Pain is a frequent symptom of head and neck cancer (HNC) but longitudinal studies investigating facial pain are scarce. We aimed to investigate prevalence of facial pain, its effect on health-related quality of life (HRQL) and trismus-related symptoms in a HNC cohort.n = 194) were prospectively followed post completion of radiotherapy (RT). Outcome measures included facial pain, HRQL, trismus-specific symptoms, and maximal interincisal opening (MIO).Patients (Facial pain was reported by 50% at baseline. Corresponding figures for 3-, 12-, and 60 months post-RT were 70%, 54% and 41%. Moderate to severe pain was reported in 29–44% of patients reporting pain during the study period. Patients reporting pain scored significantly worse on more HRQL variables and trismus symptoms, as well as had significantly smaller MIO at all follow-up time points.Facial pain was common in HNC patients pre- and post-RT and remained prevalent up to 5 years after completion of RT. Reductions in MIO were associated with more facial pain. Pain was also associated with worse HRQL. Head and neck cancer (HNC) is the fifth fastest increasing cancer type in Sweden Pain is a common symptom among HNC patients, either due to the cancer itself or as a result of acute or late adverse effects of treatment Few studies have to date described radiation-induced trismus and its association to pain longitudinally. The longest thus far is by this research group, for up to 3 years after completion of radiotherapy in a cohort half the size of the current study As the prognosis of HNC is improving with modern oncological treatments and a large subgroup of HNC are expected to live many years after their cancer treatment, research focusing on mapping pain and improving HRQL after HNC treatment is warranted. Hence, the aim of this prospective observational study is to investigate the prevalence of facial pain, as well as its effect on HRQL and trismus-specific symptoms in patients with HNC for 5 years post-RT. A secondary aim includes investigating the correlation between facial pain and the degree of maximal interincisal opening.Participants were recruited from the weekly multidisciplinary tumor board meeting at Sahlgrenska University Hospital in Gothenburg, Sweden between 2007 and 2012. Patients with newly diagnosed HNC that fulfilled the inclusion criteria were consecutively invited for study participation. Inclusion criteria included age ≥ 18 years, planned for primary radiotherapy with curative intent and tumor site in oral cavity, oropharynx, nasopharynx or cervical carcinoma of unknown primary (CCUP). Since the cohort was going to be used for multiple studies regarding postradiation trismus, additional exclusion criteria were applied, i.e., the presence of trismus prior to treatment and a tumor site where one would not normally expect trismus as a complication . Patients were also excluded if they had recurrent disease, surgical treatment only, insufficient Swedish language skills and performance status or mental capacity too poor to partake in examinations or respond to questionnaires. Patients were followed prior to radiotherapy (baseline), 3 months, 12 months, and 60 months post-radiotherapy completion.n = 121), mainly those with advanced tumor stages, also received induction (cisplatin and 5-fluorouracil) or concomitant (weekly cisplatin) chemotherapy according to regional guidelines at the time. For oropharyngeal and nasopharyngeal cancers, non-surgical oncological treatment regimens were used.Traditional external radiotherapy with curative intent was given according to regional guidelines. Between the years 2007 and 2009, accelerated hyperfractionated radiotherapy was administered to patients , consisting of 1.7 Gray (Gy) doses given twice daily, 5 days/week . During the time period 2010–2012 however, the other half of patients received accelerated fractioning 1–2 times daily in 2–2.4 Gy fractions, 5 days/week . Sixty-two percent (Advanced stage (III–IV) oral tumors were typically also treated with surgical excision, including neck dissections. In cases where the tumor was assessed to be unresectable, chemoradiotherapy was administered instead. Other tumor sites where surgical removal was performed including neck dissections were salivary gland cancers and sinonasal cancers. In selected CCUP cases, neck dissection was performed prior to non-surgical oncological treatment.Adult Comorbidity Evaluation 27 (ACE-27) was recorded at baseline. The ACE-27 is a validated comorbidity instrument widely used in head and neck oncology. It includes the assessment of 27 elements from twelve organ systems. Based on the amount and severity of comorbidities, it provides an overall comorbidity score of 0–3, where 3 indicates maximum severity MIO was measured in millimeters with a ruler and registered at each time point. A maximal interincisal distance of ≤ 35 mm as proposed by Dijkstra et al. The EORTC QLQ-C30 was developed for assessing the quality of life of cancer patients. It is comprised of multi-item scales as well as single items, including five functional scales, three symptom scales, a scale regarding global health and quality of life and six single items An additional Head and Neck disease specific module, the EORTC QLQ-HN35 was also utilized. The EORTC QLQ-HN35 consists of seven multi-item scales assessing pain, swallowing, senses, speech, social eating, social contact and sexuality in addition to 11 single items For the EORTC questionnaires, a 4-point Likert scale was used, and scores are then transformed to a scale from 0 to 100, where high points correspond to high function on the functioning scales and Global HRQL, whilst high points correspond to a higher symptom burden on the symptom scales and items The GTQ is a validated trismus-specific questionnaire, developed to be used as a complement to the objective measure MIO and was registered at all study time points. It is composed of 21 items in total, where 13 items are incorporated into the domains jaw-related problems (7 items), eating limitations (4 items), muscular tension (2 items) and the remaining single 8 items assess facial pain, pain associated with trismus, trismus affecting work, leisure or social life. In the GTQ, eight items in total are directly related to facial pain. Score ranges from 0 to 100, where a high score indicates a high symptom burden The primary variable “Intensity of facial pain during the last month” was reported on a 7-point Likert scale where 1 point equals no facial pain and 7 points equates to unbearable pain. Furthermore, 2–3 points are considered mild pain, 4 points moderate pain and 5–6 points severe pain. The GTQ has been previously described in detail U-test for continuous variables, Mantel–Haenszel Chi Square test for ordered categorical variables, and Chi Square test for non-ordered categorical variables. Wilcoxon signed rank test was used for continuous variables within groups over time. Spearman’s correlation test was used to analyze the correlation between the degree of pain and MIO. Cohens’ convention was used for interpretation of correlations. A correlation coefficient of 0.10 represents a weak or small association, 0.30 is considered a moderate correlation and 0.50 or larger represents a strong or large correlation The GTQ variable “Intensity of facial pain during the last month” was dichotomized with the purpose of distinguishing those that had some degree of facial pain from completely pain-free patients. Standard procedures were used to calculate descriptive statistics with 95% confidence interval. The SAS version 9.4 for PC was used for analyses. For comparisons between groups, Fisher’s Exact test was used for dichotomous variables, Mann–Whitney This prospective study was conducted in accordance with the Declaration of Helsinki and was approved by the Regional Ethic Review Board in Gothenburg, Sweden. All participants gave their written informed consent before study inclusion.n = 194) was 61 years. The subjects were predominantly male (74%), currently non-smokers (77%), and the most common primary site of tumor was oropharyngeal (63%). In total, 70% of subjects presented with advanced stage disease and 61% received combination treatment with RT and chemotherapy. When comparing the groups at baseline, twice as many women were seen in the “Pain”-group than in the “No pain”-group . Furthermore, at baseline there were more smokers in the” Pain”-group (32% versus 14%). This difference was statistically significant (p =  < 0.01) and similar results regarding smoking was seen at the 12-month follow-up time point (p =  < 0.001). Regarding differences in BMI, a statistically significant difference (p =  < 0.01) was seen between the “No Pain” and “Pain” groups only at the 5-year follow-up where the “Pain”-group had higher BMI scores.Demographic data and treatment characteristics of the patient cohort stratified by reporting “No pain” versus “Pain” during the last month at each time point are described in Table A tumor site of oral cavity was also more common in the “Pain”-group than in “No Pain”-group at baseline (27% versus 6%).n = 97) reported facial pain during the last month at baseline (Table p ≤ 0.001).Half of the cohort   and moderate at the 5-year follow-up (r = 0.48).MIO was significantly lower in the pain group at all four time points Fig.  comparedThis longitudinal observational cohort study describes pain and HRQL in 194 patients with HNC at multiple time points after completion of radiotherapy with curative intent and is to our knowledge the longest prospective study to date examining the association between facial pain and restricted mouth opening in this setting.Study results show that a large proportion of treated HNC patients still suffer from facial pain long-term. Approximately 50% of the study population reported some degree of facial pain at baseline before starting oncologic treatment, which then increased to 70% at 3 months post treatment completion. This decreased to 54% at 12 months post-RT completion and finally dropped to 41% at 5 years post-RT. These results are similar to previous findings from other studies. In a cross-sectional study by Ren et al. According to the results from the EORTC QLQ-C30 and HN35 in our study, the pain group also reported worse HRQL on most scales and items in both questionnaires. Hence, a clear association was seen between reports of presence of facial pain and negatively affected HRQL. The majority of other post treatment studies regarding HNC, pain and quality of life include pain in assessment of more broadly evaluated quality of life as also noted in the mentioned systematic review by Epstein et al. Fatigue (EORTC QLQ-C30), Senses and Social eating (EORTC QLQ-HN35) at 12 months post-RT compared to 5 years post-RT in the group reporting pain. A similar pattern was observed for the EORTC QLQ-HN35 single item Dry mouth, again potentially hinting at consequences of acute treatment toxicity.Furthermore, patients who scored higher (worse) regarding pain, also appear to have a decreased MIO. Albeit this correlation was weak during the first year post-RT, a moderate correlation was shown towards the end of the study period. A possible explanation for this change in degree of correlation strength may be that acute treatment toxicities which are not directly linked to mouth opening, including oral mucositis, cause pain and discomfort during the first time-period post-RT n = 50) and were compared to a matched control group who did not undergo the structured jaw exercise program (n = 50). Fifty-nine percent of the subjects reported facial pain before oncologic treatment and more than half (51%) of the HNC survivors with trismus reported facial pain at three years post treatment completion. The patients with HNC in the Andréll study all had post-RT trismus. The higher prevalence of pain in that study population indicates that there is an important relationship between a lower MIO among HNC survivors and the risk of reporting pain. Another important finding in the Andréll study that underlines the relationship between facial pain and trismus was that the patients undergoing the structured jaw exercise program had 9 times higher chance of being pain-free at 3 years following treatment. Nonetheless, there are numerous other potential causes of head and neck pain after oncologic treatment for HNC, including osteradionecrosis, lymphedema, burning mouth syndrome and neurological damage Albeit caution should be advised when drawing conclusions regarding the causative effects of a multifactorial phenomenon such as the perception of pain, our results may point to the possibility of trismus causing pain or vice versa. In an interventional, matched control study by Andréll et al. The strength of this study lies in its prospective design with a long follow-up period of 60 months. Furthermore, the objective measurement of MIO, the use of validated, well used patient reported outcome measures and the size of the cohort also contribute to its strength. The study may be limited by the fact that the patients who dropped out of the study had somewhat worse overall health at baseline. Recurrent HNC is an important cause of local pain and the patients in the study who developed a recurrent disease were excluded. Hence this potential cause of reported pain was minimized, possibly further potentiating the risk of survival bias. Furthermore, there might be a slight risk of recall bias considering the recall time of the primary variable in this study being 1 month. In the more recent version of GTQ, the recall time for pain has been changed to 1 week. There is also limited information regarding the use of specific pain medication or if other methods have been used for alleviating pain, as well as the exact location and cause of the facial pain.Finally, most of the patients had received chemoradiotherapy, and no direct comparison of pain outcomes was made between those who received chemoradiotherapy and those who received radiotherapy alone. Therefore, the effect of chemotherapy versus radiotherapy alone could not be distinguished in this study.It is clear from the study that pain is a prevalent symptom experienced by irradiated HNC patients both short-term as well as long-term. It also has a large impact on HRQL. Hence, it is of utmost importance to follow these patients over time in order to identify and alleviate pain. Trismus may very well be a contributing factor and mouth opening ability should also be measured and structured jaw exercises initiated when trismus occurs in an attempt to increase mouth opening and reduce facial pain in the long-term within the HNC population.The study findings demonstrate that facial pain was common among HNC patients before oncological treatment as well as up to 5 years post-RT. Reductions in MIO were associated with significantly more facial pain, particularly in the long term and patients who reported facial pain also reported worse HRQL compared to those reporting no pain. The degree of facial pain needs to be evaluated continuously by clinicians to ensure that other possible methods or medications for alleviations are offered to increase the HNC patients’ chance of optimal well-being.


Introduction: The volume of total knee arthroplasty (TKA) procedures continues to increase, including among United States (US) veterans, but there is little data characterizing recovery using validated knee-related questionnaires.Methods: In this prospective cohort study, we sought to establish the feasibility of longitudinal characterization of recovery after TKA using the validated Knee Injury and Osteoarthritis Outcome Score (KOOS), specifically focusing on two of the KOOS subscales ). We solicited participants who agreed to fill out these knee-related questionnaires preoperatively and 3, 6, and 12 months after discharge following unilateral TKA within the Durham Veterans Affairs Health Care System. We examined rates of prospective completion of the KOOS and face validity of scores at each study time point. We transformed and reported scores on the 0-100 scale, with zero representing significant knee pain or poor QOL and 100 representing no knee pain or good QOL.Results: Of 200 US veterans presenting between May 2017 and 2018, 21 (10.5%) agreed to participate by filling out the KOOS questionnaire longitudinally from before surgery until one year after discharge. All 21 (100%) participants were male and completed the two KOOS subscale questions (pain and QOL) preoperatively. Of those, 16 (76.2%) also completed KOOS at 3 months, 16 (76.2%) at 6 months, and seven (33.3%) at 12 months. Compared to mean preoperative values , the KOOS subscale scores had significantly improved by 6 months after TKA  but plateaued at 12 months . The magnitude of improvement in absolute scores, pain and QOL, was similar and significant at 12 months compared to preoperative values with an increase of 41.13 (p=0.007) and 38.98 (p=0.009), respectively.Conclusion: Primary TKA in US veterans with advanced osteoarthritis may lead to improved patient-reported KOOS pain and QOL subscale measures at 12 months compared to preoperative scores, with the majority of improvement occurring by 6 months. Only one in ten US veterans approached preoperatively agreed to complete the validated knee-related outcomes questionnaire prior to undergoing TKA. About three-quarters of those veterans also completed it both three and six months after discharge. Collected KOOS subscale scores demonstrated face validity and showed substantial improvement in pain and QOL over the six-month postoperative period. Only one in three veterans who completed the KOOS questionnaire preoperatively also completed it at 12 months, but this does not support the feasibility of follow-up assessments beyond 6 months. To better understand longitudinal pain and QOL trajectories in US veterans undergoing primary TKA for advanced osteoarthritis and to improve study participation, additional research using the KOOS questionnaire may add further insights into this underreported population. It has been demonstrated that total joint arthroplasty lessens pain and enhances the quality of life (QOL) in individuals with advanced osteoarthritis . In partOutcomes and recovery trajectories following TKA, however, have not been fully explored in the US veteran patient population with painful osteoarthritis. Much-needed information on such trajectories in this cohort cannot be extrapolated from non-veteran patient populations due to known differences in sociodemographics, medical comorbidities, and health-related QOL scores between groups ,6. In adThe Knee Injury and Osteoarthritis Outcome Score (KOOS) is an accepted, validated, and reliable patient-reported outcome measure following TKA and has been used in registries and value-based payment models -10 to idThe management of perioperative pain following TKA has improved with increasing emphasis on multimodal analgesia to minimize opioid use . Our aneThis prospective cohort study (#1968) was approved on October 21, 2016, by the Institutional Review Board at VAHCS in Durham, North Carolina, and conducted in compliance with the 1996 Health Insurance Portability and Accountability Act and adhered to all tenets of the Declaration of Helsinki. All participants provided written informed consent. This manuscript adheres to applicable EQUATOR guidelines. All data were de-identified.Veterans with advanced knee osteoarthritis who were undergoing TKA at the Durham VAHCS between May 2017 and May 2018 were eligible. The TKA procedure was performed at the Durham VAHCS by orthopedic surgeons who were employed at both the Durham VAHCS and its academic affiliate, the Duke University Health System. Inclusion criteria included completion of the self-administered KOOS questionnaire and the administration of the standard multimodal analgesic protocol for acute perioperative pain management. The standard multimodal analgesic protocol included preoperative oral acetaminophen 975 mg and celecoxib 400 mg, intraoperative spinal anesthesia with hyperbaric bupivacaine 10-15 mg, intraoperative or postoperative placement of a continuous nerve block catheter infusing 0.2% ropivacaine at 6-8 cc/hour beginning after the spinal anesthetic had worn off and up to 72 hours postoperatively, postoperative oral opioid oxycodone immediate release 5-10 mg every six hours as needed as well as intravenous hydromorphone 0.25-0.5 mg every two or three hours as needed, and postoperative scheduled nonopioids oral meloxicam 5-10 mg daily and oral acetaminophen 650 mg every six hours. Discharge prescriptions varied based on patient analgesic needs and included oral oxycodone-acetaminophen immediate release 5-325 mg every six hours as needed and oral meloxicam 5-10 mg daily for 10 days. Further quantitative details were not collected.All KOOS questions were completed by the patient on paper and answered based on their experience during the previous week. The KOOS questionnaire consists of 42 questions that comprise five validated subscales: pain, symptoms, activities of daily living (ADL) function, sport and recreation function, and QOL . A LikerThe trajectories of KOOS pain and QOL subscale measures across 12 months were assessed. The primary outcomes were the change in the mean score of each KOOS pain and QOL subscale domain from preoperatively to 12 months postoperatively. These two KOOS subscale scores at the three-month and six-month visits were secondary outcomes.Specific patient characteristics, duration and type of non-surgical treatments, and pain management patterns were not available. Mean KOOS pain scores and QOL scores as well as margins of error were calculated at each time point. Unpaired t-tests compared each of the KOOS subscale mean differences at each of the four time points. A two-sided p<0.05 was considered significant. The absolute change score with a margin of error was calculated for the preoperative to 12-month interval, preoperative to 3-month interval, 3-month to 6-month interval, and 6-month to 12-month interval. Confidence intervals (95%) were also calculated for each change score.At the Durham VAHCS, 200 eligible US veterans with advanced osteoarthritis undergoing unilateral primary TKA were approached during the study period, and 21 (10.5%) agreed to participate. All 21 (100%) were male and underwent unilateral primary TKA as scheduled. All 21 veterans received the standard multimodal analgesic protocol for acute perioperative pain management as described. All 21 (100%) completed the KOOS questionnaire preoperatively; 16 (76.2%) completed KOOS at 3 and 6 months, and 7 (33.3%) completed KOOS at the 12-month study timepoint.Compared to preoperative values , mean KOOS pain and QOL scores improved in US veterans after primary TKA during the 12-month postoperative period  (p=0.007). Both scores peaked at 6 months  and were then maintained through 12 months   (p=0.250)  (p=0.009). Three months postoperatively, KOOS QOL scores improved from a mean of 11.91 + 4.99 preoperatively to 34.38 + 10.73, for a change score of 22.47 + 11.83  (p=0.001) (Figure Over 12 months, the magnitude of improvement in mean pain and QOL scores from preoperative values was similar, with a change score of 41.13 + 21.88 and 38.98 + 21.20, respectively.This prospective cohort study assessed US veterans undergoing TKA for advanced osteoarthritis who completed the KOOS questionnaire preoperatively as well as at 3, 6, and 12 months postoperatively. The serial assessment of two validated KOOS subscales, pain and QOL, estimated one-year recovery trajectories, demonstrating that both pain and QOL improved significantly after TKA in this V-veteran cohort. Most of the improvement in both subscales occurred within the first six months after surgical intervention. Pain scores appeared to improve more than QOL scores within the first three months postoperatively; however, between three and six months, QOL scores improved more than pain scores. As TKA continues to become increasingly widespread ,13-15.Our data are a meaningful addition to the existing body of research that examines veteran-centered TKA outcomes ,16. SingIn a randomized controlled trial of non-veterans in Denmark who completed 12 months of follow-up, Skou et al. administered the KOOS questionnaire to 46 Danish patients with moderate to severe knee osteoarthritis who underwent primary TKA followed by 12 weeks of nonsurgical treatment which included dietary advice, exercise, education, pain medication, and use of insoles, and 49 who were randomized to 12 weeks of nonsurgical treatment followed by TKA in 13 participants . PreoperThis study has some limitations. The 21 veterans who participated may be highly motivated and likely to do well following TKA, and thus our findings may be attributed to sampling bias. Reasons for non-participation were not collected; however, further research will identify barriers to study participation and study completion. The presence of individual non-response bias during follow-up may limit generalizability. In addition, the study findings may not be generalizable to women veterans, civilians, or veterans undergoing primary TKA at other VAHCS facilities or non-VAHCS sites with different operative and analgesic practices. There are variables unaccounted for that may confound our findings. We did not have detailed quantitative information regarding perioperative opioids and non-opioids nor did we include other KOOS subscales from symptoms, ADL function, or sport and recreation function, which may affect conclusions regarding the efficacy of TKA and overall recovery trajectories in veterans.The findings in this pilot study suggest that primary TKA in USvVeterans with advanced osteoarthritis may lead to improved patient-reported KOOS pain and QOL subscale measures at 12 months compared to preoperative scores, with the majority of improvement occurring by 6 months. This pilot study also examined the feasibility of longitudinal assessment of knee-related pain and QOL after surgical intervention and found that only one in 10 US veterans who were approached preoperatively agreed to complete the validated knee-related outcomes questionnaire prior to undergoing TKA. About three-quarters of those veterans also completed it both three and six months after discharge. Collected KOOS subscale scores demonstrated face validity and showed substantial improvement in pain and QOL over the six-month postoperative period. Only one in three veterans who completed the KOOS questionnaire preoperatively also completed it at 12 months, however, which does not support the feasibility of follow-up assessments beyond six months. Routine longitudinal assessment of knee-related pain and QOL recovery trajectories after TKA seems feasible up to six months after discharge using the KOOS questionnaire. To better understand longitudinal pain and QOL trajectories in US veterans undergoing primary TKA for advanced osteoarthritis and to improve study participation, an additional study using the KOOS questionnaire may add further insights into this underreported population.


Each patient received two injections by the same researcher, one using the standard injection technique with medium intensity coughing technique and the other only the standard injection technique.there was a statistically significant difference between patients’ mean scores on pain severity and satisfaction levels after injections administered by the two techniques (p= 0.000). Also, it was found that gender affected pain severity relating to the injection but did not affect the level of individual satisfaction.the medium intensity coughing technique was found to reduce pain severity and increase patient satisfaction in general surgery patients receiving subcutaneous low molecular weight heparin injections. Trial registration: NCT05681338. LMWH is a type of heparin which is prepared by the depolymerization of the widespread form of heparin, and can only be given by the subcutaneous route-3)3). LMWH is frequently used as a treatment and particularly as a protective in clinical situations where there is a risk of thromboembolism or where thromboembolitic events have occurred-4)4). LMWH has advantages such as high bioavailability, a powerful antithrombotic effect and a lowered risk of bleeding, making it increasingly preferred in clinical applications.Today, medications are given by the oral and parenteral routes. One method of parenteral drug administration is subcutaneous injection, the method of introducing the medications under the dermis into the adipose tissue. The types of medication generally administered by the subcutaneous route are vaccinations, insulin, hormones and low molecular weight heparin (LMWH)-11)11). Also, a sensation of pain occurs as a result of tissue damage occurring with the introduction into the tissue of the LMWH solution. This can cause adverse effects in the patient such as anxiety, a disturbance in body image, pain in the injection area, refusal of treatment, and even a loss of trust in the nurses. For this reason, it is of great importance to implement strategies that will be of use in protecting patients from these kinds of adverse effects during the administration of subcutaneous heparin.Generally occurring local side effects of the administration of LMWH by the subcutaneous route are reported to be bruising, hematoma and pain at the injection site. One complication frequently complained of by patients is pain; this is caused by the presence of pain receptors in the subcutaneous tissue. It is reported that after subcutaneous heparin injections, various factors can cause complications at the injection site. In particular, factors which can lead to pain complications are seen to mostly arise from the injection technique, and there are studies evaluating non-pharmacological methods for managing pain developing in connection with subcutaneous heparin injection. These studies recommend techniques such as applying manual pressure to the injection area,12)12), extending the duration of the injection or injecting slowly-16)16), using the ShotBlocker  apparatus,17)17), and cold application to the injection site,18)18).In health institutions, one of the most important responsibilities of nurses is the safe administration of medications-21)21). It is reported that its potential mechanism relies on the Valsalva maneuver and on directing the attention elsewhere-23)23).Recently, the use of the coughing technique as a different non-pharmacological method in the management of pain developing from various invasive procedures has attracted attention. It is underlined that this technique is easy to learn, does not take time, and does not involve extra cost or equipment-21)21). The increase in pressure in the subarachnoid space brings the segmental pain prevention pathways into action, and this has the effect of reducing the perception of pain,22)22). It has also been reported that as a result of the Valsalva maneuver, this technique has an antinociceptive effect, reducing the perception of pain in connection with vagal nerve stimulation. During this maneuver, the vagus nerve is stimulated in connection with baroreceptor activation, and this has an antinociceptive effect-27)27). Also, the antinociceptive effect has been explained as occurring through central inhibition relating to the noradrenergic, serotogenic and endogen opioid systems with vagus nerve stimulation,28)28). On the other hand, it has been reported that another mechanism of the coughing technique depends on the method of directing the attention elsewhere and of diverting the attention so that the person does not feel pain, and that it increases a person’s tolerance of pain,30)30). Studies in the literature dealing with the coughing technique report that it is effective in reducing pain in interventions such as peripheral intravenous catheterization-23)23), taking a blood sample, or vaccination,21)21).The coughing technique increases intrathoracic pressure and stimulation of the autonomic nervous system, thereby causing an increase in heart rate and blood pressure, a higher level of pressure in the subarachnoid space and baroreceptor activation,22)-(23-(2322)- by a doctor. The Strengthening the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) guidelines was also used for this studyA Patient Description Form, a Visual Analog Scale, and the Visual Individual Satisfaction Scale were used in collecting the research data.2 was classified as underweight, 18.5–24.99 kg/m2 as normal weight, 25–29.99 kg/m2 as overweight, and 30 kg/m2 or more as obese.This form included contained four questions for getting information about the patients’ age, gender, height, weight and body mass index (BMI). BMI was classified according to the World Health Organization (WHO) classification: below 18.50 kg/m. Pain severity measurements were evaluated in millimeters.In evaluating the severity of pain felt by the patients during subcutaneous injections, a 10 cm long vertical VAS was used, on which one end represented no pain, and the other end the worst possible pain. The VAS is a commonly used pain assessment scale in clinical settings. Its validity and reliability in measuring the severity of pain in adults have been demonstrated.During the administration of the injection, an evaluation was made to determine individuals’ satisfaction using the Visual Individual Satisfaction Scale, which consisted of a vertical 10 cm scale with “I’m very satisfied” written at one end of it and “I’m not at all satisfied” at the other. The Visual Individual Satisfaction Scale incorporated the characteristics of the well-known Visual Analog Scale (VAS). VISS is a valid scale widely used in adults to assess individual satisfactionThe necessary permission to conduct the research was obtained from the Clinical Research Ethics Committee of the Medical Faculty of Bursa Uludag University (Decision No: 2022-6/18). Also, oral and written approval was obtained from the patients for their voluntary participation in the research, after information had been given.After the voluntary participation of the patients included in the research had been secured, their descriptive characteristics were collected from the Patient Description Form. After that, they were given information on the use of the VAS and VISS. Each patients received two injections. All injections were given once a day and were administered each morning at 11:00. All injections were administered to the upper part of the right or left arm on the outer area by the same researcher. The reason for performing the injections was that the patients were in the surgical clinic, most had incisions in the abdominal area, and the nurses in the clinic preferred the upper arm as the injection area. FigureThe injections were randomly allocated to injection sides for one of two injection methods. The two different injection techniques applied included in the research are given below.Injection method I: Before receiving the subcutaneous LMWH injection, the patient was asked to take a deep breath and cough once with moderate intensity to empty her/his lungs. After 10 seconds, the patient was asked to take a deep breath and cough a second time with the same intensity,22)-(23-(2322)-. Numerical data was examined by the Shapiro-Wilk test as to whether it showed normal distribution. Distributions of descriptive information on patients obtained as a result of the study were given as means and SDs. Since the data was found to be normally distributed, the non-parametric Wilcoxon signed rank test was used in dependent groups, and the Mann-Whitney U test and Kruskal Wallis-H test were used for two independent variables. The level of statistical significance was determined as p < 0.05.2 TableIt was found that 56% of the patients participating in the research were male, their mean age was 60.48±12.76 years, 29% were in the clinic for a cholecystectomy operation, 38% were overweight, and their mean BMI was 26.69±5.56 kg/mTableTableSubcutaneous LMWH injections are an important part of drug administration. One of the basic responsibilities of nurses is to protect patients from preventable side effects by the use of correct techniques,13)^. T^. T13)^.Therefore, it is important that there is a need for research into an effective, easily applied technique because of uncertainties concerning which technique to use in order to control pain and increase satisfaction when giving subcutaneous LMWH injections, considering factors such as heavy pressure of work, rapid patient turnover, the large number of patients and the lack of time, especially for healthcare professionals working in surgical clinics. In this regard, it was seen in the results of this study that the medium intensity coughing technique used during subcutaneous LMWH injections significantly reduced patients’ pain severity in comparison with injections given by the standard technique. No studies were found in the literature examining the effect of this technique in the administration of subcutaneous LMWH injections, but it was seen that it had been considered in connection with the management of pain developing in connection with other invasive nursing procedures.. Similarly, a study investigated the effect on pain of techniques such as coughing, squeezing a stress ball, or blowing into a spirometer while performing peripheral intravenous catheterization on healthy adults. It was found in the study that the lowest mean pain severities resulted from the application of the medium intensity coughing technique. In studies on the subject conducted with pediatric patients, it is reported that the coughing technique was an effective method in reducing pain during vaccination,21)21) and during the collection of blood samples. The results of these studies are seen to be similar to our research. It is stated in the literature that the coughing technique reduces pain by providing an antinociceptive effect working in parallel with the study mechanisms relating to baroreceptor activation-21)21) and vagus nerve stimulation-28)28). It has also been reported that this technique is helpful in pain management, as it relies on the most frequently used attention diversion technique in bringing pain under control,29)29). From this information, it can be said that the coughing technique is effective in reducing the pain arising from subcutaneous LMWH injections, depending on the potential mechanisms mentioned above.In a study on the subject, it was concluded that the coughing technique was effective in reducing pain during peripheral intravenous catheterization, and was an equivalent technique to the method of complex distraction. Studies have found that the mechano-analgesia technique, when compared with the standard technique of reducing the pain of subcutaneous LMWH injections, increased patient satisfaction, and that the manual pressure method increased comfort levels. Along with reduction of pain, an increase in patient satisfaction is expected. Although the methods used to control pain are different, it is seen that the techniques which were effective in reducing pain in the results of the studies mentioned above also increased satisfaction with the injection. Evaluated from this aspect, the increase in satisfaction with the injection with the coughing technique, with which patients reported less pain in our study, was assessed as a likely result.As a result of this study, the conclusion was reached that reported satisfaction levels after subcutaneous LMWH injections performed with the technique of getting patients to cough were significantly higher than after injections administered by the standard technique. It is reported that patient satisfaction is one of the important indicators of the quality of nursing services, and is accepted as a desired result of health services. Similarly, it was found in the present study that the mean pain severity of female patients following an injection administered by the coughing technique was significantly higher than that of male patients, but that the variable of gender did not affect the level of satisfaction of patients after an injection. In some studies in the literature in which different techniques were used to reduce the pain felt during subcutaneous heparin injections, a significant correlation was found between pain severity and gender, but in others, it was concluded that there was no such correlation,36)-(37-(3736)-37) and satisfaction level,12)12) connected with subcutaneous heparin injection. It is seen that the findings of our study are similar to the results of these studies. However, one study investigated the effect of manual pressure applied for different lengths of time following subcutaneous heparin injection on pain and bruising, it was concluded that the mean pain severity of overweight and obese patients was significantly greater than that of underweight or normal weight patients. In our study, it was found that the pain severity of obese patients was greater than that of underweight, normal weight and overweight patients, although this did not reach the level of significance. It has been reported in other studies that obese individuals experience pain more intensely-39)39). Also, it has been reported that because pain receptors are found in the subcutaneous tissue, stimulation of this region will cause a feeling of pain-11)11). Although the results of our study are similar to the literature in this respect, it is though that these differences between studies may arise from differences in the injection technique, the region of the body where the injection was given, and the patients’ mean body mass indexes.It was found as a result of this study that the variable of patients’ body mass index did not significantly affect the mean scores of pain severity and satisfaction level after injection by either method. Examining studies in the literature, it was found that they concluded that the variable of body mass index had no effect on the pain severityNurses are often undecided as to what technique to use in order to manage this pain in patients and to increase satisfaction, and there is a need for an effective technique which is easy and simple to use. In this way, this study makes a contribution to the literature on non-pharmacological methods used to reduce the pain of subcutaneous LMWH injections and to increase satisfaction with the injection. An important contribution of the study to the literature and its originality is that it is the first study to assess the use of the coughing technique with subcutaneous LMWH injections.One of the most widespread complications arising in connection with the administration of subcutaneous LMWH injections is pain. Nurses are often undecided as to what technique to use to manage this pain in patients and to increase satisfaction, and there is a need for an effective technique that is easy and simple to use. In this way, this study contributes to the literature on non-pharmacological methods used to reduce the pain of subcutaneous LMWH injections and increase satisfaction with the injection. Furthermore, considering that it is simple and free to use on patients, this technique can provide great convenience in the clinical field for health professionals, particularly nurses, in terms of pain management via safe subcutaneous heparin injections.This study has some limitations. The most important limitations are that the results could not be generalized because the subcutaneous heparin injection was applied only to the patient profile in the general surgery clinic, only on the outer side of the upper arm as the application area, and with 0.6 mL as the application dose. For this reason, it is recommended that comparative studies be conducted by repeating the study on different injection sites, with different application doses, and with different patient profiles.The results of the current study found that the medium intensity cough technique applied to patients during the administration of a subcutaneous LMWH injection reduced the severity of the patients’ pain and increased the level of satisfaction which they felt with the injection. Also, it was found that the variable of gender affected pain severity relating to the injection, but did not affect the level of individual satisfaction. In addition, it was found that there was no correlation between the variable of BMI and the severity of pain and level of satisfaction.


Background: Postoperative trigeminal neuropathy may be seen after surgery for middle and posterior cranial fossa lesions. Although neuropathic pain is a cause of reduced quality of life, global consensus on postoperative pain management is lacking. Mirogabalin besylate is a selective ligand for the α2δ subunit of voltage-gated calcium channels. Although mirogabalin has been used for patients with postherpetic neuralgia and painful diabetic peripheral neuropathy, few reports have assessed the effect on postsurgical neuropathy. In this report, we describe a clinical effectiveness of mirogabalin for trigeminal neuropathy after skull base surgery. Case description: Case 1: A 51-year-old female with right trigeminal schwannoma was operated on via the anterior transpetrosal approach. She had tingling and numb feelings in the right face postoperatively. Mirogabalin was orally administered after the operation. Her continuous facial numbness immediately improved. Case 2: A 55-year-old female with left middle fossa base meningioma extending into the infratemporal fossa was operated on via the infratemporal fossa approach. She had a tingling feeling in the left face postoperatively. Mirogabalin was orally administered for this symptom after the operation, which gradually improved. Conclusions: Mirogabalin may show significant pain relief for patients with trigeminal neuropathy after skull base surgery. Further studies using a larger number of patients are warranted to confirm these findings. Skull base surgery is a highly specialized field that addresses tumors and other abnormalities on the base of the skull. Surgery at the skull base is frequently challenging due to its constrained surgical field and the proximity of crucial neural and vascular structures. The manipulation of the skull base entails the inherent risk of temporary or permanent neurologic deficits . The incThe anterior transpetrosal approach is employed when dealing with lesions in the cerebellopontine angle or anterior pontine region. It is particularly well-suited for trigeminal schwannomas or tentorial meningiomas extending into Meckel’s cave. The infratemporal fossa approach is a method of accessing lesions located just beneath the middle cranial fossa from a lateral direction. The infratemporal fossa is located at the boundary between the neck and the cranial base, involving multiple medical specialties such as neurosurgery, otolaryngology, and maxillofacial surgery. The mandibular branch of the trigeminal nerve passes through the oval foramen, entering this region.Both skull base approaches are sometimes associated with trigeminal nerve neuropathy. Painful trigeminal neuropathy often manifests as a prolonged or nearly continuous condition. Commonly, it is described as a sensation of scorching heat, constriction, or a pain akin to being punctured by needles. Painful trigeminal neuropathy is difficult to treat pharmacologically . Althoug®), developed by Daiichi Sankyo, represents a gabapentinoid formulation approved in Japan. Previous studies have shown that α2δ subunits of voltage-gated calcium channels are significant for the trafficking and physiological function of the calcium channels. α2δ-1 subunits of voltage-gated calcium channels play a key role during neuropathic pain progression, which results from the injury to sensory nerves. α2δ-1 subunits of voltage-gated calcium channels are strongly up-regulated in somatosensory neurons following nerve damage. α2δ-1 and α2δ-2 subunits were identified as the therapeutic targets for the gabapentinoids [Mirogabalin besylate  signal intensities with small cystic areas A. Fast iThe patient experienced mild tingling and numb feelings in the right face postoperatively. Although oral non-steroidal anti-inflammatory drugs (NSAIDs) and/or acetaminophen were administered for five days, they were not effective in reducing her symptoms. Oral formulations of mirogabalin are available in 2.5, 5, 10, and 15 mg tablets with a recommended starting dose of 5 mg twice daily with weekly increases by 5 mg up to a maximum dose of 15 mg. Therefore, mirogabalin  was orally administered six days after the operation. Her continuous tingling and numb feelings improved  signal intensities A. EdematThe patient had a tingling feeling in the left face postoperatively. Although oral NSAIDs and/or acetaminophen were administered for two days postoperatively, they were not effective in reducing her symptoms. Therefore, mirogabalin  was orally administered three days after the operation for the symptom, which gradually improved (VRS: 3 to 1 , mRS: 1 For both patients, the most frequent adverse drug reactions, including nasopharyngitis, somnolence, dizziness, peripheral edema, drowsiness, and cerebellar ataxia , were noNeuropathic pain is a problem that plagues many patients. The efficacy and safety of mirogabalin have been previously demonstrated for several types of neuropathic pain, such as diabetic peripheral neuropathic pain  and postIn general, the clinical guideline recommends NSAIDs, gabapentin or pregabalin, and ketamine for post-operative pain management . First, Recently, mirogabalin was assessed in patients with thoracic postsurgical pain . Oral anIn the area of skull base surgery, painful trigeminal neuropathy is known to be difficult to treat pharmacologically . NeuropaNeuropathic pain represents not a singular ailment, but rather a syndrome induced by a multitude of diverse pathogenic mechanisms. Recently, integrated multimodal treatment with the current treatment facility, including various medical disciplines, were recommended for chronic neuropathic pain based on the patient’s medical history. Further studies are needed to establish an integrated, cause-specific, cost-effective approach for patients after skull base surgery .Herein, we report the usage of mirogabalin in patients that suffer mild trigeminal neuropathy. As both patients were aware of taking medication for neuropathic pain, there was a possibility of the placebo effect intervening. Therefore, we must discuss confounding factors that might have influenced the observed outcomes. Mirogabalin is expected to be an important new treatment option for the patients with trigeminal neuropathy after skull base surgery, which should be followed by a study that includes patients with severe neuropathy. Admittingly, it may be that mirogabalin provided some/minor relief to these two patients to help to accelerate the course. In general, NSAIDs and acetaminophen are effective for wound pain but not for neuropathic pain. Therefore, the effect of mirogabalin should be compared with other antineuropathic drugs, including pregabalin. In particular, pregabalin is a common prescription drug which is typically used to treat neuropathic pain, anxiety, and restless leg syndrome . DetaileMirogabalin may show significant pain relief for patients with trigeminal neuropathy after skull base surgery. Mirogabalin may be expected to be an important new treatment option for patients after skull base surgery. Furthermore, it may be also helpful for not only postoperative treatment but also preoperative management for tumors involving the trigeminal nerve, such as schwannoma and meningioma. However, drug efficacy studies should be carried out by comparison with the effect of placebos or other painkillers. Further studies using a larger number of patients are warranted to confirm these findings.


Inhaled Δ9-THC doses did not vary significantly between sexes (p > 0.05) except in the first month of treatment. Pain reduction and sleep improvement were similar for both sexes (p > 0.05). The overall rate of AEs was equal and relatively low at 10%  = 0.05, p = 0.820). A secondary analysis of pharmacokinetic data showed no significant differences between sexes in Δ9-THC and its metabolite pharmacokinetics, cardiovascular measures, or AE severity (p > 0.05). Conclusions: Uniform MC treatment via the Syqe MDI showed no sex differences in short-term effectiveness, safety and pharmacokinetics, nor in long-term effects, under “real-life” conditions. These findings provide insights into MC treatment which may inform clinical practice and policy-making in the field.Background: Clinical studies on medical cannabis (MC) treatment have shown sex-related differences, including higher susceptibility to adverse events among women and greater analgesia among men. Here, we used the Syqe metered-dose inhaler (MDI) and a single chemovar to analyze sex differences. Methods: A total of 1249 Israeli chronic pain patients were assessed for pain intensity, sleep and adverse events (AEs) over 240 days. Results: Following the first two weeks, no significant sex differences were found in the effectiveness or safety of MC treatment ( Chronic pain diagnoses are more common in women than in men . For exa9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) that exert pharmacological effects via the endocannabinoid system, a neuromodulatory signaling system that has widespread functions [9-THC in female rats, who also demonstrated antinociception to a painful stimulus that was not observed in male rats in a tail withdrawal assay [The cannabis plant contains phytocannabinoids such as ∆unctions . Animal unctions ,9,10. Anal assay .9-THC’s psychoactive effects at a lower dose than men [A study of pain in humans  reportedthan men . In termthan men , includi9-THC concentration in the blood following inhalation of low doses of MC [max between patients and a dose–response analgesic effect [MC can be consumed via different routes, most commonly by inhalation  , which aes of MC . Previouc effect ,17. We rc effect , but witc effect .Here, in order to assess sex differences in effectiveness, safety and PK, while eliminating potential variability between women and men in MC cultivar combinations, we performed a secondary analysis of data from two published studies with the Syqe MDI ,17 with A total of 1249 patients from Israel who were treated with MC via the MDI were analyzed in this study. Of them, 109 patients did not sign the patient support program (PSP) consent form and 20 additional patients chose not to initiate treatment following enrollment. Although safety analyses were performed for all patients , efficac2(1) = 44.16, p = 0.04) when all time points were combined (p > 0.05).All 1120 patients who signed the consent form were included in the current analysis. Of them, 524 (47%) patients stopped treatment at different times for various reasons during the 1260 days of treatment, and 409 (37%) stopped at six months . Notablycombined . Howevercombined  or in thcombined  (p > 0.00) (p > 0.05). None of the women were pregnant or breastfeeding at enrollment nor throughout the study. About half of the patients had previous experience with MC treatment prior to using the inhaler . Previous use of MC inflorescence by men was higher  than by women  (χ2(1) = 12.52, p < 0.001) and men had consumed significantly larger doses of MC (23.0 ± 13.1 gr/M) compared to women (19.6 ± 10.8 gr/M) (χ2(1) = 9.9, p < 0.005).At baseline (D0) , of the 2(1) = 4.41, p = 0.04 and χ2(1) = 16.47, p ≤ 0.001, respectively). Other, more comprehensive MC indication/comorbidity comparisons between the sexes are presented in Most patients  were prescribed MC treatment due to chronic pain. An additional 98 patients (9%) had chronic pain as the non-primary MC indication diagnosis, bringing the total to 91% (n = 1017) of the patients with a chronic pain diagnosis. Chronic pain indication, and specifically, chronic neuropathic pain, were more frequent among men  than among women  (χp > 0.05) for women  and men  (p < 0.05).Comorbidities were reported by 793 patients (71%), with similar rates  . Men had9-THC dose started at D1 with a mean ± SD of 579 ± 374 mcg, increasing linearly to 1500 ± 947 mcg at D30, then plateaued by D90 to a daily dose of 1600 ± 1300 mcg, which remained stable and similar in all follow-up time points. When examining the raw daily Δ9-THC doses in mcg, at a few initial follow-up time points , men consumed significantly higher daily doses relative to women (χ2(1) = 0.15, p < 0.01, χ2(1) = 0.13, p < 0.05 and χ2(1) = 0.12, p < 0.05, respectively) (9-THC did not differ between men and women at any of the follow-up time points (p > 0.05) (The average daily aerosolized Δctively) A. Howeve > 0.05) B. Follow0 and in the first follow-up time point (D7), the average weekly pain intensity was statistically higher among women than men (χ2(1) = 0.11, p < 0.01 and χ2(1) = 0.14, p < 0.01, respectively). At the following time points, pain intensity was similar between the sexes (p > 0.05). The mean change in pain intensity from D0 was similar at most follow-up time points (p > 0.05), except for D14, when women exhibited superior reduction in pain intensity (−1.20 ± 1.60 NPS points) compared to men (−0.96 ± 1.90 NPS points) (χ2(1) = 0.13, p < 0.05) (At D < 0.05) . The paip > 0.05). Overall, sleep latency improved , sleep duration improved . For both sexes, AEs were reported significantly more frequently at the initiation of the treatment and gradually decreased. There were no differences in the distribution of AE reports between males and females at the specific follow-up time points.There were no differences in the distribution of AE reports in general between men and women (~10% for both sexes) (2(1) = 0.05, p = 0.820) . Of these, 29 were reports of the passing away of the patient unrelated to MDI treatment and an additional 159 reports were deemed unrelated to the device or to the MC administered via the inhaler by Syqe’s nursing director. Thus, 227 treatment-related AE reports were analyzed. These were reported by 125 (10%) of the 1249 enrolled patients, with at least one AE in at least one individual follow-up time point  . Of notep > 0.05). The most frequent AE PTs were dizziness (excluding vertigo) , cough , headache , sleepiness  and sore throat . The frequency of all other AEs was <1%. Specific AEs were not significantly different between the sexes  [We re-analyzed patients that were administered a single uniform dose of 1000 mcg Δ. (2014)  and 25 p. (2014) . Notably9-THC and its metabolites, 11-hydroxy-Δ9-THC and Δ9-Carboxy-THC, at any of the time points (p > 0.05)  which were found to be relatively stable, regardless of the administered dose of Δ9-THC  . Nonethef Δ9-THC . NotablyThere were no significant differences between males and females in blood pressure and heart rate .p > 0.05)  at any time point ( > 0.05) .It is now widely accepted that women may process pain and respond to analgesics differently than men . These d9-THC PK. As all patients were treated using the MDI, it allowed them to inhale precise, low doses of Δ9-THC, resulting in low inter-individual variability of blood concentration of Δ9-THC and its metabolites. While the mechanism of the clinical effects of Δ9-THC metabolites 11-hydroxy-Δ9-THC and Δ9-carboxy-THC are not yet fully understood, literature reviews on this issue humans are lacking and some in vivo studies suggested no to weak biological effects [9-THC doses of the other routes produce high Δ9-THC plasma levels , much h50 ng/mL  as WallaL [9-THC .14 time point. The percentage of reduction in pain intensity (27%) was comparable or even somewhat better (23%) following 240 days of sublingual/smoked/vaped MC [Our analysis shows that at the endpoint of efficacy analysis (240 days of treatment), patients reported significant pain reduction with a mean of 1.58 points, or 2.60 points following imputation of missing data, without any difference between men and women other than at the Dvaped MC .Although 26% of the patients in the current study reported no decrease in pain intensity at the end of the titration phase and 5% reported worsening of pain, these patients elected to continue using the inhaler, possibly as almost half of these patients experienced an improvement in sleep characteristics. Sleep measurements were found to be improved to a similar degree for both sexes. A previous study on MC and sleep found similar results  and it hNotably, there were no differences between the sexes in AE rates. The rate of AEs during the study was low (10%), and most were reported during the titration phase, essentially disappearing following the attainment of a stable treatment regimen. In our previous studies ,31, as w9-THC /cannabis compared to females, the weight-adjusted dose was the same for both sexes. This is interesting with regard to physicians who do not think of dosing based on weight and the current study results suggest that physicians should pay more attention to this aspect in medical cannabis treatment.Of note, in the current study and in our previous one , althougIn addition, contrary to previous studies on MC for chronic pain treatment in which MC quantities increased over time , we founSex differences in MC treatment may be prevalent in aspects that were not assessed in the current study. Cuttler et al. (2016) reported that men used cannabis more frequently than women and more for recreational purposes, while women used cannabis more for medical indications . Cannabi9-THC dose in the aerosol and not for the rest of the cannabis components that are emitted in the aerosol. Nonetheless, using one unique cannabis cultivar and the metered doses that are possible via the MDI should at least indicate some consistency of the other components. Sixth, due to the heterogeneity of the data relating to concomitant medications use, no sub-analyses were performed to assess the possible confounding effects.This study has several limitations. First, like in most clinical studies on pain, the analyses relied on an NPS, which is a subjective tool for assessing pain intensity. Moreover, since women often experience and communicate pain differently than men, this and other systemic biases have to be acknowledged. Second, due to the ongoing nature of the study design and the 47% total attrition rate throughout the years of data collection, the sample size became smaller at each time point. This might have impacted the statistical results due to an increase in variability. Third, due to the heterogeneity of the sample, some of the treatment etiologies and the previous experience with MC measures varied significantly between the sexes. Fourth, this was an open-label study, with no randomization and with no placebo arm. Thus, it could be argued that some of the results were due to a placebo effect. Fifth, the sample size of the female groups for the PK studies is relatively small (n = 3–6); this calls into question the validity of sex comparisons for this measure. Nonetheless, this is the most comprehensive data currently available in the literature. Fifth, the MDI controls solely for Δ9-THC-rich MC was approved by the Israeli Ministry of Health (IMOH). Most licenses are issued for CNCP, preferably of neuropathic origin [Three forms of MC consumption are approved in Israel: inflorescences (for smoking or vaporizing administration), oil extracts  and the Syqe MDI. The latter can be used only by patients for whom the use of Δc origin . There a9-THC. Δ9-THC serves as an indicator for other phytocannabinoids, terpenoids and additional molecules in the whole inflorescence that are aerosolized concomitantly with it. Comprehensive information on the MDI and its use can be found in our previous publications [9-trans-tetrahydrocannabinol acid (THCA), THC, cannabigerolic acid (CBGA), cannabidiol acid (CBDA) and cannabinol (CBN). The Syqe MDI 1.1 is configured to use a vapor chip (VC) that delivers an aerosol containing either 250, 500, 750 or 1000 mcg Δications ,17,35,36Syqe Medical provides all patients who use its MDI with a free patient support program (PSP). Upon joining this program, the patients provide informed consent, which allows data collection by the company’s PSP nursing team. In this study we retrospectively analyzed the data of all patients who were enrolled in the program between September 2019 and January 2023. Analysis of the collected data was approved by the Technion—Israel Institute of Technology’s Ethics Committee (#125-2021). The PSP also includes a call center that archives every AE report. This study was purely observational, using anonymized data, and not interventional .Treatment regimen: Once approved to use the Syqe MDI, a predefined amount of MDI cartridges per month was prescribed by the treating physician to each patient along with an individualized treatment regimen .9-THC twice per day. Thereafter, patients could add small incremental doses in accordance with their titration plan, which was subjected to either the absence of AEs for three consecutive days, or the presence of tolerable AEs, defined as AEs perceived by the patient as not preventing him/her from continuing the treatment . Dose titration was supported and monitored by a designated PSP nurse, who assisted the patient in reaching a stable treatment regimen with as few AEs as possible. Dose titration for most patients began with a dose of 250 mcg Δ9-THC dose was calculated at each follow-up time point based on the patient’s treatment regimen . AEs were actively assessed by an open question: “Have you experienced any AE since the last follow-up?” at each follow-up visit. AEs were also recorded by the call center if a patient called to report such events spontaneously. AEs were categorized according to the MedDRA system organ class (SOC) for systems classification and by preferred term (PT) for the specific AEs.Average weekly pain intensity was measured by a numerical pain scale (NPS) ranging from 0 (“no pain”) to 10 (“worst imaginable pain intensity”). Sleep timing (latency and duration) and quality were assessed by the Pittsburgh Sleep Quality Index (PSQI) . Daily ΔPatient attrition from the program was recorded at predefined times: 1, 7, 14, 21, 30, 60, 90, 120, 180, 240, 360, 540, 720, 900, 1080 and 1260 days following treatment initiation. The reasons for attrition were also documented during the same call and assessed by an open question.Data were collected by the company’s PSP nurses based on outcomes reported by the patients. A baseline meeting during which the nurse instructed the patient on using the inhaler was held either in person at the patient’s home, by zoom video meeting or by a phone call. In this meeting, the nurse interviewed the patient about previous MC treatments, co-morbidities and concomitant medication use. Women were asked if they were pregnant or breastfeeding. Patient demographics like age, sex and body mass index (BMI) were also recorded. Inasmuch as possible, the same PSP nurse collected data on pain intensity and AEs by phone at predefined times as described above. At each call, women were also asked again if they were pregnant or breastfeeding. Patients were asked if they were continuing to use the MDI and if not, what the reason for stopping was. Patients were instructed to call the PSP support service if technical issues arise.In this study, we reanalyzed the previously published, prospectively collected data of all patients who were enrolled in the program between September 2019 and October 2020 [9-THC was evaluated, and no efficacy data were collected. The second MDI PK study was a randomized, 3-arm, double-blind, placebo-controlled, cross-over trial [9-THC single inhalation per visit, 1000 mcg Δ9-THC single inhalation per visit and placebo (VC that does not contain Δ9-THC). In that study, we assessed the pharmacokinetics of Δ9-THC and its metabolites Δ9-carboxy-THC and 11-OH-Δ9-THC, in addition to the presence of symptoms that were scaled on a continuous rating  of both frequently reported cannabis-related AEs  feeling, nausea, throat soreness and tiredness) and frequently encountered positively perceived effects . No sex differences were evaluated in these previous publications. The studies were conducted in the Pain Research Unit of Rambam Health Care Campus , following approval by the Rambam Health Care Campus ethics committee (RMB 0131-13). All participants provided written informed consent. Patients were enrolled in the study after meeting the following criteria: (1) aged 18 years or older; (2) suffering from neuropathic pain of any type for at least 3 months; (3) stable analgesic regimen for at least 60 days that included MC; (4) normal liver function , normal renal function (defined as a serum creatinine level <1.50 mg/dL) and normal hematocrit (37–52%); (5) negative pregnancy test (β human chorionic gonadotropin pregnancy test), when applicable; and (6) possessed a valid license from the Israeli Ministry of Health to receive MC. Exclusion criteria were the presence of significant cardiac or pulmonary disease, history of a psychotic disorder, pregnancy or breastfeeding, or presence of non-neuropathic pain.The first study assessed the PK, safety and analgesic effect of a single 1000 mcg inhalation dose via Syqe’s MDI , conducter trial , conduct9-THC elimination 30–60 min following cannabis smoking [Notably, patients in those two PK studies were not cannabis naïve but were requested to refrain from consuming MC for at least 12 h prior to using the MDI. The washout period duration was based on findings reporting Δ smoking .0 (baseline) and at least one report for any of the follow-up time points. Categorical variables are presented as numbers and percentages. Distribution was assessed by the Shapiro–Wilk test of normality. Data with non-normal distribution are presented as the median and interquartile range (IQR) and normally distributed data are presented as mean ± standard deviation (SD). R software (V.1.1.463) with arsenal [p-value was lower than 0.05. Due to the prospective nature of the data, sample sizes are different between time points. Thus, demographic data in the results refer to the baseline (D0) time point only. Last observation carried forward (LOCF) was performed for patients with missing data and was carried forward for all subsequent observation points for the average weekly pain intensity outcome measures as a sensitivity analysis.Only intention-to-treat (ITT) population analyses were performed for all patients who were treated with the inhaler and had data for D arsenal , atable  arsenal  and tidy arsenal  packages arsenal  was usedIn conclusion, uniform MC treatment via the Syqe MDI showed no sex differences in short-term effectiveness, safety and PK, nor in long-term effects under “real-life” conditions and with no differences in attrition rates. These findings provide valuable insights into the effectiveness and safety of MC treatment for both sexes and may inform clinical practice and policy-making in the field. As such, regulators of the MC markets need to consider that sex-based MC product selection is not supported by the published literature. Hence, clinicians should be guided to a more evidence-based approach for MC treatment.


Optimal pain management is one of the core elements of Enhanced Recovery After Surgery (ERAS®) protocols and remains a challenge. Acupuncture (AC) is an effective treatment for various pain conditions. Systematic and personalized allocation of acupoints may be decisive for efficacy.Based on the predominant pressure sensitivity of six gastrointestinal (GI) checkpoints (G1-G6), we devised a method to detect personalized patterns of pain and a corresponding set of acupoints. We performed a single AC treatment with semi-permanent needles and assessed the visual analogue scale (VAS) score, pain threshold based on pressure algometry (PA), and temperature changes on abdominal skin areas before and 5 min after AC.Between April and June 2021, thirty-eight patients were prospectively included in this pilot study. The mean reduction in subjective pain sensation as assessed by VAS was 86%, paralleled by an augmentation of the pain threshold as measured by PA by 64%. A small but significant increase in the skin temperature was observed above the abdominal surface. These effects were independent of the type of surgery.Checkpoint acupuncture may be a complementary tool for postoperative pain management. Further investigations are needed to explore this analgesic effect.The online version contains supplementary material available at 10.1007/s00423-023-03051-8. Postoperative pain is one of the major complaints , 2 and fAcupuncture (AC) has become an increasingly popular modality for the treatment of acute and chronic pain . AdditioThe study was designed as a prospective proof-of-principle study investigating the analgesic effects of checkpoint AC in patients after abdominal surgery. Informed consent was obtained before enrollment, according to a clinical trial protocol approved by the local Ethical Committee (EK 2021-604).Adult patients who underwent elective or emergency abdominal surgery with a postoperative pain score of ≥3 on a 10-point visual analogue scale (VAS) were eligible. Sufficient language communication skills were necessary for inclusion in the study. Patients with needle phobia, relevant actively treated psychiatric conditions such as bipolar disorder, chronic pain syndrome prior to surgery, polyneuropathy, relevant bleeding disorders, impaired mental state, and poor German language communication skills were excluded.All participants underwent standard pain management according to the ERAS® protocol. On surgical ward, patients were given scheduled baseline analgesics, such as paracetamol or dipyrone (1g every 6 h). Oxycodone with naloxone  was used as the first-line rescue medication. If no adequate pain relief was achieved, immediate release oxycodone was prescribed (10 mg upon request).Patients who underwent bowel followed a highly standardized Bowel-ERAS®-Protocol within our ERAS®-qualified department. Other patients followed local, highly standardized clinical pathways integrating the ERAS®-variables .Acupuncture rationale: Acupuncture was performed based on our established checkpoint concept (G-points) , 22, whiNeedling technique: length, diameter, pressure of insertion, and depth of insertion were identical by using semi-permanent needles  , 25. We All patients received a single AC treatment after surgery. The needles remained until discharge. Verbal communication was reduced to a minimum.Other treatment components: No additional treatment was administered.The study acupuncturists  performed acupuncture on a daily basis for several years.Control or comparator interventions: As this was a preliminary pilot study focusing on feasibility and practicality, no control group was included.Study reporting was conducted according to the STRICTA guidelines :AcupuncAC was applied as an additional element in the standardized multimodal approach to relieve pain after abdominal surgery. In this study, we examined six defined regions located in the abdominal cavity Fig.  and 2 2, 22. EacAfter verifying the inclusion and exclusion criteria, VAS was assessed. The temperature was measured on all six visceral indicator points (G1–G6) using a touchless infrared thermometer . The most pressure-sensitive checkpoint was detected by careful palpation, and the pain threshold was assessed via digital PA (PCE instruments-FM 200 device) , 27.Patients were treated with AC points selected according to checkpoint diagnosis Table , Fig. 2.Following a 5-min resting period, all parameters of Examination 1 were re-assessed.t test for two paired samples was used, as appropriate. For the comparison of two independent subgroups, Wilcoxon two-sample test was performed. The results of the statistical test were considered statistically significant at p<0.05.SAS software  was used for all statistical calculations. For qualitative factors, absolute and relative frequencies are given. Quantitative variables approximately normally distributed are presented by mean value and standard deviation . For skewed or ordinal scaled data, median and range are given . Graph Pad Prism (Version 9.4.1) was used to create the figures. In order to compare parameters before and after intervention, a Wilcoxon test or a Between April and June 2021, thirty-eight patients were included in this pilot study. Twenty-one (55%) were female, and 17 (45%) were male. Mean age was 50.9±17.1 (23-80) years. Thirty-three patients (87%) underwent elective surgery, and five patients (15%) underwent emergency surgery (Table p<0.0001). Figure Before AC, the median VAS score for all 38 patients was 5.5 (3–9) indicating significant pain. Following acupuncture, the median VAS score was 0 (0–5) with an average reduction by 86% , compared to 21.8N (2.0N–79.9N) after AC, indicating a clinically relevant pain reduction and augmentation of the pain threshold by 67% on average. Hence, a highly significant difference was detected between the algometric measurement before and after treatment was detected . No differences were observed above other G-points.With means of 36.9°C ±0.4°C before and 36.7°C ±0.2°C after the intervention, a significant difference has been measured above G1 .AC had similar pain-releasing effects without a significant difference Fig.  between Analysis of subgroups revealed that the type of surgery was linked to a tendency towards certain checkpoint syndromes. The largest subgroups included bariatric and colorectal surgeries (supplementary Table p<0.0001), as shown in Fig. Overall, patients undergoing bariatric surgery showed reduced pain levels by 86.7% on average, with a median VAS score of 6 (3–9) before and 0 (0–3) after acupuncture  to 29.3 N  above G1 and G2. No differences were observed above the other G-points.After AC, the bariatric patients showed slight but significant lower temperature levels than before , indicating a moderate pain. Through AC, a significant pain reduction of 80% was achieved, reaching a median VAS of 0  increased from 4.1N (2.6N–12.8N) to 6.7N (3.6N–21.6N) after. This results slightly failed to reach statistical significant .For G1 and G4, slight but significant temperature changes could be observed for this subgroup . Nine out of ten patients showed either G1- or G3-syndrome . After AC, the patients experienced pain of a median VAS 0  equaling a pain reduction of 93% percent on average. Eight patients showed a complete pain remission (VAS 0). Pain reduction was statistically significant (p = 0.0156) . After AC, an augmented pain threshold of 15.4N (2N–79.9N) could be observed (–25. Aftep>0.05).Temperature changes above the indicator points were not significantly different


Aims were to examine gender differences in patients with gout with regard to a) self-reported gout severity, b) illness perceptions (IP), c) impact on daily activities and Quality of Life (QoL), d) advice from healthcare professionals, e) having changed dietary- or alcohol habits.n = 1589) were sent a questionnaire about demographics, gout disease severity, IP ) and disease management. T-tests, Chi square tests, ANalysis Of VAriance (ANOVA) and linear regression models were used for gender comparisons.Adult patients with gout identified in primary and secondary care in Sweden between 2015 and 2017 (n = 177 (20%), experienced more severe gout symptoms (p = 0.011), albeit similar frequencies of flares compared to men. Women experienced modest but significantly worse IP with regard to consequences, identity, concerns and emotional response (p < 0.05) as well as daily activities such as sleeping (p < 0.001) and walking (p = 0.042) and QoL (p = 0.004). Despite this and a higher frequency of obesity in women  and alcohol consumption in men (p < 0.001), obese women had received significantly less advice regarding weight reduction  compared to obese men. On the other hand, women reported having acted on dietary advice to a larger degree.Eight hundred sixty-eight patients responded to the questionnaire. Women, Despite only modestly worse gout severity and perception, women appear to have been given less information regarding self-management than men. These gender differences should be given attention and addressed in clinical care.The online version contains supplementary material available at 10.1186/s12891-023-06416-8. Gout is the most common inflammatory arthritis characterized by acute flares of pain and swelling in one or more joints, most commonly in the first metatarsophalangeal . In addiGout is more common in men and less well studied in women. Several comorbidities, such as osteoarthritis, obesity, renal disease/failure, hypertension and treatment with diuretics  have beeIP is defined as an individual’s idea of their illness. Depending on how patients perceive their illness it could directly influence aspects of the disease management . IP can The aims of the present study were therefore to examine gender differences in patients with gout with regard to a) self-reported gout severity, b) IP, c) impact on daily activities and QoL, d) advice from healthcare professionals, e) having changed dietary- or alcohol habits.In this cross-sectional questionnaire study patients were recruited from a rheumatology clinic and 12 primary care centers in Western Sweden. All Individuals ≥ 18 years of age and with ≥ 1 International Classification of Diseases (ICD-10) diagnosis of gout (ICD-10 codes M10), documented at a health care visit to a physician during a period of two years (Jan 2015 through Feb 2017) were identified and sent a questionnaire.The questionnaire included questions about gout characteristics , comorbidities, demographics, occupational status, education, well being, alcohol use and dietary changes made due to gout, functional status and Brief Illness Perception Questionnaire (B-IPQ). Non-responders received a second mailing of the questionnaire and ten percent of the final non-responders were randomly selected and interviewed by telephone. The proportion of women was larger in non-responders compared to responders, but the telephone interviews indicated no major differences with regard to gout symptoms .2. To assess well being numeric rating scales (NRS) measuring pain, fatigue and global health were used and a higher score indicates more pain, fatigue and worse general health. Alcohol use was measured by how many Swedish standard units  consumed per week. Functional status was assessed by Health Assessment Questionnaire (HAQ) [Educational level was dichotomized into Low (≤ 12 years) and High (> 12 years). Disease duration was defined as years from first gout diagnosis. Occupational status was defined as retired or working/unemployed/student. Obesity was defined as BMI ≥ 30.0 kg/mre (HAQ) . Dietaryre (HAQ) ) with a Consequences (beliefs regarding how illness will impact one’s life), Timeline (beliefs regarding chronicity of illness), Personal control (beliefs regarding controllability of illness), Treatment control (beliefs regarding controllability of treatment), Identity (how the illness is defined by symptoms), Concerns (beliefs regarding the concerns of the disease), Understanding (how much the illness is understood) and Emotional response (the impact of the illness on emotions). The scales are scored on an 11-point NRS scale (0–10), with higher scores representing greater perceived psychological burden of illness.B-IPQ includes 8 dimensions: All participants were informed in writing that the reported data would be published and returning the questionnaire was considered informed consent. Ethical approval was granted from the Ethical Review Board of Gothenburg, Sweden (519–16). The study was carried out in accordance with the Declaration of Helsinki. Informed consent was obtained from all subjects and/or their legal guardian(s).p-value < 0.05 was considered statistically significant. SPSS version 27  was used for statistical analysis.Data are expressed as mean (standard deviation (SD)) for continuous variables and number (percentages) for categorical variables. Continuous variables were compared with students t-test and categorical variables with Chi-square test. For age-adjusted comparisons between genders, ANalysis Of VAriance (ANOVA) and linear regression models were used. A Of the 1589 individuals with an ICD-10 diagnosis of gout who were mailed a questionnaire, 868 (54.6%) responded. The proportion of men was 80%, mean age was 70 years for men and 75 years for women , differences that remained after adjustment for age. Within the dimensions of personal control, timeline and understanding, there were no significant differences between gender . Among obese patients (Body Mass Index: BMI ≥ 30 kg/m2) more men  had been given advice about weight reduction, despite that obesity was considerably less frequent in men  treating patients with gout, only 4 out of 32 GPs reported that they gave lifestyle advice to patients with gout, despite that many GPs considered dietary factors to be important contributors to gout . DiffereIn our study there was a gender difference with regard to self-management strategies and advice from health care professionals. Men and women have been shown to have different educational needs in other chronic rheumatic diseases . In the Some limitations should be acknowledged. First, due to the cross-sectional design we were unable to analyze predictors of greater perceived IP or to what extent IP longitudinally affects disease outcome. Second, results may not be applicable for non-responders, although our limited analyses of this group did not demonstrate any major gout phenotype differences. Third, misclassification of gout diagnosis could present a problem, but previous validation studies of gout diagnoses given in our health care system have demonstrated a high validity , 37. In The study also has several strengths. First, it includes a broad spectrum of patients with a range of disease severity, treated in either primary (the majority of patients) or specialized care. Second, few studies have specifically addressed gender differences in IP, impact on daily life and lifestyle changes made by gout patients.In our study we demonstrate that women tend to score their disease as slightly more severe compared to men, although women have an IP similar to men. Despite these overall similarities, in our setting men and women are given different advice regarding disease management and differ with regard to implementation of given advice. These differences call for further investigation of how to tailor and optimize health care advice and treatment of gout in subgroups of patients.Additional file 1: Suppl Table 1. Age-adjusted gender comparisons of Brief-Illness Perception Questionnaire stratified by self-reported goutseverity.