Orthodontists use mini-implants temporarily as an effective mode of skeletal anchorage devices. The placement of mini-implants can cause pain and discomfort to the patients. Patients often develop swelling, and the pain could interfere with their daily activities. Practitioners tend to prescribe antibiotics and pain medication for management.  The main objectives of this study are to evaluate the pain perception and discomfort due to mini-implant placement experienced by the patient and evaluate the interventions for pain management commonly practiced among orthodontists.  The study was designed as a questionnaire-based cross-sectional study. A total of 271 patients were assessed, for whom 625 mini-implants (ranging from 1.2 to 2 mm diameter and length 8-14 mm) were placed. Pain scores were assessed using the VAS and the “Faces” pain rating scale to collect data about discomfort in daily activity and function. Data was collected from 244 patients. A total of 155 orthodontists were questioned regarding the prescription of medications and the interventions for managing pain and adverse effects.  Average pain score among female subjects was 16.71 and among men was 13.5. The highest pain scores were recorded for palatal mini-implants with an average score of 36.29 and the least for interradicular mini-implants with an average score of 9.02. Among the subjects, 47.9% of them took analgesics, and the most commonly prescribed analgesics were paracetamol (39%). Swelling at the site is where the mini-implants were placed, and ulceration due to implants were commonly dealt with the excision of the surrounding soft tissue, composite placement, and palliative care with oral analgesic gels.  Female subjects had more mini-implants placed, and female subjects had also given more pain scores than their male counterparts. Palatal mini-implants caused the highest pain, followed by mini-implants placed at the infrazygomatic crest and the buccal shelf region. Palatal mini-implants caused maximum discomfort during speech and eating, followed by the mini-implant in the buccal shelf and the infrazygomatic crest region that also caused difficulty in yawning and laughing. Infiltration anesthesia was commonly given for the placement of interradicular implants and extra-alveolar mini-implants. Paracetamol was the most prescribed by the orthodontists, and more than half the doctors did not regularly prescribe antibiotics. One of the most significant challenges for orthodontists is to achieve successful orthodontic treatment without losing any anchorage . AlthougThe insertion of a mini-implant necessitates expertise and technique; slippage of the mini-implant during placement can result in soft tissue damage, which can be mitigated by utilizing a self-tapping approach, although it must still be done with caution , 7. PatiAnalgesics are the primary modality to reduce pain. There is no universal or standard pain reliever. Ibuprofen, aspirin, aceclofenac, and acetaminophen are among the most commonly prescribed nonsteroidal anti-inflammatory medications (NSAIDs) . These mThere is a vast lacuna in literature concerning the pain and comfort of patients being treated with TADs and a lack of knowledge in managing the adverse effects. Thus, the purpose of this study is to evaluate the patient's pain perception and discomfort as a result of mini-implant insertion and the pain management strategies typically used by orthodontists. The objectives of the study were to evaluate the pain perception when using mini-implants at different sites and gender differences and how it affects the daily activities and function; to evaluate the use of anesthesia, antibiotics, and analgesic postmini-implant placement; and to evaluate the most common causes of pain and interventions by using two separate questionnaires among patients and orthodontists.The Institutional Review Board approved the study protocol, questionnaire, and informed consent of Saveetha University. After receiving oral and written consent from patients based on the need of treatment mechanics, mini-implants were placed for the subjects. This study inserted mini-implants in the interradicular sites, infrazygomatic crest, buccal shelf, palate, and anterior midline. All of the mini-implants were manufactured by Favanchor and were made of titanium. The insertion site and indication determined the size of the mini-implant.The inclusion criteria are all subjects who reported orthodontic treatment and for whom mini-implants were placed as an adjuvant anchorage. 271 patients were enrolled in this study, and mini-implants were placed. 244 patients responded to the questionnaire, and the others refused to participate in the study. Among these, 625 mini-implants (ranging from 1.2 to 2 mm diameter and length 8-14 mm) were placed in total. This study evaluated all the mini-implants placed in various sites including the interradicular, palatal, infrazygomatic crest, and buccal shelf region. The practitioner assessing questionnaire was shared with 200 doctors. Among practicing orthodontists and postgraduate students, 155 doctors filled the questionnaire. Those who had experience with placing TADs were also questioned regarding the protocol they follow for anesthesia, the medications they prescribe, and their preferred management methods in situations of adverse effects. This study was conducted between January and July 2021.These patients were given a self-assessment questionnaire. Patients' perception of pain was recorded using a questionnaire that was distributed using an online survey link. The visual analog scale was assessed using the standard 10 cm metric scale. Questions pertaining to discomfort were designed that correlate with the daily function and activities of the patient. These questions were answered using the Wong-Baker Faces Pain Rating Scale. VAS score was used to assess the pain and swelling. The patient's daily activity could be effectively affected, and the factors we took into consideration were leisure, speech, ability to eat hard and soft food, drinking, laughing, and yawning. These questions were given a score rating of 0-5, given that 0 meaning no discomfort to 5 indicating worst pain. Patients were also questioned about their use of pain medication postplacement of mini-implants. No patient answered the questionnaire more than 1 month after the mini-implant was placed.The orthodontists were questioned regarding the prescription of antibiotics and pain medication after the placement of TADs; they were also questioned regarding the adverse effects of swelling, soft tissue entrapment, and their call for management. Local anesthesia is used by topical application, infiltration, or via block for placement of mini-implants. The need and the preferred route of administration was asked. Despite administration, patients often tend to experience pain during the mini-implant placement or the driver's detachment from the head of the implant postplacement.The data thus collected were used to assess the pain and discomfort of the patients as well as the management options for pain and other side effects experienced after mini-implant placement.The statistical analysis was done using the IBM SPSS statistics 20 software. Descriptive statistics were evaluated for the orthodontists who answered the questionnaire and the subjects for whom mini-implants were placed. Graphs were obtained based on the VAS pain scores and Faces pain scores.The questionnaire was collected from 244 subjects who underwent treatment with mini-implants. The patients who did not complete the questionnaire were excluded from further analysis. For 75% of the patients, interradicular mini-implants were placed, 12% had implants placed at the IZC, 9% had implants placed in the buccal shelf, and 8.5% of patients had mini-implants placed in the palate. The mean age of the patients was 23.9 ± 6.4 years, with 156 females and 88 males consenting.The questionnaire was circulated among 200 orthodontists, and 155 filled it. The mean age group of the orthodontists was 30 ± 6 years, 83 were female, and 71 were male; 90 of them were postgraduate students, and 64 were practicing orthodontists. 124 doctors had an experience of fewer than 5 years, 12 doctors between 5 and 10 years, 10 of them with an experience of 15 years, and 8 of them more than 15 years.(1) Pain Perception of Patients. The pain score was evaluated for a score of 70, and the highest score recorded was 49, and the minimum score was 0. The maximum pain recorded was 49 for palatal mini-implants.(2) Gender Differences. More female patients reported orthodontic treatment, and more female patients were treated with temporary anchorage devices. Among them, the female patients had stated an average pain score of 16.71, and on average, the pain score among male patients was 13.5 (was 13.5 .(3) Type of Implant. The average pain score for the implant placed at the infrazygomatic crest was 31.8, at the buccal shelf was 30.35, and at in the palate was 36.29, whereas the interradicular mini-implants had an average pain score of 9.02. This suggested that the implants placed in the extra-alveolar site almost had aching pain, but no pain to mild pain was only present in the case of interradicular mini-implant (-implant .(4) Daily Activities and Function. In On questioning, if the patient skipped work after being placed with mini-implants, 72% did not take any break from work. Among those who missed work, 44% of them missed work for one day, whereas few took leave from work up to 3-7 days. 77.4% of subjects did not have any difficulties in continuing their leisure activities. 29.5% of patients reported having disturbed sleep postimplant placement.(5) Use of Anesthesia for Mini-Implant Placement. All the orthodontists confirmed that local anesthesia is needed to place mini-implants. For placement of interradicular mini-implants, 82% of doctors gave infiltration, 14.9% said only topical anesthesia would be sufficient, and very few doctors gave a nerve block. In order to place extra-alveolar screws at the infrazygomatic crest, buccal shelf, or the ramus, the requirement of a nerve block was suggested by 48.5% of the doctors, and 51.5% of doctors felt that infiltration of the local anesthetic would be sufficient. 30% of the patients complained of pain despite the anesthesia, and 20% reported having discomfort during detachment of the driver after the implant was placed. The majority of them did not have any pain during placement.(6) Most Common Cause of Pain as Reported by Practitioners. The most common cause of pain as reported by orthodontists is that their patients reported pain at the site of insertion (35%) followed by ulceration caused due to implant (28%). The lesser common causes that caused pain to the patient were incorrect placement (14%) and infection (13%). Few patients had reported pain and discomfort due to difficulty in eating and swelling (4%).(7) Specific Hygiene Instructions to Patients. The majority of the doctors had advised the use of mouth-rinse postplacement. Some had suggested that mouth rinse was done with chlorhexidine, while others had suggested salt in lukewarm water. Few doctors suggested cleaning the implant head with a soft toothbrush or ear bud dipped with chlorhexidine and, most importantly, preventing any food accumulation.(8) Use of Antibiotics and Analgesics. When the patients were asked if they took analgesics after the placement of mini-implants, 47.9% of the patients had used analgesics. According to the patients, the most common drug prescribed to them was paracetamol (39%) followed by aceclofenac (11%) and ibuprofen (7%). Most of the patients did not recall the drug they had taken (43%).57% of the doctors had reported that they do not prescribe antibiotics after mini-implant placement, but the remaining 43% gave antibiotics routinely after the placement. 14 doctors did not specify what antibiotics they prescribed. Amoxicillin was the most commonly prescribed, followed by ciprofloxacin. 70% of the doctors routinely prescribed analgesics. The most commonly prescribed NSAID was paracetamol or acetaminophen (80%), followed by ibuprofen and aceclofenac.(9) Intervention and Management for Pain. 48% of doctors said they did not observe any swelling or soft tissue overgrowth where the mini-implants were placed, whereas 52% reported soft tissue overgrowth. The most common intervention during soft tissue swelling that the practitioners did was to remove and reposition the implant as suggested by 60% of the doctors. The second most common intervention was to excise the soft tissue, followed by assessing the situation. Most of the doctors had observed ulceration only sometimes (59%), 10 doctors had reported they observed ulceration very often, and 25% had never observed their patient developing any ulcer. When the patient developed an ulcer, 54% of the doctors wanted to place composite on the head of the screw, to prevent repeated soft tissue overgrowth, 49% gave oral ulcer gels either alone or as an adjuvant, and 25% of practitioners gave palliative care with placement of wax on the implant head.Pain is a subjective phenomenon and often is tedious to assess and depends on various variables. It tends to vary based on gender, age, the site of mini-implant placement, and the subject's previous experience of pain . In our The scores for pain in our were relatively lesser for interradicular mini-implant with an average of 9.02. In a randomized trial conducted by Ganzer et al., it was pointed out that there was pain and discomfort associated with the placement of mini-implants, but this pain was lesser in intensity in comparison to postoperative pain following tooth extraction . On compWe observed a high pain score in the palatal region (36.29) followed by the mini-implants placed in the infrazygomatic crest region 31.8) and at the buccal shelf (30.35). The mini-implant placement in this region often requires a higher torque value due to the higher bone density and often experiences high levels of pain immediately postplacement . In a co and at tDu et al. had compared in a study the pain in microimplants, mini-implant, and miniplates. They had recorded a VAS score of 61.1 mm. They had observed a high VAS score when a palatal mini-implant was placed due to irritation to the tongue . The higMost of the orthodontists we questioned preferred the use of infiltration anesthesia before the placement of the mini-implant. It is not uncommon for certain practitioners to place mini-implants by merely using topical anesthesia. Patients are often anxious about the injection . Local aMaintenance of utmost sterilization protocol is essential in order to prevent infection, and more than half the doctors do not recommend the use of antibiotics postplacement. Patients are also instructed to regularly use mouth rinse and clean the surface of the implant head in order to prevent the accumulation of plaque that can lead to inflammation and infection. In contrast, most practitioners readily prescribed analgesics, and paracetamol was the most commonly prescribed drug. Ibuprofen, acetaminophen, and aspirin are often used in relieving orthodontic pain. These are also commonly prescribed after placement of mini-implant , 30. AneThe limitations of this study are as follows: the questionnaire was not given at a set interval, and most of the previous studies had shown that the maximum VAS scores were recorded between 1 and 6 hrs after insertion of the mini-implant. There is a reduction of pain after about 1-week postplacement of the mini-implant . Our stuPractitioners should be aware of the discomforts experienced by their patients in order to achieve maximal treatment efficacy and happy compliant patients. During placement of mini-implants, female patients reported more pain. The mini-implants placed in the palatal, infrazygomatic crest, and the buccal shelf region reported high pain scores and affected daily functions. Analgesics should be prescribed to ensure pain-free treatment with TADs. Proper placement techniques and effective palliative care should be utilized to prevent the development of ulceration, soft tissue enlargement, and swelling.


Myofascial neck pain is a common musculoskeletal problem caused by presence of trigger points and local and referred pain patterns. Chronic neck pain is responsible for the involvement of joints, ligaments, fascia and connective tissue as well. The objective of this study was to assess the effect of Maitland mobilization in patients with myofascial chronic neck pain.In this randomized, placebo treatment-controlled trial, 30 patients consecutively aged 25-45 years meeting inclusion criteria were isolated into two groups. The study group was treated with Maitland mobilization consistently for eight weeks while the control group got placebo treatment for a similar timeframe. Visual analog Scale (VAS), Neck disability index (NDI) and cervical range of motion (ROM) questionnaire was filled by patients before, intermediate and after the intervention to evaluate the severity of pain, functional ability and range of motion.Following eight weeks of treatment, when compared the post treatment effects of both groups, the significance value for VAS was 0.008, for NDI p=0.030, for Flexion p=0.573, for extension p=0.001, for right rotation p<0.001, for left rotation p=0.002, for right and left side bending p<0.001.The study concluded that Maitland mobilization grades (I-IV) are effective in reducing pain and improving functional level of NDI scale and the ranges of cervical spine in patients with myofascial chronic neck pain. Neck pain is a most common issue which has manifold impacts on economy of society.7Mobilization grades are used to reduce pain and increase range of motion in patients with different disabilities. Maitland mobilization is one of the most common approach that is used by physical therapist.11When patient is capable to perform more than sixty percent of normal range of movements due to pain then techniques are applied to increase range and to reduce pain in affected joints and muscles.So many studies have been conducted on Maitland mobilization concept to reducing pain and improving range of motion (ROM). Some studies used Maitland mobilization Grades I & II only and some used grades III & IV only. The rationale behind this study was to evaluate the theory that Maitland mobilization may reduce pain symptoms, neck disability and improve cervical range of motion in myofascial chronic neck pain. So, this study provided us with fresh first hand and local evidence of Maitland mobilization concept (Grades I-IV).This interventional randomized controlled  preliminary was performed from August to September 2020 in the Riphah Rehabilitation Center, Lahore. After informed written consent thirty (30) consecutive patients Forty patients were contacted out of which 30 patients were met the inclusion criteria and recruited by non-probability consecutive sampling. Patients were divided into two groups, Maitland mobilization (study group) and conventional physiotherapy (placebo group) by randomization sequence computer-generated numbers by a biostatistician and allocation was sealed in opaque envelopes to ensure concealment. If patients were dropped out due to Covid-19 pandemic, the new patients were included according to above criteria. Patients were examined by a physiotherapist and were allotted to study or control group (n=15 each). Patients were thoroughly examined to rule out any pathology to fulfill inclusion criteria. Cervical ranges were measured through goniometer. Palpation technique was used to check the presence of trigger points in trapezius and levator scapulae muscle (both techniques were assessed in sitting position). A predesigned Performa was used to collect demographic data as age and gender of patient.The study group was treated by manual therapist with Maitland mobilization and manipulation techniques including postero-anterior Maitland mobilization (Grade I & II) for C1-C2, Maitland lateral PA glide (Grade-III & IV) for C3-C6 and Maitland mobilization with thrust (Grade-IV) for cervicothoracic junction. Frequency of mobilization was two days a week for eight weeks. While intensity of mobilization was Grade-3 and 4 based on the Maitland concept.All numerical data was subjected to statistical analysis with Mann Whitney U Test. Kolmogorov–Smirnov and Shapiro–Wilk test was used for normality data between the groups. P-value ≤ 0.05 was considered significant.Thirty patients meeting the inclusion criteria were considered. After drop out due to Covid-19 pandemic, two new patients in study group and one new patient in placebo group were again added by selecting through the above procedure. Kolmogorov Smirnov and Shapiro-Wilk were applied as tests for normality and there found all the data normative (p ≥ 0.05) throughout the assessment. Out of 30 patients, 12 (40%) male and 18 (60%) were female. The mean age of the study group was 34.87±6.70 years, while the mean age of placebo group was 36.13±6.50 years, the minimum age was 25 years while maximum age was 45 years.In our study As regards neck disability index, no critical difference between the two groups was seen at the start of study (p=0.567). The acquired outcomes were comparable for cervical range of motion, demonstrating a statistically significant difference in cervical extension simply after the treatment period (p ≤ 0.003) while non-significant in cervical flexion range of motion after treatment (p ≥ 0.573).Cervical right and left rotation were measured from beginning and end of treatment course . The meaAdditionally, cervical right-side flexion and left side flexion was measured from beginning and end of treatment course . The meard grade to 4th grade of Maitland concept).Comparison was made between the impacts of Maitland mobilization in addition to physical therapy interventions in patients with myofascial chronic neck pain. Results of above-mentioned study showed reduced pain and increased range of motion and improved neck disability index (NDI) with Maitland therapy when it was compared with control group. Although, participants in both groups showed decreased in pain over time. But the pain reduction in Maitland group was because of neuro physiological, sympathetic and psychological effects of mobilization.It is noted that changes in sessions are valid and seen long-lasting changes with immediate effect also.16Current study results showed Maitland mobilization and manipulation was valuable in improving outcomes. Many studies have explained correlation of neck muscle atrophy and neck pain. Decrease in muscle strength is caused by inhibition effect of pain and muscular changes.Pain free ROM is important for normal movement. Low score of NDI in all subjects are due to reduction of pain and increased in range. Moses MJ, et al.In current study, at first week, fourth week and eighth week mean difference between values of Neck Disability Index, Visual Analogue Scale and range of motion of spine such as flexion, right and left side flexion, extension and rotation of all sides was concluded. Mean and standard deviation of above-mentioned data can be seen in This study was conducted on patients with trigger points in trapezius and levator scapulae. We did not look for the effects of distant trigger points or the latent trigger points that did not showed jump sign. In addition as a baseline treatment consisting of TENS and moist heat was also given to both groups throughout the study period which masks the effects of single technique because it had its own analgesic effects. Study was not conducted for a long time period to check the reoccurrence of MTrPs in the selected subjects which can be observed to rule out the long-term beneficial therapy. Moreover, eight weeks is not a prolonged follow up. There should be a follow up for long duration to check the reoccurrence of trigger points and associated complaints.Maitland mobilization technique (grades I-IV) is effective in reducing pain and improving functional level of NDI scale and the ranges of cervical spine in patients with myofascial chronic neck pain. There was statistical difference between the groups to favor Maitland techniques.MS: Provided concept/research design and did data collection.NA and AN: Did statistical analysis and manuscript writing.MS & NA: Did editing of manuscript and project management.NS: Did critical revision of the manuscript for important intellectual content.NA & MS: Takes the responsibility and is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


There is no consensus on best content, set-up, category of involved healthcare professionals or duration of rehabilitation-programs for patients with chronic musculoskeletal pain, and outcomes show varying results. Individual care regimes for sub-groups of patients have been proposed.To describe the type of interventions used in a physiotherapist-led, rehabilitation-program for patients with chronic musculoskeletal pain, refractory to preceding treatments. A second aim was to report clinical outcomes at 1-year follow-up after the intervention period.All patients referred to physiotherapist within a specialist pain-unit due to being refractory to preceding treatments, and deemed fit to undergo physiotherapy-based, individualized rehabilitation during 2014–2018 were consecutively included and followed-up 1 year after ending the program. The inclusion was based on structured ‘clinical reasoning’ using the referral, examination and on patient-relevant outcome measures. The individual interventions, recorded according to a manual used when reading the patients’ medical records, were described. Primary outcomes were clinical results of perceived pain, disability and overall health at start, discharge and 1 year after discharge.In total, 274 patients  were included, suffering from chronic, severe, musculoskeletal pain  and moderate disability. The most frequent interventions were education, sensorimotor training, physical activity-advice and interventions for structures/functions  for a median of nine sessions during five months. Despite refractory to preceding treatments, 45% of the patients rated clinically important improvements on pain, 61% on disability and 50% on overall health at discharge and the figures were similar at 1-year follow-up.A physiotherapist-led, one-to-one, rehabilitation-program of median nine sessions during five months, combining individualized education, sensorimotor training, physical activity-advice and interventions for structures/functions rendered clinically relevant improvements on pain, disability and overall health in half of the patients at 1-year follow-up. Since the cohort consisted of patients refractory to preceding treatments, we believe that these results warrant further studies to identify the subgroups of patients with chronic musculoskeletal pain that will improve from new, distinctive, resource-effective rehabilitation-programs involving individualized rehabilitation. Chronic musculoskeletal pain, CMP, concerns pain lasting more than 3 months , is comm. Additionally, and in line with studies for acute/subacute musculoskeletal pain, outcomes vary [Treatment for early (acute/subacute) musculoskeletal pain is often delivered in primary care  accordinmes vary , 16, 20.In recent years, individual care regimes for sub-groups of patients with chronic pain have been proposed , stressiTo explore such an alternative rehabilitation option, a Physiotherapy Pain Rehabilitation Program, PT-PRP, was launched in 2011 at a specialized pain rehabilitation unit in southern Sweden. At that time, a number of patients were referred to the unit due to being refractory to preceding treatments  reporting a level of complexity in their unresolved pain problems that neither matched the requirements of primary care, nor interdisciplinary pain rehabilitation. The PT-PRP was conceived as a patient-centered option for patients with CMP, requiring one-to-one physiotherapy. The underlying treatment philosophy to the PT-PRP focused on the optimization of patients’ value-based activities and participation, using physiotherapist-led-interventions . The trFor management and evaluation purposes of the PT-PRP, also program-goals were expressed for the outcome of the program, describing the patients´ experiences of pain, activity and common health, as evaluated by patient-relevant outcome measures, PROMs, collected at start, discharge and 1 year after discharge, showing yearly promising clinical results. To investigate the PT-PRP content and outcomes for a larger population, all data from patients enlisted during 2014–2018 are evaluated in the present study, forming a basis for a future RCT .The main aim of this study was to describe the type of interventions used in a physiotherapist-led rehabilitation-program for patients with CMP refractory to preceding treatments and therefore referred to specialized care. A further aim was to report clinical outcomes at 1-year after end of the intervention period.The PT-PRP was developed to meet the clinical demands of individualization but also the demands of resource efficiency and patient relevant outcomes and had recurrently been accredited according to international standards of quality, value, and outcomes through a consultative accreditation process (CARF ). Since Inclusion and exclusion of the program followed a structured, written routine based on: 1) the written referral, 2) questionnaires with PROMs, and on 3) clinical examination according to ‘clinical reasoning’ , 29, 30.All referrals were screened by a senior physiotherapist who verified that the patient suffered from chronic (> 3 months) musculoskeletal pain, and that the patient was 18 years or older. Additionally, a primary screening for exclusion was performed from the referral, and then followed up during the later examination, concerning: acute psychiatric illness or acute crisis, if the patient had urgent social- or economic difficulties or was in a present alcohol- or drug abuse and if the patient had social or psychological consequences hindering the improvement of physiotherapeutic interventions. The referrals were sent mostly from primary care (either directly or via the Unit’s own interdisciplinary assessment teams where the physiotherapist was one of the team-members) or from orthopedic-, rheumatology-, oto-rhino laryngology clinics due to persisting pain-related complaints, refractory to preceding treatments at the referring caring facility.After the referral screening, questionnaires with PROMs were sent to the patient with queries about pain, activity-limitations, pain management, perceived health and consequences in life. The PROMs were sent at start, at discharge and 1 year after discharge. For specific content; see “Assessment and questionnaires…” and “Global assessments…” below.When the patient was examined in the PT-PRP, pain modalities (nociceptive/neuropathic/nociplastic pain), joints, muscles, nerves, functions and activities were analyzed also including the perspective of sensorimotor control in functional movements and joint stabilization . MoreoveThus, the physiotherapist used the combined information of the referral, the examination, the PROMs and the medical records data to decide on whether or not the patient had a complexity of pain problems that could benefit from further rehabilitation led by a physiotherapist in specialized care in a one-to-one relation (not group-rehabilitation) or if the patient required interdisciplinary pain rehabilitation instead. This decision was made according to ‘clinical reasoning’, defined as a “process in which the therapist, interacting with the patient and others (such as family members or others providing care), helps patients structure meaning, goals, and health management strategies based on clinical data, patient choices, and professional judgment and knowledge” , and comUsing the structured routine described above, all patients with CMP that between Jan 1st 2014 and 20th Nov 2018  that were referred and then admitted to participate in the PT-PRP, were consecutively included in the present study.Based on the referral, the examination and the PROMs, the type of interventions used were individualized as for type, number of interventions, frequency and length of the rehabilitation. However, the length of the rehabilitation did not exceed 6 months at the unit since that was the maximum time the patient was allowed to stay before discharged from the rehabilitation-program or to be referred to another facility. The choice of intervention was based on ‘clinical reasoning’ and in accordance with evidence-based medicine and in discussion with the patient, and thus not specifically predefined prior to the start of the program. To create a goal-oriented rehabilitation, each patient in collaboration with the physiotherapist, formulated value-oriented, activity-based goals at start of the rehabilitation, likely to be achieved during the program. The patients’ activity-goals were used for patient motivation, when discussing the choice of interventions and when to decide the end of the program. The PT-PRP also included home-exercises as an essential part of the rehabilitation. Notably, the interventions used in this study were not at the discretion of the researchers, meaning that the interventions were not offered only to this particular study-population, and were delivered according to regular care .i) the first author studied the development of treatment categories as described in prior literature of primary care physiotherapy interventions [ii) these categories were discussed with all physiotherapists at the unit  and 10 categories were agreed upon, iii) the first author used the 10 categories to scrutinize five medical records (not used in the present study). The list of categories were adjusted, finally settled, and a manual was written on how to read and categorize all interventions found in the medical records Table Data on what specific interventions that each patient engaged in during the rehabilitation-program was collected by the first author by reading the medical records for all 274 patients in the cohort using the following manual. The manual was developed from the following steps: ventions , ii) theThe physiotherapists, a total of 11 Registered Physical Therapists involved in the PT-PRP during the five years of the study, were all trained in Sweden and with particular formal qualifications and expertise on assessment and rehabilitation in acute and chronic pain, orthopedics, Orthopedic Manual Physical Therapy, sensorimotor control and on rehabilitation and specific interventions in patients with CMP. All physiotherapists had 2016–2018 taken part in an education program at the unit, aiming at including also an approach inspired by the tenets of Acceptance and Commitment Therapy (ACT), in the program, for example by emphasizing a value-oriented perspective and committed actions based on the patients’ values in goal-setting, using mindfulness as an intervention for contact with the present moment, and also, when appropriate, focus on the improvement of value-oriented functions over reducing pain. Two physiotherapists had PhD degrees allowing for research competence.The patients answered questionnaires at the start and at discharge of the rehabilitation-program (or after a maximum of 6 months) and at 1 year after discharge of the rehabilitation-program (1-year follow-up). The primary outcome was: perceived pain during last week on Numeric Pain Rating scale (NPRS) , 0–10 , and also one question used in the Swedish Quality Registry for Pain Rehabilitation, SQRP : “Has yoTwo questions were used to monitor the amount of weekly physical activity. At start, at discharge and at 1-year follow-up the patients answered: 1) “For how long do you practice leisure exercise per week, for example walking, biking or gardening? Count the total sum of minutes spent ”: this was categorized as “less than 30 min/week”, “30–60 min/week”, “60–90 min/week”, “90–150 min/week”, “150–300 min/week”, “more than 300 min/week” , and 2)p ≤ 0.01 were considered statistically significant. All calculations were performed using IBM SPSS Statistics 25.The study was a longitudinal cohort-study and descriptive statistics were used to analyze frequencies and distribution. The interventions used are presented in proportions (%) and a cluster analysis was performed to calculate the most common combination of interventions. Moreover, clinical outcomes such as the patients’ ratings of pain, disability and health status at start, discharge and at 1-year follow-up were calculated. The following minimal clinical important differences (MCID) for improvement were used; NPRS, minimum two points , 45, disThe study was approved by Swedish Ethical Review Agency (Dnr: 2019–03701).During the study period Jan 1st 2014 to 20th Nov 2018, a total of 486 consecutive patients were referred to the physiotherapy department and eligible to be included. All individuals that started the rehabilitation program and were included at a date that allowed for follow-up at discharge and at 1-year after discharge in the PT-PRP were included. Due to administrative changes and the development of the questionnaires for clinical purposes, 82 patients were excluded because of changes in the early versions of the questionnaires, and hence there were no follow-up data for these patients. Also, during the almost 5 years of the study, 130 patients discontinued or postponed their rehabilitation-program due to for example new injury, surgery or developed new illness that was not known at inclusion, Fig. The four interventions practiced by most patients in the PT-PRP were education, sensorimotor training, physical activity-advice and interventions aiming at improving structures and functions, as demonstrated in Table p < 0.001 respectively, Table The patients’ ratings of NPRS, DRI and EQVAS improved between start and discharge, and between start and 1-year follow-up, p < 0.001, and was reduced to 26% at 1-year follow-up but was still improved when compared to start, p < 0.001 Table p = 0.367), and 74% of the patients still rated that the rehabilitation had improved or much improved their ability to manage life circumstances. There was also a statistically significant improvement in the proportion of patients rating a rather/very/extreme anxiety or depression, 23% at start vs 16% at 1-year follow-up, p = 0.006 Table At start of PT-PRP, only 11% of the patients rated a high ability to reduce pain/ailment . At discharge of the rehabilitation-program this was improved to 34%, p = 0.001). Also, most of the patients, rated at discharge of the program that the rehabilitation had improved their ability to be physically active  and at 1-year follow-up, there was no significant reduction in improvement (p = 0.775), since still 69% of the patients rated that the rehabilitation period had improved their ability to be physically active Table The patients’ ratings of physical leisure exercise of minimum 150 min or more/week improved from 36% at start, to 43% at 1-year follow-up  at the specialized pain-unit, can be a key factor. Also valuable is the extended one-to-one time offered for each session , according to structured methods that are in line with accredited standards [Reflections on the uniqueness of the PT-PRP and the prerequisites to deliver such a program can be made from a clinical point of view. One corner stone might be the advanced knowledge and experience held by the physiotherapists in the PT-PRP in the examination and rehabilitation of tandards . The clotandards , or whenp ≤ 0.01.In the present study we have performed many comparisons, and to avoid chance findings due to multiple testing we conservatively set the significance level at We used the medical records to identify interventions used in the rehabilitation-program. This method is not validated, and the difference between writing a medical record for medical purposes as compared to using and collecting this data for scientific purposes could have influenced the data collected. Also, this procedure could involve a risk for miss-classification as described above; for example could the category “education” could have been used in a broad perspective in the medical record , containing interventions that could have been categorized elsewhere. On the other hand, this procedure avoided the problem discussed by Forsbrand et al. who concluded that “self-reporting” of intervention-data into a predefined protocol did not fully reflect the actual behavior of what interventions were performed . AnotherThe number of patients excluded due to changes in data collection (82 patients) and the number of patients that chose to discontinue the program (130) during the 5 years of data collection are a limitation of the study to be taken into account. Further, there was no comparison group to the clinical data, since the main aim of the study was to describe the interventions used in the rehabilitation-program. Still, we argue that since the patients had been refractory to preceding treatments at the prior caring facility with persistent complaints, they could be regarded as their own control.At program inclusion, decision making was based on structured ‘clinical reasoning’ , but no predefined, criteria developed for scientific reasons were used during this process since this was part of regular, clinical practice. This is a limitation of the study, especially when considering reproducing the procedure, and the exact decision-making criteria used, made by the physiotherapist in collaboration with the patient, remains to be addressed in a forthcoming study.We are aware that employment or working status is a highly important factor in chronic pain , 57 and In conclusion, for half of the patients, referred due to refractory to preceding treatments at the prior caring facility and with persistent complaints of CMP, a combination of individualized education, sensorimotor training, physical activity-advice and interventions for structures/functions rendered promising clinically important long-term improvements on pain, disability and overall health after only nine, one-to-one physiotherapist-led rehabilitation sessions.


Pain following craniotomy is challenging. Preoperative anxiety can be one of the controllable factors for prevention of post-craniotomy pain. The main objective of this prospective observational study is to determine this relationship in patients undergoing scheduled craniotomy from February to June 2021. After excluding patients with Mini-Mental State Examination (MMSE) ≤ 24 points, we administered a preoperative State Trait Anxiety Inventory (STAI) questionnaire. We recorded the patient’s analgesic assessment using the Numerical Rating Score (NRS) at 1, 8, 24, and 48 h after surgery. A total of 73 patients were included in the study. Twelve others were excluded due to a MMSE ≤ 24 points. The main predictors for NRS postoperatively at 1, 8, 24, and 48 h were STAI A/E score, male gender, youth, and depression. We identified a cut-off point of 24.5 in STAI A/E for predicting a NRS > 3 (sensitivity 82% and specificity 65%) at 24 h postoperative and a cut-off of 31.5 in STAI A/R (sensitivity 64% and specificity 77%). In conclusion, preoperative STAI scores could be a useful tool for predicting which patient will experience at least moderate pain after craniotomy. The identification of these patients may allow us to highlight psychological preparation and adjuvant analgesia. Craniotomy has been considered less painful than other surgical interventions because of the lack of nociceptors in the brain tissue. However, we now know that this is not true. The incidence of postoperative pain is high, and its intensity can range from moderate to severe . Recent Inadequate management of acute postoperative pain is deleterious since it increases morbidity, changes in quality of life, functionality, and delays in recovery time. It is also unfavorable for the healthcare system because it increases costs . SpecifiOne of the controllable factors for prevention of post-craniotomy pain is preoperative anxiety. A relationship between preoperative anxiety and acute postoperative pain in surgeries other than craniotomies has been defined . AnxietyThe main objective of this prospective observational study is to determine the relationship between preoperative anxiety and postoperative pain in patients undergoing scheduled craniotomy under general anesthesia. As secondary objectives, we assess preoperative risk factors for preoperative anxiety, and which perioperative variables can predispose a patient to suffer from greater postoperative pain.Clinicaltrials.gov, accessed on 22 December 2021 (NCT04720248). All methods followed good clinical practice. All patients over 18 years old who were to undergo scheduled supratentorial craniotomy and who signed informed consent were included. Exclusion criteria were: patients suffering from disabilities or cognitive impairment defined as a score ≤24 points in the Mini-Mental State Examination (MMSE), or patients who could not collaborate on the postoperative clinical assessment. This manuscript follows the STROBE guidelines [This prospective observational study evaluated preoperative anxiety and postoperative pain in patients scheduled to undergo craniotomy in a university hospital from February to June 2021. The study was approved by the Ethics Committee of Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain , and prospectively registered at idelines .Preoperative anxiety was evaluated using the Anxiety Scale State-Trait Anxiety Inventory (STAI), a questionnaire developed by Spielberg et al. in 1970 . A SpaniUpon hospital admission, an independent investigator performed the MMSE. If the score in this examination was higher than or equal to 24 points, preoperative anxiety was evaluated using the STAI questionnaire. After administering the STAI questionnaire, patients were instructed on how to perform postoperative NRS to evaluate postoperative pain. Demographic preoperative data were collected: age, gender, weight, height, body mass index (BMI), educational level (dichotomized as elementary education or higher education), and physical status score according to the American Society of Anesthesiologists (ASA) (from 1 to 5). The patient’s medical history was also recorded: depression, anxiety, rheumatological illnesses, and previous use of drugs such as metamizole, corticosteroids, antidepressants, and chronic use of analgesics. Histopathological results of the craniotomy were also collected.−1) to allow orotracheal intubation and in continuous infusion during surgery to ensure intraoperative immobility. As analgesics, continuous infusion of remifentanil or boluses of fentanyl or tramadol were used following clinical practice to maintain intraoperative hemodynamic stability. Patients also received intraoperative non-opioid analgesic drugs (metamizole or paracetamol). If corticosteroids were given intraoperatively, it was also recorded along with the dosage. At the end of the surgery, the neuromuscular blockade was reversed and the tracheal tube was removed. The appearance of intraoperative complications and the placement or not of drains were recorded. The anesthesiologist in charge of the intraoperative management of the patient was not aware that the patient was participating in a study evaluating postoperative analgesia. Patients were transferred to the postoperative Intensive Care Unit (ICU) under the care of an independent clinician. They were transferred to the surgical ward 24 h after the surgery. In the absence of allergies, all patients received an endovenous continuous infusion of metamizole 12 g during the first 48 postoperative hours. If patients were allergic to metamizole, paracetamol 1g each 6 h was prescribed. An investigator, who was blinded to the patient’s preoperative anxiety assessment, collected the patient’s analgesic assessment using NRS at 1, 8, 24, and 48 h after surgery. Follow-up ended 48 h postoperatively.All patients underwent elective craniotomy under general anesthesia. The diagnostic  and the type of craniotomy was recorded according to the surgical incision , as well as the duration of the intervention. Intraoperative anesthetic management was carried out according to standard clinical practice. Patients were monitored with electrocardiogram, peripheral oxygen saturation, invasive arterial pressure, and bispectral index . General anesthesia was performed using continuous propofol infusion to maintain BIS 40–60, using cisatracurium in bolus  was calculated to find the best cut-off values of the STAI A/E and STAI A/R to predict the NRS ≥3 at the first and 24 h postoperatively and expressed as AUC. Sensitivity and specificity were calculated to choose the best cut-off values. A From the 85 patients assessed for eligibility during the study period, 12 were excluded due to a score of ≤24 points in the MMSE. Consequently, 73 patients were included in the study. The characteristics of the patients and the intraoperative variables are summarized in The incidence of nausea was 1.4%. No postoperative vomiting was recorded. Pain assessment was performed postoperatively on all patients. The mean NRS was 3.26 + 1.97 at the first hour, 2.56 + 1.71 at 8 h, 2.04 + 1.46 at 24 h, and 1.84 + 1.20 at 48 h. The optimal variables to predict postoperative NRS were calculated. The optimal variables found were: STAI A/E, age, female gender, ASA physical status 3–4, depression, and MMSE for NRS at the first postoperative hour; STAI A/E, age, female gender, depression, parietal/occipital craniotomy, and length of surgery for the NRS at 8 postoperative hours; STAI A/E, age, female gender, ASA physical status 3–4, depression, parietal/occipital craniotomy, and length of surgery for the NRS at 24 postoperative hours; and STAI A/E, age, length of surgery, and use of intraoperative dexamethasone for NRS at 48 postoperative hours. We identified that a cut-off point of 24.5 in STAI A/E was the best one to predict NRS ≥ 3, with an area under the curve (AUC) of 0.60 with sensitivity 62% and specificity 65% at the first postoperative hour, and an AUC of 0.69 with a sensitivity 82% and specificity 65% at the assessment performed at 24 postoperative hours. However, in the STAI A/R questionnaire, 22.5 was the cut-off point that best defined a NRS greater than 3 in the first postoperative hour, with an AUC of 0.5 and with a sensitivity 33% and a specificity 77%, and the cut-off point of 31.5 was better to define NRS at 24 postoperative hours with an AUC of 0.68, sensitivity 64%, and specificity of 77%  can increase the risk of bleeding, which is highly dangerous in neurosurgical patients. Given that the pharmacological management of pain control is a challenge, several studies have focused on discovering other variables that could intensify or mitigate pain. Looking for strategies to improve pain control, ERAS (Enhanced Recovery after Surgery) programs have also reached neurosurgery . It has On one side, the use of adjunctive therapies could help ameliorate pain. In a recent systematic review of pharmacological interventions for the prevention of acute postoperative pain in adults following craniotomy, it has been indicatedthat NSAIDs rank first for their efficacy . HoweverOn the other hand, as we have already mentioned, psychological preparation prior to surgery can reduce postoperative pain due to its psychological component. This may involve several strategies described in previous studies : providiRegarding the scale chosen to assess anxiety, most prospective studies on preoperative anxiety have used STAI. . HoweverIn this study, we observed that both STAI A/E and STAI A/R are capable of predicting that the patient will experience at least moderate pain at 24 h, with an 82% and 64% sensitivity and a 65% and 77% specificity, respectively. Given these sensitivity and specificity values, if one of the two had to be chosen, we would select the most sensitive (STA A/E). In addition, the cut-off point of the STAI A/R is too high to be used, so few patients would obtain this score and would benefit from this screening.Regarding the variables that could affect post-craniotomy pain, we found that the most important was the STAI A/E score. However, we also stated that other factors can influence postoperative pain such as male gender, youth, and depression. Young patients have a higher incidence of pain. Currently, it is known that the probability of experiencing post-craniotomy pain is reduced by 3% for each year of life . It has Analyzing the risk factors for preoperative anxiety, we did not find a significant relationship with the preoperative variables analyzed. In many studies, women have higher levels of anxiety than men ,28. We aWe acknowledge some potential limitations in the present study. First, the incidence of chronic pain 3 months postoperatively was not analyzed. Considering the high incidence of chronic pain after craniotomy, this outcome could have been interesting and relevant, since its presence actually reduces the quality of life of our patients. Second, excluding patients using the MMSE may be a quick technique, but could also be inaccurate. It has been reported that cognitive impairment is frequent in patients who are going to undergo craniotomy  and for In conclusion, this is the first study in patients scheduled for craniotomy under general anesthesia showing that preoperative STAI scores could be a useful tool for predicting which patient will experience at least moderate pain after craniotomy. The early identification of these patients may allow us to insist on several aspects, such as psychological preparation and adjuvant analgesia. A preoperative visit performed by a specialist  with a psychologist could reduce preoperative anxiety and, thus, influence the appearance of postoperative pain.


The presence of the GG genotype in the rs6318 polymorphism of the 5HTR2C gene had a protective effect on PONV , when the GG variant of the rs11214763 polymorphism of the 5HTR3B gene, when the risk of PONV was 1.65-fold higher . Pain intensity was significantly higher among women with GG genotype of the rs6296 polymorphism of the 5HTR1B gene .; (4) Conclusions: the evaluation of serotonin concentration predicts requirement for opioid pain relief medication. The polymorphisms of the serotonin receptors affect the intensity of postoperative complaints.(1) Background: there is a steady increase in the number of procedures performed via minimally invasive surgery, which have many benefits, but post-operative nausea and vomiting (PONV) and significant pain are still a common problem (2) Methods: 300 infertile women (18–40 years old) undergoing minimal invasive surgery. Interventions: laparoscopy and hysteroscopy performing, evaluation of postoperative symptoms, serotonin concentrations assessment, identify genetic polymorphisms. (3) Results: serotonin concentrations were significantly lower among women who required opioids ( The past two decades have witnessed a steady increase in the number of procedures performed via minimally invasive surgery (MIS) including laparoscopies and hysteroscopies. Benefits of MIS include faster recovery, better cosmetic results and often improved outcomes. However, short-term sequelae include post-operative nausea and vomiting (PONV) and significant pain, affecting, respectively, approximately 30% , and up 3 receptor antagonists are effective and safe antiemetics [It has been proposed that a potential mechanism of action of sex hormones on mood, perception of pain and nausea related to effects on serotonin concentration ,6. Indeeiemetics ,8. In adiemetics ,10,11. Tiemetics . Severaliemetics ,14.The aims of the study were to analyze the incidence of PONV and postoperative pain following combined hysteroscopies and laparoscopies, and to determine whether serotonin play a role in these symptoms. 2. The subjects were recruited among the patients of the Clinic of Infertility and Reproductive Endocrinology, Poznan University of Medical Sciences, between January 2016 and January 2017. Women between 18 and 40 years old were deemed eligible and included in the study. Written informed consent was obtained from all participants. To minimize a potentially confounding effect of diet, and since tryptophan is a substrate for serotonin production [The prospective study evaluated 300 infertile women undergoing laparoscopy combined with hysteroscopy. Mean age was 32.5 ± 5 years; mean BMI of patients: 23.3 ± 4.1 kg/moduction , all subIO2 (fraction of inspired oxygen) was maintained between 40–50% in all subjects. Fentanyl (every 20–30 min), rocuronium (every 30–40 min) and sevoflurane or desflurane were administered to maintain adequate anesthesia. Extubating was performed after respiratory muscle function returned to normal. Analgesic treatment was based on an analgesic ladder. When the severity of pain was >4 points on the NRS scale, an opioid was given and when the intensity of pain was lower, patients received a non-opioid drug . If vomiting occurred, 4 mg of ondansetron was administered intravenously.All patients were premedicated 1 h before surgery with midazolam (7.5 mg). Fentanyl, propofol and rocuronium were used to induce anesthesia. After preoxygenation by spontaneous ventilation, patients were anaesthetized and thereafter intubated. To minimize the risk of PONV, active ventilation before intubation was avoided. F2). Subsequently, the laparoscope and an additional 2–3 trocars were inserted, as required. Each patient underwent chromopertubation using methylene blue to assess the patency of the fallopian tubes. Mean operative time was 47.55 ± 29.5 min.Indications for the surgery were as follows: suspicion of endometriosis, polycystic ovary syndrome (PCOS), suspicion of tubal occlusion, ovarian cysts, uterine myomas or idiopathic infertility. Hysteroscopies was performed concomitantly with laparoscopies. At the time of laparoscopy, a Veress needle was placed via a small periumbilical incision followed by an insufflation of carbon dioxide to attain intraperitoneal gas pressure of 12–14 mmHg pressure  was used to measure serotonin concentrations. Genomic DNA was extracted from peripheral blood leukocytes using the QIAGEN System , according to the manufacturer’s protocol, to identify genetic polymorphisms . Standardized data aggregation allowed measuring the intensity of complaints in one individual in comparison to the rest of the group. To determine the relationship between polymorphisms of analyzed genes and the prevalence of PONV and postoperative pain, Fisher’s exact test and the Chi-Square Test have been used. Odds ratio (OR) and 95% confidence intervals were calculated. The Hardy-Weinberg distribution was evaluated using an online calculator ).Statistical analysis was performed using Statistica 13.1 program. p = 0.618).High-intensity PONV was observed in 121 women . No relationship between serotonin concentration and PONV intensity was found. Mean serotonin concentrations in the low-intensity and high-intensity PONV groups were 183.5 ± 138.4 ng/mL and 175.65 ± 132.1 ng/mL, respectively (p = 0.18), a statistically significant relationship was observed between the requirement for opioid pain relief medication (morphine or tramadol) and serotonin concentrations. Serotonin concentration was significantly lower among women who required opioid administration (mean 160.35 ± 104.0 ng/mL) as compared to levels of serotonin (mean 216.15 ± 182.1 ng/mL) in women who did not require opioids (p = 0.001). The relationship between serotonin concentrations and opioid requirement is presented in p = 0.12). High intensity pain was reported by 144 subjects (48%). Despite the absence of a significant relationship between self-reported pain intensity (aggregate score of subjective assessment of the patient within a given group) and blood serotonin concentrations (p = 0.008). The presence of the GG genotype of the rs1121476 polymorphism of the 5HTR3B gene was associated with a 1.65-fold higher risk for PONV , whereas the presence of the GG genotype of the rs6296 polymorphism of the 5HTR1B gene was associated with an increased risk for high intensity postoperative pain . The distribution of alleles and genotypes of the analyzed polymorphisms and the odds ratio score for . The evaluation of the genetic polymorphism of the serotonin receptors (rs6318 polymorphism of the 5HTR2C gene) revealed that the CC genotype was associated with lowered odds of development of PONV  postoperative pain and PONV are still an important problem; (ii) serotonin concentration was significantly lower among women who required opioids six or more hours after surgery; and (iii) polymorphism of several genes (encoding serotonin receptors) is associated with greater (5HT3B) and lower (5HTR2C) risk for PONV and greater risk for post-operative pain (5HTR1B). p = 0.006). Opioid analgesics act predominantly at the injury site , which is the result of nociceptor stimulation [Pain after laparoscopy may be at the incision site—‘surgical wound pain’ and ‘non-surgical wound pain’—or be located in the supraclavicular area (referred pain) . Carbon mulation ,27, rathThere are plenty of different factors which influence levels of serotonin in the blood, ex.: diet rich in tryptophan , diabeteTo assess PONV we used 0/1/2 scale which was easy to understand ad explain for patients. Nausea was defined for patients as feeling sickness in the stomach and sensation of unease and discomfort, often perceived as an urge to vomit. Retching and vomiting were not distinguished as in other studies. In the study of McKenzie and al.  authors IO2 (fraction of inspired oxygen) was maintained between 40–50% in all subjects so this factor could not influence on difference in PONV. In the study of McKeen DM et al., the authors assessed the role of intraoperative supplemental oxygenation in prevention of PONV after gynecological laparoscopy . They deWe also found that the carriers of the GG genotype of the rs11211476 polymorphism (5HTR3B gene) had a statistically significantly higher risk for PONV. Varying intensity of nausea in patients with different variants of this polymorphism indicates that despite being located in the intron of the 5HTR3B gene, it may play a role in gene splicing and affect its expression . In a study by Lehmann et al., pregnant carriers of the CC variant of the rs1176744 gene polymorphism of the HTR3B receptor gene required higher doses of antiemetic drugs, while the AG variant in case of the rs3782025 polymorphism was associated with lower susceptibility to vomiting . In anotp < 0.05). To date, no clinical significance of this polymorphism has been documented [In our study, we demonstrated that the carrier state of the GG genotype of the rs6296 polymorphism of the 5HTR1B gene was linked with a 1.66-fold higher risk for postoperative pain. Carriers of the GC and CC variants reported significantly lower-intensity complaints (cumented . It is acumented . DifferePain as well as nausea and vomiting after gynecologic laparoscopy and hysteroscopy are common and constitute a significant clinical problem. Serotonin evaluation may be a useful predictor of the requirements for opioid pain relief drugs. Polymorphism rs6318 of the 5HTR2C gene and rs11214763 of the 5HTR3B gene have an effect on the severity of postoperative nausea and vomiting, while the polymorphism of rs6296 of the 5HTR1B gene plays a role in the intensity of postoperative pain.


Additionally, the interaction between time and different local analgesics (p < 0.001) was observed. In patients in whom 0.5% levobupivacaine has been used, significantly lower VAS pain scores were recorded at each time point assessed, in comparison with the patients who received 2% lidocaine or the patients from the control group in whom no local anesthetic was applied (p < 0.001). Furthermore, in patients in whom 2% lidocaine was administrated, significantly lower pain levels according to VAS were reported than in those from the control group, except for the time point at 24 h after surgery when pain levels were comparable. Concerning the postoperative pain control, the number of patients who requested oral analgesics postoperatively was significantly lower in the group of patients in whom local anesthetic was administrated intraoperatively  compared to the patients who did not receive any local anesthetic during the surgery  (p < 0.001). Conclusion: A significant reduction in postoperative pain intensity and analgesics consumption in patients undergoing laparoscopic varicocelectomy who received intraoperative local anesthetic was observed. The best effect on postoperative pain intensity, according to the VAS score, was achieved by 0.5% levobupivacaine.Background: The main goal of the present randomized clinical trial was to investigate the effects of subcutaneous administration of two different local anesthetics at trocar incision sites at the abdominal wall in combination with intraoperative intraperitoneal instillation of local anesthetics, on the character of postoperative pain, in adolescents who underwent laparoscopic varicocelectomy. Methods: A total of 60 patients with a median age of 16 years, who received laparoscopic varicocele repair, were included in this randomized clinical trial. The patients were randomly assigned to three study groups receiving 2% lidocaine, 0.5% levobupivacaine, or the control group. The Visual Analogue Scale (VAS) was used by a blinded nurse at four different time points  to measure pain intensity. Results: The significant effect of time on the pain intensity ( A varicocele represents an abnormal enlargement of the veins within the pampiniform plexus and has been recognized as one of the most frequent causes of infertility in men, with an incidence in the pediatric population of 10–15% ,3. The uAlthough it has been shown that pain after laparoscopic surgery is significantly less compared to open surgery, it is still present at a lower intensity ,5,6. ForSince most of the published reports are among the adult population, and because the fact that the combination of incisional site and intraperitoneal analgesia has rarely been studied, the main goal of the present randomized clinical trial was to investigate the effects of subcutaneous administration of two different local anesthetics at trocar incision sites at the abdominal wall in combination with intraoperative intraperitoneal instillation of local anesthetics, on the character of postoperative pain in adolescents who underwent laparoscopic varicocele repair.All pediatric patients with varicocele who underwent laparoscopic varicocelectomy and whose parents or legal guardians agreed to participation (n = 60) were enrolled in a prospective randomized study. The study was conducted from 1 May 2019 to 17 May 2021 at the Department of Pediatric Surgery, University Hospital of Split. The inclusion criteria were otherwise healthy patients, 12–18 years of age, who underwent laparoscopic varicocelectomy. The patients who received open or microsurgical varicocelectomy, those who underwent conversion to open procedure, and patients with chronic, metabolic, endocrine diseases or systemic infections were excluded. The primary outcome of the study was the intensity of postoperative pain. Secondary outcomes were the incidence of postoperative usage of local analgesics, the incidence of postoperative complications, and the duration of hospital stay.®, Belupo, Koprivnica, Croatia) was injected at the three trocar insertion sites (2 mL at each) prior to incision, and 10 mL of 2% lidocaine was injected at the end of the procedure, under the direct visualization of the laparoscope, below and around the defect of the peritoneum at the site of varicocele. In the second group of the patients’ total amount of 6 mL of 0.5% levobupivacaine  was injected at the three trocar insertion sites (2 mL at each) prior to incision and 10 mL of 0.5% levobupivacaine was injected at the end of the procedure, under the direct visualization of the laparoscope, below and around the defect of the peritoneum at the site of varicocele. The third group was the control group; there was no local or peritoneal administration of any local anesthetic prior, during, and after the surgical procedure. The Visual Analogue Scale (VAS) was used to measure pain intensity [A total of 60 patients were randomly assigned to the study. Depending on intraoperatively administrated local analgesic, the patients were divided into three study groups (20 patients per group). In the first group of the patients, the total amount of 6 mL of 2% lidocaine . The study was registered in the ©, Linz, Austria) (4 mg/kg), and vecuronium bromide  (0.05 mg/kg). After 20 s, the laryngeal mask was inserted [The same anesthesiologist performed all procedures under general anesthesia. Induction of anesthesia was performed using fentanyl  (4 μg/kg), propofol .A 2 mL of local anesthetic was injected subcutaneously in the supraumbilical region. After 30 s supraumbilical skin incision, 5 mm in length, was performed. Through the supraumbilical incision, a Veress needle was introduced, and COinserted A. The abinserted B,C. Afteinserted D–E. At tinserted F. After As the highest level of pain is expected 6 h after the surgery, a power calculation was performed for this time point. The expected effect size f of 2.34 was estimated from scores on the VAS scale that were observed within a pilot study, including three study groups and 45 participants in total. Under the assumption of 95% of power, a significance level of 0.05, and considering the three study groups, the minimal sample size to detect large differences with the repeated measures between-the-factors ANOVA was 9 (3 per group). Although our study was powered enough, we nevertheless enrolled 20 patients per group to allow for randomization to take effect . The allocation of participants in each study group was performed by block randomization using block sizes 3 and 6. The randomization was performed by an independent statistician using computer-generated random numbers.The statistical analysis was performed using SPSS 24.0 software . In the case where no significant deviation from normality was observed, the mean and standard deviation was used to describe a distribution of a quantitative variable. Median and range were used for asymmetrically distributed quantitative or ordinal variables. Absolute and relative frequencies were used to describe the distribution of categorical variables. The significance of differences in quantitative variables between the three study groups was assessed with one-way ANOVA for independent samples or, an alternative, the nonparametric independent-samples Kruskal–Wallis test. The Chi-square test was used to assess differences in the distribution of categorical data. In cases when the frequency of events was low, Fisher exact test was used instead. For repeated measures on the VAS scale in four time-points  general linear model for repeated measures was used. We also presented the results of repeated measurements graphically by showing mean VAS values for each time-point and each study group, with the corresponding 95% CI. All the tests were two-sided, and the significance level of 0.05 was used.p = 0.006). No intraoperative or postoperative complications were recorded. A total of 60 male patients were enrolled in this randomized clinical trial. The median age of the patients was 16 (range 13–17) years. Left-sided varicocele was recorded in all study groups. The most common indication for surgery was testicular hypotrophy > 20% (n = 28 or 47%), followed by abnormal semen analysis results (n = 24 or 40%), pain (n = 15 or 25%), and bilateral varicocele (n = 1 or 2%). There was no dropout of the participants included in the study, i.e., all subjects were examined for pain intensity on the VAS scale at all time points. No differences between the study groups were found regarding demographic, clinical, and postoperative data . The stap = 0.001) as well as the interaction between time and local analgesic groups . A significant difference was detected between the groups   . p < 0.001)  . p < 0.001).Furthermore, the patients in whom 2% lidocaine was applied reported significantly lower pain intensity at VAS than those in the control group, except for the time point at 24 h postoperatively when pain levels were comparable. The results of repeated measurements were also presented graphically by showing mean VAS values for each time point and each study group, with the corresponding 95% CI. Concerning postoperative pain control, the number of patients who requested oral analgesics postoperatively was significantly lower in the group of patients in whom local anesthetic was administrated intraoperatively  compared with the patients who did not receive any local anesthetic during the surgery  . Furthermore, 2% lidocaine also showed a positive effect on postoperative pain control , but resulted in higher pain levels in comparison to adolescents who received 0.5% levobupivacaine. The adolescents who did not receive any local anesthetic intraoperatively reported significantly higher pain levels than those who received local anesthetics. Moreover, only 5–20% of patients who received local anesthetics intraoperatively required analgesics postoperatively compared with 65% of patients who did not receive local anesthetics.Many medical professionals and patients think that laparoscopic surgery is painless. Although the level of pain after laparoscopic procedures is significantly lower than after open surgery, it has been proven in various studies that laparoscopic surgery is not entirely pain-free, especially during the early postoperative period (up to 6 h) and in some cases may require a higher amount of analgesics compared to similar open procedures ,12. In aAlthough the high incidence of varicocele varies from 14% to 20% between different studies, the incidence of varicocele among infertile men is not higher than 20% in most recently published studies ,18,19. TA recent systematic review and meta-analysis of the incision-site local analgesia showed that infiltration of local anesthetics prior to incision has no benefit over postoperative infiltration. However, when local anesthetics are administered intraperitoneally, preemptive local anesthesia decreases postoperative pain compared with the patients who received anesthesia after surgery . NeverthThanapal et al. evaluated the local anesthetic application at the operative site assuming that absorption may occur via the large surface of the peritoneum, further enhancing the analgesic effect of the administered local anesthetic. The study results proved that operative site-local anesthesia significantly improves postoperative pain immediately after and up to 24 h after the procedure and reduces the postoperative analgesic consumption . SimilarAlthough Gluck et al. detected no significant differences in postoperative pain intensity among patients undergoing operative gynecologic laparoscopy who were given analgesic agents either subcutaneously or intraperitoneally, nevertheless they found that a minimum of 5 mg (20 mL of 0.25%) bupivacaine instilled subcutaneously effectively reduces postoperative pain even in diagnostic laparoscopies .Custovic et al. observed patients who underwent laparoscopic appendectomy and concluded that 0.5% levobupivacaine is the more effective agent in postoperative pain control, compared with 0.5% ropivacaine, 1% lidocaine, and the control group, and also resulted in shorter hospitalization stay. According to the VAS scale, the level of pain was the lowest among patients who received 0.5% levobupivacaine and lasted up to 48 h after the procedure. They also observed a reduction in postoperative nausea and vomiting in patients who received levobupivacaine preemptively at the skin incisions and postemptively, intraperitoneally . The levThe goal of the latest meta-analysis conducted by Abdelhakim et al., which included seven randomized controlled trials with 579 patients in total, was to review the success of the intraperitoneal application of the local anesthetics in patients undergoing laparoscopic appendectomy. The results of the analysis showed a significant improvement in the postoperative pain control in patients who received the intraperitoneal application of local anesthetics at different time points compared with the control group of patients. A reduced frequency of postoperative nausea and vomiting, less postoperative opioid consumption, and shorter hospital stay were also recorded in patients who received intraperitoneal local anesthetics during the surgery .Nowadays, anesthesiologists have a directive to avoid the excessive use of opioids for postoperative pain treatment because of their potential life-threatening side effects, such as respiratory depression, bradycardia, and hypotension in case of opioid overdose ,23,24. TA possible weakness of our study is linked to the fact that objective pain assessment is not possible since pain is solely subjective in its character. Considering that perception of pain is individual, it is almost impossible to objectively compare the results measured according to the VAS scale among our patients. Moreover, our study was conducted only in our center. Unfortunately, because of the lack of studies assessing postoperative pain in patients undergoing laparoscopic varicocelectomy, we had to compare our results to studies examining patients undergoing different laparoscopic surgeries. To implement our findings in standardized protocols for laparoscopic varicocelectomy, our results should be replicated in additional prospective multicenter studies that are fully powered, similar to our study.Compared to the control group, the level of postoperative pain was significantly lower in patients who received local anesthetic intraoperatively. The best effect on postoperative pain intensity was achieved by 0.5% levobupivacaine administered at the three trocar insertion sites and the end of the procedure, below and around the defect of the peritoneum at the site of varicocele. The patients who received a local anesthetic intraoperatively required significantly less analgesia postoperatively than the patients who did not receive any local anesthesia during the surgical procedure.


Is an intramuscular glucocorticoid injection noninferior to an intra-articular glucocorticoid injection in reducing knee pain in patients with knee osteoarthritis in primary care?This randomized clinical trial including 145 patients with symptomatic knee osteoarthritis found intramuscular injection of the glucocorticoid triamcinolone acetonide could present an inferior effect in reducing pain at 4 weeks compared with the intra-articular injection. Noninferiority of an intramuscular injection was observed at 8 and 24 weeks after injection.The findings of this trial suggest both types of injection should be considered effective strategies and that a shared decision-making process should take place between clinicians and patients with knee osteoarthritis when a glucocorticoid injection is indicated. Intra-articular (IA) glucocorticoid injection is widely used in patients with knee osteoarthritis (OA), but the safety of this technique is in question among physicians. Intramuscular (IM) glucocorticoid injection could be an alternative approach.To investigate whether an IM glucocorticoid injection is noninferior to an IA glucocorticoid injection in reducing knee pain for patients with knee OA in primary care.The KIS trial, a multicenter, open-label, randomized clinical noninferiority trial including patients with symptomatic knee OA, was conducted in 80 primary care general practices in the southwest of the Netherlands. The study was conducted from March 1, 2018, to July 28, 2020.Patients were randomly allocated to receive an injection of triamcinolone acetonide, 40 mg, either IM in the ipsilateral ventrogluteal region or IA in the knee joint. All patients were followed up for 24 weeks.The pain score at 4 weeks measured with Knee Injury and Osteoarthritis Outcome Score , with a noninferiority margin of −7 (IM minus IA). A per-protocol analysis was prespecified as the primary analysis.A total of 145 patients  were included; of these, 138 patients  were included in the per-protocol analysis. Clinically relevant improvements in knee pain were reached up to 12 weeks after the injection in both groups. At 4 weeks, the estimated mean difference in the Knee Injury and Osteoarthritis Outcome Score between the 2 groups was −3.4 . Noninferiority could not be declared because the lower limit exceeded the noninferiority margin. Intramuscular injection was noninferior to IA injection at 8  and 24  weeks. No significant difference was found among all the secondary outcomes. These results were similar for the sensitivity analysis in an intention-to-treat population. The most frequently reported adverse events were hot flush  and headache , and all events were classified as nonserious.Based on the findings of this trial, among patients with knee OA in primary care, IM glucocorticoid injection could present an inferior effect in reducing pain at 4 weeks compared with IA injection. Noninferiority of an IM injection was observed at 8 and 24 weeks after injection. This trial provides data for shared decision-making, taking into account the advantages and disadvantages of both types of injections.NTR6968Dutch Trial Registry:  This randomized clinical trial compares the effect of intramuscular vs intra-articular injection of a glucocorticoid on pain in patients with symptomatic knee osteoarthritis. Among the pain medications, intra-articular (IA) glucocorticoid injection is one of the most widely used.2 Clinical trials have demonstrated the short-term effectiveness of IA glucocorticoid injection in reducing moderate to severe knee pain.5 Several professional guidelines recommend use of IA glucocorticoid injection for patients with knee OA who have not responded to oral or topical analgesics.9Osteoarthritis (OA) is a leading cause of disability, and the knee is the most commonly affected joint.10 A 2-year randomized clinical trial showed IA injection of glucocorticoids would result in significantly greater cartilage loss.11 In addition, although rare, IA injection is associated with higher risks of septic arthritis and postoperative joint infection,12 for which a 3-month minimum interval between injection and further operations is recommended.10 Another obstacle of implementing IA injection is that, in primary care, general practitioners (GPs) may not feel competent to place the needle into the knee joint.13However, the safety of injecting a glucocorticoid into the knee is increasingly drawing concerns among physicians.14 and hand OA.15 In a double-blind trial conducted by our team, IM glucocorticoid injection was superior to placebo injection for reducing pain in patients with hip OA up to at least 12 weeks.16 To our knowledge, no study has evaluated the analgesic effect of IM glucocorticoid injection for knee OA or directly compared its effect with IA glucocorticoid injection.Intramuscular (IM) injection could be an alternative approach for glucocorticoid administration in patients with knee OA because it eliminates the direct risks of toxic effects on cartilage and septic arthritis and is easier to perform than IA injection. Intramuscular glucocorticoid injection has been reported to be beneficial in relieving pain in other musculoskeletal diseases, such as rotator cuff diseaseTherefore, we performed the KIS randomized clinical trial to assess the effectiveness of IM glucocorticoid injection in patients with symptomatic knee OA in primary care, compared with standard IA glucocorticoid injection. The primary objective was to investigate whether an IM injection is noninferior to the IA injection in reducing knee pain at 4 weeks after injection.17 The trial protocol and statistical analysis plan as approved are available in CONSORT) reporting guideline for noninferiority and equivalence trials.18KIS was a multicenter, open-labeled, parallel, noninferiority randomized clinical trial with a follow-up period of 24 weeks. A detailed study protocol has been published.17 The treating GP assessed whether there was an indication for a glucocorticoid injection for the eligible patients. The National GP guideline recommends glucocorticoid injection for patients with knee OA who have a flare of knee pain and/or do not respond to other pain medications.19 For patients with bilateral knee OA, the most painful knee was chosen as the index knee.We recruited patients between March 1, 2018, and February 11, 2020, at 80 general practices in the southwest region of the Netherlands. Final follow-up of the study was July 28, 2020. Inclusion criteria included age 45 years and older, consulted in primary care for knee symptoms during the past 5 years with knee OA diagnosed by a GP, presence of symptomatic knee OA for at least 3 months before enrollment, and moderate to severe knee pain over the past week .We excluded patients if they were using oral glucocorticoids, had received IA injection of glucocorticoids within the past 6 months, were allergic to glucocorticoids, had a local or systemic infection or recent vaccination with live attenuated vaccine, had type 1 or poorly controlled type 2 diabetes (assessed by the GP), had inflammatory rheumatic diseases , had coagulopathy (or were receiving anticoagulants), had a history of or current gastric or duodenal ulcer, had contacted an orthopedic surgeon for potential surgical management of the knee, or were incapable of completing questionnaires in Dutch or giving informed consent.17 The treating GP prepared and administered all the injections within 1 week after completion of the baseline assessment. The GPs were instructed not to use local anesthetics during the injection and were offered an opportunity of IA injection training under supervision of an experienced orthopedic surgeon (P.K.B.).Patients in the IM group received a single intramuscular injection of triamcinolone acetonide, 40 mg (1 mL), in the ipsilateral ventrogluteal region. Patients in the IA group received a single standard IA injection  of triamcinolone acetonide, 40 mg (1 mL), in the index knee.An independent data manager, who was not involved in the clinical procedure, prepared a computer generalized randomization list using 1:1 allocation. To ensure concealment of allocation, random blocks of 8, 6, or 4 were used and the digital randomization list was kept on an encrypted website. After the patient had provided written informed consent and finished baseline assessments, a member of the research team performed the randomization on the encrypted website and then informed the patient and GP of the randomization result. The researchers involved in data analysis were blinded to the treatment allocation and were required to write a concrete analysis plan before conducting the data analysis.We measured outcomes at baseline (the day of completing baseline assessments), and 2, 4, 8, 12, and 24 weeks after administration of the injection via digital or paper questionnaires. Two of us (Q.W. and P.K.B.) did the baseline Kellgren and Lawrence grade scoring blinded to the allocated treatment . A consensus meeting was held for making final decisions for discrepant grades. The primary outcome was the severity of knee pain at 4 weeks measured with the Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale .20 In addition, we measured perceived recovery and the percentage of responders defined by the OMERACT-OARSI criteria.21 Patients’ perceived recovery was measured with a 7-point Likert scale, and results were dichotomized into recovered  or not recovered . The OMERACT-OARSI responders are those with high improvements (≥50% and absolute increase ≥20 points from baseline) in KOOS pain or function score; if that level is not achieved, then improvement in at least 2 of the 3 following domains: greater than or equal to 20% and greater than or equal to 10-point improvement in the KOOS pain score, greater than or equal to 20% and greater than or equal to 10-point improvement in the KOOS function score, and patient-perceived recovery in global assessment . We measured adverse events at 2 weeks’ follow-up and asked patients about cointerventions  at all follow-up times.Secondary outcomes included the KOOS pain score at 2, 8, 12, and 24 weeks; KOOS symptom, function, sport and recreation, and quality-of-life scores ; Western Ontario and McMaster Universities Osteoarthritis Index pain, function, stiffness, and total scores ; numeric rating scale of knee pain during the past week ; Intermittent and Constant Osteoarthritis Pain ; and EuroQol with 5 dimensions and 5 response levels .22 for estimating an SD of 16 for the KOOS pain score. The minimal clinically important difference for KOOS pain score is 9.23 We prespecified the noninferiority margin at 7, which is slightly smaller than the minimal clinically important difference. A sample size of 130 patients (65 per group) was needed to achieve 80% power at a significance level of α = .05 to detect noninferiority, assuming the true between-group mean (SD) was 7 (16). Based on our prior experience in glucocorticoid injection trials, we expected a low rate of loss to follow-up of 5%.24 Therefore, we aimed to recruit 137 patients.This study was powered to test whether IM injection was noninferior to IA injection regarding the KOOS pain score at 4 weeks’ follow-up. We used data from the trial of Henriksen et al25 We included patients who received allocated injections into these analyses. Patients in the IM group who received an additional IA injection within 8 weeks were excluded from the per-protocol analysis.17 We repeated the analysis on the intention-to-treat (as randomized) principle for sensitivity analysis, which included all patients and grouped patients according to randomization.As recommended for noninferiority trials, we conducted data analysis primarily on the prespecified per-protocol principle.d) by dividing estimated mean difference by the pooled SD at each follow-up. We used generalized estimating equations with repeated measures to determine odds ratios (ORs)  and their 95% CIs over time for the outcomes of perceived recovery and OMERACT-OARSI responder. Similarly, we adjusted these analyses for baseline KOOS pain score and the same baseline covariates as in the linear mixed models.We describe baseline characteristics as mean (SD) or number (percentage) as appropriate. We used linear mixed models with repeated measures to calculate mean between-group differences  and their 95% CIs over time for continuous outcomes. An unstructured covariance structure was chosen because it resulted in the lowest Akaike information criterion. We incorporated time and time by intervention group interaction into fixed effects and adjusted the analysis for the baseline value of the outcome and covariates with clinically relevant baseline differences (>10%) between the 2 groups. We calculated the effect size  with a noninferiority margin of −7. Noninferiority was declared if the lower limit did not exceed the noninferiority margin. For other outcomes, we performed superiority tests only at the 2-sided .05 significance level.17 The amount of missing data was small (4%) and was not imputed; the above-described models take the missing values into account.26 All analyses were performed using SPSS, version 25.0 (IBM Corp).We performed an explorative, predefined subgroup analysis for assessing the interaction effects of injection and baseline severity of knee pain  on KOOS pain scores by adding the interaction term into the linear mixed models.Between March 1, 2018, and February 11, 2020, 267 patients were assessed for eligibility; of these, 145 were randomized  ; Table 1In both groups, the KOOS pain score improved over the entire 24-week follow-up period; the greatest improvements were observed 8 weeks after the IM injection and 4 weeks after the IA injection. The mean improvements exceeded the minimal clinically important difference from 2 to 12 weeks within each group . At the Both injections improved joint symptoms, function, stiffness, patient sport level, and quality of life over the entire 24-week follow-up period. The IM injection presented its greatest effectiveness at 8 weeks after injection, whereas the IA injection was most effective at 4 weeks in almost all secondary outcomes. There was no significant difference between the 2 groups at all time points for all the secondary outcomes . These rAt 2 weeks’ follow-up, 24 patients (33%) in the IM group reported 27 adverse events and 28 patients (42%) in the IA group reported 38 adverse events. The most frequently reported adverse events were hot flush  and headache , and all events were classified as nonserious (eTable 3 in P = .62). The results were consistent in the intention-to-treat population.The baseline pain severity had no significant interactive effect on KOOS pain scores between the 2 groups . The mechanism behind this difference could be related to pharmacokinetics. Given that suppression of joint inflammation by IA injection of corticosteroids is associated with a lower level of knee pain,27 an IM injection may need longer to reach an adequate concentration of corticosteroids in the knee compared with an IA injection. However, this hypothesis needs to be tested in further studies.To our knowledge, this is the first randomized clinical trial evaluating the effectiveness of an IM glucocorticoid injection for knee OA. The results are consistent with a previous trial of IM injection in patients with hip OA, with IM injection showing clinically relevant effects compared with placebo from 2 to 12 weeks and had the greatest effect approximately 6 weeks after injection.5 and Deyle et al,28 but larger than the effect (at 2 weeks) reported in the trial of Henriksen et al.22 A possible reason for the difference could be that Henriksen et al22 recruited a group of patients with less pain at baseline than in this present trial, and patients with milder pain were reported to experience a smaller benefit from glucocorticoid injection.29The analgesic effect of the IA injection presented in this trial is similar to the previous trials of Conaghan et al16 In addition, according to the baseline assessment of this study, more patients preferred IM to IA injection (47% vs 19%). These findings should be mainly considered as slight preferences and might not be extrapolated to the general population, because patients with strong preferences would probably have declined to participate in this trial. Nevertheless, this selection reflects the fact that the IM injection is a preferable approach in some cases from the perspective of the patients. Furthermore, effect sizes of between-group differences were small at all time points, and no significant differences were found in any of the primary and secondary outcomes, including joint pain, function, stiffness, patient sport level, and quality of life. It may be best to inform patients on these outcomes, especially when clinicians feel incompetent in administering an IA injection. Taken together, the findings of this trial suggest that a shared decision-making process between clinicians and patients with knee OA would be useful when a glucocorticoid injection is indicated.For clinical practice, interpretation should also include the adverse events, patient preference, and clinician’s skills. Combined with the results of a previous trial, a single IM injection of triamcinolone, 40 mg, should be considered safe because no injection-related serious adverse event was reported in patients with either hip or knee OA.30 Third, the multicenter design strengthened the generalizability of the results to other primary care clinics.This study has several strengths. First, we recruited the targeted number of patients from our sample-size calculation and had high adherence and follow-up rates. As a result, statistical inferences were consistent in the per-protocol and intention-to-treat populations. Second, we administered IM injections at the ventrogluteal region, which contains a thin layer of subcutaneous fat and helped decrease the possibility of subcutaneous injection, especially for patients who were overweight.32 Therefore, IM injection is likely to have a smaller placebo effect than IA injection. This hypothesis is supported by the previous trial in which IM injection presented a minimal placebo effect in patients with hip OA.16 Moreover, pragmatic trials are designed for simulating clinical effectiveness; elimination of the placebo effect would underestimate the real benefit.33 Second, although the noninferiority margin of 7 points was prespecified, taking clinical relevance into account, it was a subjective choice. As described in the CONSORT statement and previous noninferiority trials, an evidence-based margin rarely exists.35 Third, this trial was designed to assess the effectiveness of a single injection; however, in total, 4 patients (6%) in the IM group and 9 patients (14%) in the IA group received an additional IA glucocorticoid injection before 24 weeks’ follow-up.The trial has limitations. First, as a pragmatic trial, it was practically impossible to blind GPs and patients to the treatment allocation, and no placebo-controlled group was incorporated, so the measured effectiveness of the 2 injections might incorporate part of a placebo effect. However, as previously reported, the placebo effect of injection therapy for knee OA seems mainly derived from the use of the IA delivery methods.The findings of this trial suggest that, among patients in primary care settings with symptomatic knee OA, an IM glucocorticoid injection could present an inferior effect in reducing pain at our primary end point of 4 weeks, compared with an IA injection. An IM injection is noninferior to IA injection at 8 and 24 weeks after injection, but not at 2 and 12 weeks. Both types of injection should be considered effective strategies, and this trial provides evidence for shared decision-making between clinicians and patients, taking into account the advantages and disadvantages of both treatment strategies.