. .Fig. 1IAs medical technology including medication, equipment and educational programs progresses, surgery will be indicated for a broader patient subset. Elderly patients often have several comorbidities, and younger patients often have cardiovascular disease, have previously undergone surgery, or have renal disease that requires hemodialysis. For these reasons, identifying the preoperative risk factor is important and essential to not only spine surgery but to all surgeries in general. The stratification of comorbidities is helpful for comprehensively understanding the patient’s general condition.Degenerative lumbar disease including spondylolisthesis and lumbar spinal canal stenosis is a common and well-known pathology. It presents with symptoms that can include low back pain, leg pain, and neurologic deficits that affect daily life. Conservative therapy is usually the first choice for initial management, but if unsuccessful surgical intervention is considered. PLIF is a common general procedure for degenerative lumbar disease. The clinical outcome of PLIFs is widely recognized to be satisfactory –11. Liu The impact of comorbidities on spine surgery has been reported, but most prior studies described readmission, mortality, and complications , 16, 17.A few reports have been published about the relationship between comorbidities and clinical outcome . Yagi etIn this study, the clinical outcome of all patients was evaluated using the JOA score. Clinical outcomes were calculated fairly. We also directly compared these scores with CCI.There was a weak negative correlation between the JOA improvement rate and CCI in this study. Although we could not identify CCI as a predictor of a poor clinical outcome, this study can identify the negative influence of comorbidities on postoperative clinical outcomes after PLIF. Optimal treatment and control of a comorbidity are necessary before surgery and would be more likely to lead to a satisfactory outcome.Postoperative rehabilitation is essential to a good clinical and functional outcome. The small frequency or lack of postoperative rehabilitation due to several comorbidities might be related to poor clinical outcomes. In fact, a report in the field of ischemic strokes concluded that a higher modified CCI for stroke score was an independent predictor of poor rehabilitation success, and the authors noted the importance of comorbidities when planning rehabilitation . This coEvery correlation coefficient between CCI score and operative time, intraoperative blood loss, LOS, and direct cost was very weak. However, a higher CCI score (group 2+) was associated with a significantly longer OR time and a more expensive cost of treatment than those in group 0. In contrast to the present work, previous research studies concluded that a greater comorbidity burden as reflected by a higher CCI did not lead to a prolonged hospital stay or an increased direct cost . The difThe findings of the present study are useful and beneficial not only for spine surgeon but for patients as well. These results help surgeons to indicate a patient for surgical intervention using a PLIF, and to obtain informed consent from the patients before surgery. Preoperative comorbidities and expected clinical outcomes must be discussed with patients because they can recognize and understand their own status. Furthermore, this information helps them to decide whether they will undergo spinal surgery at all based on if it can render a satisfactory outcome.This study has several limitations. First, its sample size is small because it is a single-center study.A larger patient sample may achieve a more robust correlation between CCI and postoperative clinical outcome. Secondary, this study did not take into consideration the age of the patients. Several prior works added a 0–4 weighted score depending on the age to the original CCI score , 17. PatThis is the first effort to evaluate the relationship between CCI and clinical outcomes after PLIF, which is a common, well-known, and widely utilized procedure. The collected data from this study demonstrates several findings. CCI score was weakly correlated with clinical outcomes. The recovery rate of patients with two or more comorbidities was significantly longer than patients without a comorbidity. The development of calculation tools for comorbidity that include age and surgical measurement should contribute to predict postoperative outcome, and the surgeon must take the patient’s comorbidity status into consideration when planning a surgical intervention in order to achieve a good clinical outcome.