The objective of this randomized clinical trial was to clinically evaluate the incidence of postoperative pain after root canal treatment in symptomatic irreversible pulpitis of multirooted teeth using two different instruments design rotary file systems, namely, Protaper Next (PTN) and V taper 2H (VT2H).In this prospective randomized clinical trial, 60 patients with symptomatic irreversible pulpitis of multirooted teeth, indicated for root canal therapy, were randomly assigned to two groups according to instrument system used, namely, PTN and VT2H. Root canal treatments were performed in single visit. After treatment, the participants were asked to rate the intensity of post-operative pain on modified verbal descriptor scale after 8 h, 24 h, 48 h, and 72 h over the telephone by a second investigator. Patients were advised to call the second investigator by telephone if they felt very uncomfortable at any point of the follow-up time. At that time, they were asked to take ibuprofen 200 mg as the rescue drug.P>0.05, Kruskal–Wallis test).No statistically significant difference was found among the two groups in relation to post-operative pain and intake of analgesic medication at 4 time points assessed (The PTN system and VT2H rotary system were found to be equal in the incidence of post-operative pain and pain intensity was found to decrease with time, postoperatively, in both the rotary systems.The instrument design has little effect on post-operative pain in symptomatic irreversible pulpitis patients after single-visit root canal therapy. Treating patients with symptomatic irreversible pulpitis in a single visit are a challenge as post-obturation pain is major concern. Post-operative pain is defined as any degree of pain that occurs after initiation of root canal therapy . VaryingPost-obturation pain is multi factorial in origin and can be influenced by gender, tooth type, insufficient instrumentation, irrigant extrusion, intracanal interappointment dressing extrusion, hyperocclusion, missed canals, presence of pre-operative pain, presence of periapical pathosis, apical debris extrusion, and apical patency during root canal preparation . AnotherThe periapical extrusion of debris may induce an inflammatory reaction in the periapical area, leading to elevated concentrations of prostaglandins which usually manifests as pain. Hence, extrusion of infected debris to the periradicular tissues during cleaning and shaping is allegedly one of the principal causes of post-operative pain .et al. also [Many randomized clinical trials have noted a lesser incidence of post-operative pain with rotary systems when compared with reciprocation systems -12. Thisal. also . The desal. also .The aim of the present randomized clinical trial was to clinically evaluate the post-obturation pain in single-visit root canal treatment with two different designs of instruments mainly Protaper Next (PTN) and V taper 2H (VT2H). The null hypothesis was that there is no difference in post-obturation pain after single-visit root canal treatment with PTN and VT2H rotary system in symptomatic irreversible pulpitis of multirooted teeth.This parallel, double-blinded, randomized clinical trial was carried out after obtaining the approval of the Institutional Ethical Committee (reference no. D168401011) and registered under Clinical Trial Registry-India with register no. CTRI/2018/08/015339. The study subjects were recruited from the patients who registered in the department of conservative dentistry and endodontics.The minimum sample size required was determined to be 25 subjects per group to achieve 80% power to the study. The sample size was increased to 30 per group, to compensate for dropouts. A total of 60 patients out of which 18 male and 39 female patients of age between 18 and 45 years having multirooted teeth with symptomatic irreversible pulpitis, requiring endodontic therapy were included in the study.Patients having multirooted teeth with symptomatic irreversible pulpitis were scheduled for endodontic treatment. Patients aged between 18 and 45 years, who showed prolonged response in the tooth even after the removal of the stimulus, who had the ability to understand the pain scales and informed consent for endodontic treatment were included in the study.Patients with sinus tract, periapical abscess or facial cellulitis, known allergies, or any contraindication to opioid or non-opioid analgesics including aspirin or nonsteroidal anti-inflammatory drugs, patients with known allergy to local anesthesia, sodium hypochlorite and chlorhexidine, presence of systemic diseases such as cardiovascular disease, renal disease, and any bleeding disorders, and pregnant and nursing mothers were excluded from the study. Patients with more than 1 symptomatic tooth were excluded from the study.Patients were assessed for eligibility criteria by an investigator not involved in the study. A pulpal and periapical diagnoses were given for each tooth on taking careful history, clinical and radiographic examination based on the American Association of Endodontists (AAE 2008) diagnostic guidelines. A total of 82 patients were assessed, among which 15 patients did not meet inclusion criteria, 3 patients refused to participate. Then, 64 eligible patients were divided into two groups by randomization with sequentially numbered opaque sealed envelopes (SNOSE) with 32 patients in PTN group and 32 patients in VT2H groups with allocation sequence and assigning to intervention which was done by blinded second investigator at the time of cleaning and shaping, concealed from operator to reduce bias. Out of 32 patients in PTN group, three patients were not interested in answering telephone calls so 29 patients were analyzed. Out of 32 patients in V2TH group, four patients were not interested in follow-ups and 28 patients were analyzed .After taking case history, pre-operative pain levels were recorded using modified verbal descriptor scale (MVDS) system. Written informed consent was obtained from patients who participated in this study. All the teeth were treated by single operator. Endodontic therapy consisted of local anesthesia  administration and rubber dam isolation followed by access cavity preparation. A size # 10 stainless steel hand K-file  was used to check the patency of canal. Root ZX II apex locator  was used to determine the working length which was further confirmed using periapical radiographs After working length determination, the canal was enlarged to size # 15 using stainless steel hand K-files . At this stage, randomization was carried out by second investigator based on SNOSE method and patients were assigned to two different rotary systems, namely, PTN  and VT2H  for cleaning and shaping. The canals were prepared with the files mounted on gear reduction handpiece powered by an electric motor . The patient was blinded to the type of rotary system used for cleaning and shaping.1 (17 0.4) and X2 (25 0.6) used for preparation of narrow and curved canals, using X3 (30 0.6) for wide canals up to working length. The files were used in continuous rotary motion at the speed of 300 rpm and torque 2 Ncm.For the PTN group, Sx files  were used for preflaring of coronal and middle thirds. XFor the VT2H group, glide path file, size 13 (0.3) and size 17 (0.4) were used for initial preparation, size 20 (0.6) and 25 (0.6) were used in narrow canals, size 30 (0.6) and size 35 (0.6) were used in wide canals up to the working length in continuous rotary motion at the speed of 300 rpm and torque 2 Ncm.Irrigation was carried out using sodium hypochlorite and saline using side vented needles in both the groups. The final irrigation was completed with 2 ml of 2% chlorhexidine. After the final irrigation, canals were dried using absorbent paper points and obturated with 6% gutta-percha cone corresponding to apical preparation size and AH Plus  sealer after confirming master cone fit. Finally, the access cavity was sealed with a glass ionomer cement  liner followed by a composite restoration .All the participants received a card containing MVDS to assess pain levels after root canal treatment at 8 h, 12 h, 24 h, 48 h, and 72 h. According to this scale, the level of pain was documented in the range of 0-10 numerically and verbally as no pain (0), slight pain , moderate pain (3-5), strong pain , severe pain (8), and maximum pain . All the participants were explained about the scale verbally before the start of the procedure.Patients were contacted over telephone by the second investigator at 8, 24, 48, and 72 h time period and asked to describe the general feeling in the area of the treated tooth, pain intensity both numerical and verbal (MVDS), and intake of analgesics if any. The information so obtained was recorded at each follow-up period. None of the patients were prescribed with medication immediately after the treatment. They were asked to call the second investigator by telephone if they felt any discomfort in the treated area at any point of the follow-up time. If patient complained of pain, then they were prescribed with ibuprofen 200 mg as over-the-counter drug.P<0.05).Statistical Package for the Social Sciences software was used for the statistical analysis. The Kruskal–Wallis non-parametric test was applied to compare the incidence of post-operative pain at the 4 time points assessed. The level of significance adopted was 5%  between the PTN and VT2H groups with regard to the incidence of post-operative pain at any of the 4 time points assessed . Out of 32 patients enrolled in PTN group, three patients were lost to follow up and 32 patients in VT2H group, four patients were lost to follow up. A total of 57 patients were analyzed with 29 in the PTN group and 28 in the VT2H group. There was no statistically significant difference (assessed .The highest mean post-operative pain scores were observed at 8 h follow-up time period in both the intervention groups with a significant decline thereafter .In general, analgesics intake was confined to the first 24 h after treatment in the groups assessed. None of the patients in both the treatment groups needed analgesics at any time points assessed. None of the 57 participants reported severe pain or flare-ups during the period of study.Factors such as mechanical, chemical, microbial, immunological, gender, and psychological components may influence post-operative pain. Hence, in the present study, great care was taken to avoid all confounding factors and to minimize any unavoidable causes of post-operative discomfort. The distribution of males and females in both the groups was not statistically significant. Patients with two symptomatic teeth were excluded because pain from the one may influence the other.The present study aimed to evaluate the incidence of post-operative pain in symptomatic multirooted teeth undergoing root canal treatment due to differences in instrument design. Studies have shown that different instrument designs may have different degree of apical debris extrusion. During cleaning and shaping, dentinal debris, necrotic pulp masses, irrigating solutions, and microorganisms from the root canal may gain access to apical periodontal tissues which leads to inflammation and post-operative pain that disturbs healing of periradicular tissues . To miniThe age of the patients in our study ranged from 18 to 45 years in the PTN and VT2H groups. Out of 57 patients, 17 were male and 40 were female. In the PTN group, 10 were male and 17 were female, whereas in the VT2H group, 7 were male and 21 were female. There were no significant differences in age and gender distribution between the two groups, therefore, the effects of these variables were considered to be minimized.et al. chosen a MVDS, which is a combination of verbal descriptor scale of slight pain to maximum pain and normal rating scale of 0 for no pain to 10 for maximal pain. Hence, a MVDS has been employed in the present study [To report the intensity of pain more precisely, Wang nt study . In the In general, pain levels that the patients experienced in our investigation were moderate to severe, that is, pain scores ranging from 4 to 8, with the highest MVDS score was observed in the PTN group and VT2H group at 8 h time interval. In both the groups, the highest mean MVDS scores were seen in 8 h subgroup after the root canal treatment. These results are consistent with findings of the previous clinical studies where the incidence of pain is maximum 8 h after the procedure ,15. In tIt was observed that there was a gradual decrease in pain intensity in both groups with increasing time period. This decrease in tooth pain with increasing time is both logical and expected because this is a natural course of disease process after debridement. None of patients reported any other symptoms or complications such as post-operative swelling or paresthesia. All these facts highlight the level of care that was given to provide an atraumatic treatment protocol. In the present study, none of the patients in either of the treatment groups needed analgesics at any time period of the study.Very few randomized clinical trials with pre-operative symptoms concluded that there is a reduction in post-operative pain over a period of time, irrespective of design of the rotary system used ,16. ThisThe main parameter of a file that causes apical extrusion of debris is cross section and design of file . Even thIncidence of post-operative pain was similar in symptomatic multirooted teeth prepared with PTN and VT2H rotary systems at all-time intervals. The intensity of pain was observed to be greater at 8 h with a gradual decrease in pain overtime in both the groups. None of the patients took analgesics in the observed post-operative period in both the groups.


Kyphoplasty is the standard surgical treatment of vertebral compression fractures. We aimed to clarify the influence of kyphoplasty on the sagittal profile as well as the relation between posture improvement and pain relief. For this purpose, we evaluated various radiological parameters of the sagittal profile on whole spine standing radiographs of 73 Patients with a single vertebral fracture treated by kyphoplasty. The key outcome was the postoperative change of the sagittal vertical axis (SVA). Additionally, clinical parameters including pain scores on visual analogue scale (VAS) and use of analgesics were obtained from medical records. Pre- and postoperative radiological as well as clinical parameters were compared. Additionally, the correlation between changes of SVA and changes of local kyphotic angle (LKA) or VAS was examined. The clinical parameters as well as various radiographic parameters  improved significantly postoperatively. The improvement of SVA correlated significantly with the correction of the LKA but not with postoperative pain relief. We conclude that kyphoplasty helps to restore the global sagittal balance of the spine after vertebral fractures. The correction of the sagittal profile seems to depend on the correction of the local kyphotic angle but does not correlate with postoperative pain relief. The most common type of osteoporotic fractures are vertebral fractures2. With around 1 million incident vertebral fractures per year in Europe alone, causing costs of estimated €377 million, they constitute a major therapeutic and socioeconomic challenge in aging societies4.Osteoporosis is a major cause of fractures in elderly patients, leading to more than 8.9 million fractures per year worldwide5. Regarding operative treatment options, vertebroplasty and kyphoplasty are the most widely used techniques. While vertebroplasty mainly aims at quick pain relief by stabilizing the fractured vertebra with bone cement, kyphoplasty additionally offers the possibility to correct fracture-related deformities by inflating a balloon in the fractured vertebral body before filling it with bone cement. The efficacy of kyphoplasty for short-term pain relief is well documented and widely accepted7. However, the advantage of kyphoplasty over conservative therapy regarding pain relief seems to diminish over time8. Additionally, there is so far no study comparing the pain relief of kyphoplasty to the placebo-effect of a sham procedure8. Therefore, the key factors for the evaluation of the long-term benefit/risk ratio of kyphoplasty seem to be the restoration of lost vertebral body height and the correction of fracture-related spinal malposition.Despite their high relevance, there is still no clear consensus regarding the optimal treatment. As osteoporotic fractures are mainly stable compression fractures, both conservative and operative treatment options can be considered9. Also, thoracic kyphosis and lumbar lordosis are positively correlated, so that thoracic hyperkyphosis may result in a compensatory increase in lumbar lordosis10. A higher lumbar lordosis has been reported to be associated with lower back pain11.Such spinal malposition can have various implications. In many cases, vertebral compression fractures result in a kyphosis of the affected vertebral body. The effects are not restricted to the area of the fracture but rather affect the spine as a whole. Any increase of kyphosis will inevitably shift the center of gravity ventrally, thereby changing the weight force distribution of the remaining vertebral bodies. This explains why hyperkyphosis is not only a common result of vertebral compression fractures, but also in itself an independent risk factor for future fractures14. Yet, the effect of these local changes on the global sagittal profile of the spine has been hardly examined so far. Only few studies have been conducted in small populations and came to conflicting conclusions18. This lack of knowledge about the potential long-term benefits constitutes an important limitation when trying to determine the appropriate indication of the kyphoplasty. As a result, most guidelines remain rather vague and recommend the intervention only after a futile conservative treatment attempt5. The potential long-term advantages of a restored sagittal profile are not taken into account as no reliable evidence to this effect is available.There is consistent evidence that kyphoplasty can achieve  height restoration of the fractured vertebraeTherefore, more detailed knowledge about the effect of kyphoplasty on the sagittal profile of the spine is urgently needed for a differentiated evaluation of the long-term risk/benefit ratio and to thereby allow for more precise treatment recommendations for vertebral compression fractures.In the present study, we hypothesized that percutaneous balloon kyphoplasty has a significant impact on parameters of the sagittal profile of the spine and conducted a retrospective analysis of patients treated in our department.For this retrospective cohort study we included consecutive patients that received balloon kyphoplasty of a single vertebra due to a vertebral compression fracture between January 2014 and December 2018. Kyphoplasty was performed in a standardized manner with the patients being placed in a lordosing prone position and using a biportal technique. Only patients with pre- and postoperative upright whole spine radiographs obtained within not more than 30 days before and after the operation were eligible. All patients had undergone a futile conservative treatment attempt prior to the operation. Patients were excluded if they had received additional spinal operations  or sustained new vertebral fractures between pre- and postoperative radiographs. Patients were also excluded if they had undergone a prior instrumented spinal fusion including L5/S1 as this would not have allowed a reliable measurement of spinopelvic parameters.19. The mean values from independent measurements by two reviewers  were used for statistical analysis in order to minimize the risk of systematic bias. The following parameters were measured: angle between cephalad and caudad endplate of the fractured vertebra ; angle between the cephalad endplate of the vertebra proximally adjacent to the fracture and the caudad endplate of the fractured vertebra ; angle between the cephalad endplate of the vertebra proximally adjacent to the fracture and the caudad endplate of the vertebra distally adjacent to the fracture ; distance between the C7 plumb line and the rear edge of S1 ; angle between the sacral endplate and a horizontal reference line ; angle formed by a line connecting the centre of the hip with the centre of the sacral endplate and a vertical reference line ; angle between the cephalad endplate of L1 and the caudad endplate of L5 ; angle between the caudad endplate of Th12 and the sacral endplate ; angle between the cephalad endplate of Th10 and the caudad endplate of L3 ; and the angle between the cephalad endplate of Th4 and the caudad endplate of Th12 . The key outcome was defined as the postoperative change in SVA.Pre- and postoperative lateral whole spine standing radiographs were evaluated regarding radiologic parameters of fracture morphology and global sagittal profile Fig. . Image aIn addition, clinical data including the presumed time of the fracture (defined as the moment of symptom onset), pre- and postoperative pain at rest or in motion  and need of analgesics  were obtained from the medical records.Statistical analysis was performed using SPSS software version 23 . Mean and standard deviation were calculated for descriptive patient characteristics. Pre- and postoperative values for VAS scores (at rest and in motion) and radiographic measurements were compared using Student's t-test for paired samples. Pre- and postoperative need for analgesics according to the WHO pain ladder were tested for significant differences using Wilcoxon signed-rank test. The difference between pre- and postoperative radiographic parameters was tested for correlation with pre- and postoperative differences in VAS score and LKA by calculating Pearson's correlation coefficient.The study was approved by the institutional review board of Charité – Universitätsmedizin Berlin (EA1/188/18). The study was carried out in accordance with relevant guidelines and regulations.A total of 73 patients (average age 70 years) were identified that matched the inclusion criteria Table . All incPatients showed a significant decrease in pain at rest and in motion Table . FurtherThe detailed pre- and post-operative radiographic measurements are depicted in Table The correlation analysis revealed a significant correlation between pre-/postoperative difference in SVA and pre-/postoperative difference in LKA Table . However31 patients presented with a positive sagittal imbalance (defined as SVA > 50 mm) preoperatively. In the subgroup analysis of these patients, the mean SVA decreased from 84.36 (±32.48) to 58.61 (±33.3). The mean increase in SVA was 25.75 (±27.43) (p < 0.001). 25 patients still had a positive sagittal imbalance postoperatively.17. However, two other previous studies did not find a significant change in SVA after kyphoplasty. One reason for this might be the timed passed since the occurrence of the fracture. In our study, the average time between fracture and kyphoplasty was 1.2 months. In both studies that did not find a change in SVA postoperatively, the time from injury to kyphoplasty was either much higher with an average of 3.4 months15 or not reported at all16. In a reverse conclusion, a long conservative treatment attempt might actually reduce the benefit of a subsequent kyphoplasty and cause sustained postural disadvantages to the patient as fracture consolidation hinders LKA restoration. However, there is no consistent data available yet regarding the influence of surgical timing on vertebral height restoration22.In the present work, we have conducted the largest study so far regarding the influence of kyphoplasty on the sagittal profile of the spine. Our results show a significant improvement of the SVA in patients with vertebral fractures after kyphoplasty. This result is of wide-ranging significance as it suggests a long-term benefit of kyphoplasty over conservative treatment. The results are in concordance with those from a smaller previous study, which included 21 patients7. However, this observation might also raise suspicion regarding the origin of the postoperative SVA improvement. It seems plausible that pain relief by itself might lead to a more upright posture, even in the absence of a local height restoration of the fractured vertebra. In this case, one would have to suspect the effect of kyphoplasty on posture to be temporary as the acute fracture-related pain often fades over time under conservative treatment as well. Therefore, we examined for the first time whether the global postoperative changes of spinal alignment correlate rather with postoperative pain relief or vertebral body height restoration. Our results demonstrate that postoperative improvement in SVA correlates significantly with the correction of the LKA, but not with postoperative pain relief. This is remarkable, as it might indicate a long-lasting advantage of kyphoplasty over conservative treatment. However, it should be noted that the patients included in our study had (on average) only mild to moderate pain with an average VAS score of 3.7 at rest and 5.1 in motion. A stronger relationship between VAS and SVA might be conceivable in other populations where patients have stronger preoperative pain and therefore a more pronounced pain-related spinal malposition preoperatively. Theoretically, it is therefore possible that there might be an even better restoration of the sagittal profile in patients with stronger preoperative pain than in our cohort. However, this does not influence the correlation between LKA restoration and SVA improvement observed in our study independently from pain relief. Those to profit particularly from the procedure seem to be patients with a severely compromised posture preoperatively as the mean postoperative improvement in SVA was more than twice as high in patients with a positive sagittal imbalance preoperatively as compared to the general cohort.Apart from the radiographic benefits of the operation, we also observed a significant pain reduction in our patients postoperatively. This is in keeping with existing studies on the short-term clinical outcome after kyphoplasty24. Finally, we performed multiple testing using data from the same patients, which may result in a risk of erroneous inferences. We this issue in our statistical analysis by rigorously adjusting the p-values according to the established Bonferroni-Holm method.Despite our efforts for a rigorous methodology to ensure reliable results, there are limitations to our study and the results should be interpreted accordingly. As the study relies on the assessment of retrospectively gathered patients treated with kyphoplasty, it is not possibly to precisely quantify the actual advantage over non-surgical treatment. Prospective studies will be needed to evaluate the long-term effect of the restoration of the sagittal profile on quality of life. Yet, existing literature indicates that the adverse effects of vertebral compression fractures on the quality of life, physical function, mental health, and life-span are related to the severity of the spinal deformity and partly independent of pain, which suggests a significant benefit from a restoration of the sagittal profileAs a conclusion, we think that our data provide important new points to consider when deciding upon conservative vs. operative treatment in patients with vertebral fractures. While guidelines mainly recommend to consider kyphoplasty only after a futile conservative treatment attempt, treating physicians should also keep in mind that patients  might benefit from a restored posture irrespective of pain relief and that this might only be possible for a certain time after fracture occurrence.


In 2013 pregabalin was subsidised by Australia’s Pharmaceutical Benefits Scheme (PBS) for neuropathic pain. Since the subsidy, pregabalin prescribing has been increasing in Australia and so has related harm. There are concerns it is being prescribed for indications other than neuropathic pain, which have little evidence of efficacy.To describe pregabalin prescribing in Australian general practice.A cross-sectional study of patients attending 445 general practice sites in the national MedicineInsight database from March 2012–February 2018.The following aspects were calculated: the proportion of prescriptions that were for pregabalin per year; the prevalence of pain conditions in patients prescribed pregabalin; and same-day prescribing of pregabalin with opioids or benzodiazepines.n = 56 772) had a recorded diagnosis of neuropathic pain. Among people prescribed pregabalin without a recorded diagnosis of neuropathic pain, 43.5% (n = 24 927) had a diagnosis of back problems, 8.8% (n = 5073) chronic pain, and 26.4% (n = 30 146) had no pain diagnosis. Pregabalin was prescribed the same day as an opioid to 38.1% of patients  and a benzodiazepine to 13.1% of patients (95% CI = 12.5% to 13.7%). Patients with a diagnosis of chronic pain had the highest rate of same-day prescribing of pregabalin with an opioid  or a benzodiazepine Prescribing increased from 13 per 10 000 to 104 per 10 000 prescriptions between 2012–2013 and 2017–2018. A total of 1 891 623 patients were identified of whom 114 123 (6.0%) were prescribed pregabalin; 49.7% (Substantial increases in pregabalin prescribing were identified in Australian general practice, but only half of patients had a neuropathic pain diagnosis recorded, the only approved indication for subsidy. High rates of same-day prescribing with opioids and benzodiazepines may put patients at increased risk of harm. Pregabalin use and related harm have increased substantially in Australia since its public subsidy in 2013, but little is known about the conditions for which it is being prescribed. It was found that approximately half the patients prescribed pregabalin in general practice (between 2012 and 2018) had a recorded diagnosis of neuropathic pain during the study period, the only approved indication for subsidy, with many patients having recorded diagnoses of other pain conditions, such as back problems and chronic pain, for which pregabalin is not indicated. Same-day prescribing of pregabalin with opioids or benzodiazepines was common, despite the increased risks associated with these combinations. This study has identified subgroups of patients prescribed pregabalin who may be at increased risk of harm owing to potential off-label prescribing and co-prescribing with other sedative medicines.1 In recent years, its use has increased markedly in North America, Europe, and the UK.4 In Australia, pregabalin dispensing nearly tripled in the first 4 years since it started to be subsidised in March 2013 by the PBS, the national programme that provides access to approved medicines.5 There are concerns it is being overprescribed,6 with several studies finding high rates of off-label use, particularly for non-neuropathic pain conditions where evidence of benefit is unclear.7Pregabalin is a gabapentinoid with anticonvulsant, analgesic, and anxiolytic properties. It is registered in Australia for the treatment of neuropathic pain and seizures, while it is also approved for generalised anxiety disorder in Europe and fibromyalgia in the US.10 When pregabalin is taken in combination with other medicines with sedative properties, particularly opioids and benzodiazepines, it can lead to central nervous system depression, with the greatest risk observed with high doses.11 In Australia, pregabalin recreational use, poisonings, and deaths have all been increasing,11 with a tenfold increase in pregabalin misuse-related ambulance attendances between 2012 and 2017.9 Pregabalin has also been associated with an increased risk of suicide.12 In the UK, pregabalin was reclassified to a controlled substance in 2019,13 and the Therapeutic Goods Administration (TGA), which regulates medicines in Australia, has been considering approaches to optimise safe use of pregabalin.14Pregabalin has abuse potential, and is commonly misused in people with a history of substance use disorder or psychiatric problems.15 there is limited evidence for its efficacy for other types of pain, such as low back pain without neuropathic pain17 or with sciatica.18 Pregabalin is subsidised by the PBS solely for the treatment of neuropathic pain refractory to treatment by other medicines and not as a first-line therapy. However, previous work has identified that use of sub-therapeutic doses (25 mg) without up-titration is common, which is not consistent with treatment for neuropathic pain.19 To date, little is known about the conditions with which patients prescribed pregabalin have been diagnosed. The objective of this study was to describe patterns of pregabalin prescribing in Australian general practice, including: patterns of pregabalin prescribing over time; sociodemographic and clinical characteristics of patients prescribed pregabalin; and the prevalence of same-day prescribing of pregabalin with opioids and/or benzodiazepines.While pregabalin is effective in reducing pain associated with certain types of neuropathic pain, such as diabetic neuropathy and postherpetic neuralgia,20 It is described in detail elsewhere.21 The data include patient demographic and clinical data recorded as part of routine clinical practice, including current and past prescribed medicines and diagnoses. Patients are assigned a unique identifying number at each practice site they attend allowing them to be followed in the database longitudinally over time.A descriptive cross-sectional analysis was performed using Australian general practice clinical data from the MedicineInsight programme from 1 March 2012–28 February 2018. MedicineInsight collates de-identified electronic health records from the clinical information systems' best practice and medical director from consenting practices, which represents approximately 8% of Australian general practices.21 As some patients may have also visited general practices not contributing data to MedicineInsight, to maximise the probability of capturing relevant prescription and diagnostic information, a cohort of regularly attending patients ('active patients') was identified, who are likely to have received most of their care at participating practices. 'Active patients' were defined as those with ≥3 consultations in the previous 2 years at the same practice, in accordance with the Royal Australian College of General Practitioners' definition.22 Patients’ postcodes of residence were mapped to the Accessibility/Remoteness Index of Australia (ARIA+),23 and the Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD).24All patients aged ≥18 years were included at the 445 general practice sites, which met the data quality requirements at the time the MedicineInsight data were extracted for this study in May 2018.Eligible Australian residents receive subsidised access to prescribed medicines listed with the PBS for the general population, or the Repatriation PBS (RPBS) for eligible veterans and their families. MedicineInsight captures PBS, RPBS, and private prescriptions. Private prescriptions can be written if the patient does not meet the specific PBS or RPBS subsidy requirements for prescribing a listed medicine and the patient pays the entire cost out-of-pocket. Prescription counts included all issued prescriptions.Since 2005, pregabalin has been registered in Australia for treatment of neuropathic pain in adults, or adjunctive therapy in adults with partial seizures. Pregabalin has been subsidised for veterans through the RPBS since February 2008, and for the general population through the PBS from March 2013, solely for the treatment of neuropathic pain refractory to other medicines. It is neither registered nor subsidised for generalised anxiety disorder or fibromyalgia, for which it is approved in other jurisdictions. Pregabalin prescriptions were identified from the MedicineInsight data using the active ingredient obtained from the 'medicine name' and 'medicine active ingredient' fields.16 and unspecified chronic pain, a category that includes many types of pain. Depression was also identified, as it should be prescribed cautiously in people with depression, and mood changes are listed as potential adverse effects of pregabalin.25The recording of several relevant diagnoses were examined. This included neuropathic pain or sciatica, and epilepsy, which are indications approved by the TGA. Diagnoses of other pain conditions were identified, specifically back problems, a common off-label use of pregabalin,In conjunction with medical, pharmacist, and clinical coding specialists, a search strategy was developed to identify conditions of interest from multiple data fields. While the data contain a 'reason for prescription' field, it is not completed for approximately 70% of prescriptions. As a result, the linking of recorded conditions directly with pregabalin prescribing could frequently not be done and so potential prescribing indications were identified using information from a combination of the 'reason for prescription', 'reason for encounter', and medical history (diagnosis) fields, including both coded (using Docle or Pyefinch codes) and free-text data. Diagnoses could be recorded at any time over the study period, including at a visit prior to prescribing of pregabalin, if pregabalin was a second-line therapy, or at a later visit, if the diagnosis was initially suspected and only later confirmed. A full list of included terms is in Supplementary Table 1. Patients could have multiple conditions recorded over the study period; if they had at least one diagnosis of neuropathic pain, they were counted in that group. To determine if neuropathic pain was adequately captured in the data, its recording in all active patients was also measured, not just those prescribed pregabalin.Same-day prescribing of pregabalin with opioids and/or benzodiazepines was examined. A list of included medicines is in Supplementary Table 2. At the time of this analysis, only same-day prescribing in practices that used the best practice clinical information system for the whole study period could be examined owing to a technical issue, which represented 56.5% of patients prescribed pregabalin.As the number of active patients changes over time, to examine trends in pregabalin prescribing the proportion of all prescriptions that were for pregabalin per year were calculated, rather than counts or number of patients. The 95% confidence intervals (CIs) adjusted for practice clustering were calculated using PROC SURVEYFREQ and PROC SURVEYMEANS in SAS. Data analyses were conducted using SAS (version 9.4).Over the 6-year study period, there were 54 147 527 prescriptions of which 404 098 (0.8%) were for pregabalin. The rate of pregabalin prescribing increased from 13 per 10 000 prescriptions in the year prior to the PBS subsidy (March 2012–February 2013) to 104 per 10 000 prescriptions in year 5 post-subsidy (March 2017–February 2018) . Post-suThe 75 mg tablet was the most common strength prescribed. Prior to PBS subsidy, it represented 56.9% of all pregabalin prescriptions, decreasing to 42.9% of prescriptions in 2017–2018 . Prescribing of higher strength tablets (150 mg and 300 mg) has remained relatively constant, while prescribing of the 25 mg tablet has increased, from 8.5% of prescriptions prior to the subsidy to 28.7% in 2017–2018.; Supplementary Table 3). Women aged ≥50 years were more likely to be prescribed pregabalin than men. Compared with the full study cohort, patients prescribed pregabalin were more likely to live in regional areas  and areas with more socioeconomic disadvantage  of whom 114 123 (6.0%) had ≥1 pregabalin prescription. The median number of prescriptions per person was 1.4 , and the mean was 3.5 (95% CI = 3.5 to 3.6). Pregabalin prescribing increased with age, with 14.7% (95% CI = 14.2% to 15.3%) of patients aged 80–89 years prescribed pregabalin  (n = 24 927) had a diagnosis of a back problem and 8.8% (n = 5073) chronic pain. Throughout the study period, 30 146 patients (26.4%) had no recorded pain diagnosis. Only 1.0% (n = 1147) of patients had an epilepsy diagnosis, and 29.0% (n = 33 142) had a recorded diagnosis of depression.In the full cohort, 6.1% (95% CI = 5.7% to 6.4%) had a diagnosis of neuropathic pain during the study period (Supplementary Table 4). Half of the patients prescribed pregabalin had a recorded diagnosis of neuropathic pain (including sciatica)  . Among pn = 4732, 70.4%, 95% CI = 68.9% to 71.9%), or a benzodiazepine  than people with other diagnoses . They had similar sociodemographic characteristics to the full cohort of patients prescribed pregabalin . Pregabaiagnoses . Males aiagnoses .10 Lastly, increasing prescribing of the 25 mg tablet strength over the study period was observed, despite it being intended for dose titration only.This is the first study to describe the conditions with which patients prescribed pregabalin were diagnosed in Australian general practice. It was found that pregabalin prescribing increased eightfold over 6 years, with nearly one in seven patients aged 80–89 years receiving a prescription. Only half of the patients prescribed pregabalin had a neuropathic pain diagnosis recorded during the study period, even though it is the only PBS-approved indication, and over one-quarter had no recorded pain diagnosis. Same-day prescribing of pregabalin with opioids and/or benzodiazepines was high, despite the risks associated with the use of multiple sedative medicines.21 Unlike other national prescribing datasets in Australia, these data contain diagnoses recorded in general practice. The main limitations of these data are that the reason or indication for prescribing was not commonly recorded, and thus conditions could not be directly linked with pregabalin prescribing. Thus, other fields were relied on, such as medical history and reason for encounter, and conditions were identified over the entire study period to maximise the chance of identifying relevant diagnoses. This approach was necessary as neuropathic pain is typically a chronic condition lasting for years28 and clinicians may record the diagnosis in the medical history only once at initial diagnosis, even if it is managed for years. A study of pregabalin prescribing in UK general practice found that relying on diagnostic information from the day of prescribing severely underestimated the prevalence of neuropathic pain.29 However, not all recorded diagnoses of neuropathic pain were necessarily related to the prescribing of pregabalin. Additionally, some diagnoses may be missing as, for confidentiality reasons, MedicineInsight does not collect data from the unstructured area of the medical record contained in progress notes.The MedicineInsight database provides national coverage of general practices, and the included patients are broadly representative of the Australian population.19 While the study does not have information on prescribed dose, the 25 mg tablet is intended for dose titration purposes, and on its own it is not considered a therapeutic dose for neuropathic pain.30 In international studies, prescribing of pregabalin for unapproved or off-label indications is common.31 A 2019 study of pregabalin prescribing in UK general practice found that 55% of pregabalin prescriptions were off-label, primarily for non-neuropathic pain,2 while in a 2019 German study only 26% of people prescribed pregabalin had a neuropathic pain diagnosis.7 High rates of concomitant use of pregabalin, opioids, and benzodiazepines have also been observed in the US and the UK,3 and in patients initiating pregabalin, a majority had previously been prescribed or dispensed opioids.32The study identified 114 123 people prescribed pregabalin over the study period, representing 6% of all active patients, with increased prescribing of the 25 mg tablet strength. This is consistent with a 2020 Australian study that found that 5.3% of Australians initiated pregabalin over the same time period, including 15% of people aged ≥85 years, with high rates of dispensing of the 25 mg tablet strength without up-titration.34 and thus under recording may be minimal. Second, this may represent off-label prescribing, which is common in international studies. The increased prescribing of low strength tablets (25 mg) also points to prescribing for indications not well supported by evidence such as anxiety or insomnia,15 potentially putting patients at risk of unnecessary adverse effects such as somnolence, dizziness, and falls in older adults.35The study has identified substantial increases in pregabalin prescribing in Australian general practice over time. Approximately half of the patients had no definite diagnosis of neuropathic pain or epilepsy recorded, for which there are several potential explanations. First, neuropathic pain may be under recorded by GPs, or recorded with a non-specific term such as 'chronic pain'. However, the prevalence of neuropathic pain observed in the full cohort (6%) are similar to those observed in other Australian and international studies,18 in contrast with other types of neuropathic pain such as postherpetic neuralgia or diabetic neuropathy.15 However, differentiating between pain syndromes is not straightforward, and finding effective treatment for chronic pain is challenging.37 High rates of prescribing of pregabalin combined with opioids or benzodiazepines in people with chronic pain were observed, despite the well-established risks.10 While there is little evidence of efficacy of opioids for treatment of neuropathic pain,38 pregabalin may sometimes be prescribed as adjunct therapy with opioids as it may reduce opioid consumption.39 Nevertheless, this combination should be used sparingly as it predisposes patients to harm, particularly in patients with pre-existing psychiatric problems or a history of substance use.10 In contrast, there are few situations where pregabalin should be prescribed with benzodiazepines.A sciatica diagnosis was common in the present study's cohort (12%). In Australia, pregabalin is subsidised for neuropathic pain without any distinction for subtype and there is limited evidence of efficacy of pregabalin for sciatica,40 The TGA has recently advised changes to pregabalin’s product information and a targeted education strategy to increase prescriber awareness of the extent of pregabalin misuse.14 The aim of this is to increase awareness among prescribers of the potential harm associated with pregabalin, particularly in patients at high risk of adverse events such as people with depression, substance use disorders, or older people.The study has identified at-risk patient groups, owing to potential off-label prescribing and co-prescribing with other sedative medicines. However, the work also highlights the need for complete and accurate recording of diagnoses and reasons for prescribing in medical records, to better understand how and why medicines are being prescribed, both for clinical practice and research. This is especially important as Australia is currently moving toward greater use of electronic health records and primary care data for research.


Many of our rheumatic patients report that weather and seasons affect their symptoms.  The purpose of this study was to examine the effect of meteorological parameters within seasons on rheumatoid arthritis (RA) symptoms.  A retrospective longitudinal study from July 2017 to August 2018 was conducted. Data from three consultations for three seasons were collected and included a tender and swollen joint count, a disease activity score for 28 joints (DAS28), and patient's pain assessment from their computerized medical record. The weather conditions  registered during the same day of consultation for each patient were obtained. Then, the statistical correlation between each meteorological parameter and RA parameters was determined using the multiple linear regression analysis. p=0.027) in winter. A similar result was obtained in summer with precipitation (p=0.003). The pain intensity in the summer was negatively correlated with minimum temperatures and atmospheric pressure. However, there was no correlation between meteorological parameters and disease objective parameters for all seasons. Multiple linear regression analysis showed that weather parameters appeared to explain the variability in four RA predictors in the summer. No significant associations were observed in the spring.  The data of 117 patients with a mean age of 50.45 ± 12.17 years were analyzed. The mean DAS28 at baseline was 2.44 ± 0.95. The winter in Oujda is cold (average temperature between 10°C and15°C) compared to summer (24.5°C–32.7°C). The spring is wetter with a 71% average humidity. Overall, the tender joint count was significantly correlated with hygrometry ( Our study supported the physicians' assumption regarding the effect of climate on pain in RA patients. The effect of climate on rheumatoid arthritis (RA) symptoms is frequently addressed by our patients. There are conflicting results in the literature, and it is unclear whether the effect is a coincidence or a direct effect. Among the arguments advanced to explain the inconclusive findings reported on the climate effect on pain, we find seasons. Seasons are defined by climate at a particular place on the earth. Seasonality is a phenomenon that has been frequently reported to be related to various conditions in humans, including diseases , 2, growFurthermore, symptom and particularly pain analysis is one of the difficulties encountered among the studies on weather effects on arthritic patients. Indeed, pain is difficult to objectify as it is a subjective experience with considerable inter- and intraindividual variations. Moreover, even if the study on weather parameters is regarded to be simple, the interrelation between weather parameters and human beings is complex; in addition, seasonal variations should be taken into consideration .Fortunately, in recent years, the identification and evaluation of RA have become more accessible and more precise. Furthermore, during the last decade, the treatment of RA has undergone considerable evolution; thus, our patients are usually in remission. Few studies have addressed this question after the era of disease activity score (DAS28) within the current state of the art.http://www.fr.climate-data.org).The specific peculiarities of climate from different geographic areas could also be a possible explanation for controversies found within reports. The climate of Oujda city—located to the northeast of Morocco—is classified as dry (steppe climate) with an average temperature of 16.7°C and an average annual precipitation of 338 mm   for every patient, were obtained from patients' electronic medical records. The meteorological parameters during the day of every clinical evaluation were recorded. The requirement of informed consent was waived owing to the retrospective nature of the study.The patients were included if they were diagnosed with rheumatoid arthritis according to the American College of Rheumatology and the European League Against Rheumatism (ACR-EULAR) criteria of RA (2010) and if their data were available for three seasons. These patients were receiving RA treatments according to national recommendations . Patients with a very active disease (DAS28 > 5.1), which may have needed RA therapy adjustment and those with unavailable data on more than two seasons, were excluded.Data on the meteorological conditions during the same day of consultation for each patient were obtained from the ANGADs Airport Weather Center . Minimum and maximum temperatures were assessed in degrees Celsius (°C). Precipitation on the day of the visit was indicated in millimeters (mm), atmospheric pressure in millibars (Mb), and wind velocity in meters per second (m/s). Relative humidity (%) was also collected.The number of painful joints (TJC) and swollen joints (SJC) was extracted from the patients' medical records. Disease activity was calculated by DAS28 using the erythrocyte sedimentation rate (ESR), which was available for the same visit. DAS28ESR is a composite score that includes TJC and SJC of 28 joints, patient global assessment of the disease, and ESR . Remissip < 0.05.The data were analyzed by the IBM® statistical package for social sciences software (version 20). The descriptive analysis of the patients and meteorological parameters during the seasons was made. Correlations using the Pearson test were applied to identify any associations between meteorological parameters and disease variables for each season. Then, we performed a multiple linear regression analysis to study the effect of adjustment of meteorological parameters on disease parameters. The parameters of each season were analyzed separately. The dependent variables were tender joint count, swollen joint count, pain intensity (VAS), and DAS28. Age, BMI, and the presence of Sjogren's syndrome were added to models of regression for all meteorological parameters in a season. Our cutoff value for statistical significance was The effect of 6 meteorological parameters on 117 patients during three seasons, which included a total of 346 consultation days (the data for 5 visits were not available), was studied. The average means of meteorological parameters collected for three seasons are shown .The mean age of our patients was 50.45 ± 12.17 years. Women accounted for 86.3%. The majority of our patients were in a remission state of the disease according to their mean DAS28 for the three seasons .p=0.027) and pain intensity (p=0.01) with humidity in the winter. In the summer, minimal temperature (p=0.024) and barometric pressure (p=0.04) were associated with pain intensity. However, we observed no significant association between meteorological and RA parameters in the spring  whereas BMI and age were not associated with disease activity parameters for all seasons.The pain intensity (VAS) was associated with Sjogren's syndrome presence only in the summer in multiple linear regression  could not be studied. Despite these limitations, the retrospective design allowed to avoid the patients' and physicians' awareness bias. In addition, this is the first study from our region, which contains objective and subjective measurements, that evaluates RA disease activity with meteorological parameters during three seasons.This study showed the possibility of weather effects on RA patients' pain depending on seasons, especially the effect of extreme temperatures. In addition, the presence of Sjogren's syndrome affected pain intensity perception in our patients in the summer. Our results confirm that previous studies in the literature cannot be generalized and should take into consideration seasonal variation, geographic discrepancies within studies, and other factors , which may be the subject of future studies.


The study described in this paper was conducted to assess the short-term outcomes of intra-articular administration of hyaluronic acid in patients with symptoms of temporomandibular joint disorders. A group of 40 patients suffering from temporomandibular joint disorders underwent a series of hyaluronic acid intra-articular injections. Questionnaires and clinical examinations were conducted to assess stress exposure of the subjects and to evaluate short-term treatment outcomes, i.e., reducing joint and muscle pain and increasing the mobility of the mandible. A weak positive correlation between stress exposure and pain was observed. As a result of treatment, 61% of subjects revealed a total reduction of muscle pain, while joint pain completely resolved in 88% of patients. Mandibular mobility increased by 11%, 31%, 9%, and 11% regarding opening, protrusive, and lateral right and left movements, respectively. The study confirms the short-term effectiveness of intra-articular administration of hyaluronic acid on reducing joint and muscle pain in patients with articular disc displacement. The treatment positively affected the mobility of the mandible in all directions. The verification of late treatment effects of hyaluronic acid viscosupplementation requires the continuation of the research. Temporomandibular joints (TMJs) belong to the category of synovial joints in the human body, where joint surfaces are lubricated by the synovial fluid produced by the synovial membrane lining the joint capsule. The synovial fluid consists mainly of hyaluronic acid (HA)—an anionic, nonsulfated glycosaminoglycan and lubricin—a surface-active mucinous glycoprotein.An appropriate concentration of HA in the synovial fluid is crucial for proper tissue elasticity and for reducing friction between the joint surfaces of the bone and the synovial disc. In this way, the viscoelastic properties of the synovial fluid protect the chondrocytes against mechanical damage caused by excessive pressure. HA is also responsible for suppressing stresses generated inside the joint when subjected to trauma. In addition, HA has antioxidant properties, reducing the amount of free radicals present in the joint cavity. HA also facilitates the penetration of nutrients from the blood through joint mucus into the joint cartilage. Finally, by interacting with collagen, HA forms a barrier against microorganisms and toxins.Viscosupplementation, i.e., supplementation with a component of synovial fluid in the form of intra-articular injections, is one of the possible solutions to reduced HA levels in joint cavities in chronic inflammation, already successfully used in the treatment of knee osteoarthritis . ImportaTemporomandibular disorders (TMD) and related pain are becoming an increasingly common social problem. Patients suffering from TMJ pain seek help from specialists in various fields of medicine, including prosthodontists, orthodontists, neurologists, and physiotherapists. Importantly, the effects of monotherapies are often insufficient due to the interdisciplinary nature of the problem. Given the unsatisfactory results of current medical solutions and the scarcity of research on viscosupplementation with HA , in this study, we decided to investigate the effects of this therapy in patients with TMD.This study was conducted in accordance with the Declaration of Helsinki. All procedures involving human subjects were approved by the Ethics Committee of the Pomeranian Medical University in Szczecin . Written informed consent was obtained from all subjects. The study included 40 adult patients with symptoms of masticatory system disorders, who qualified for intra-articular HA injections in accordance with the guidelines published by Escoda-Francoli et al.  and deveAll patients who qualified for the study complained of pain, which was diagnosed as associated with TMJ dysfunction. The therapeutic regimen proposed by Abouelhuda et al.  was adopThe group of 40 patients consisted of 36 women and 4 men, aged 18–69 years (43 years on average). The duration of symptoms before inclusion in the study ranged from 1 month to 20 years (the median was 11 months). In addition, 95% of respondents reported exposure to psychological stresses of varying intensity. According to the protocol of the International Network for Orofacial Pain and Related Disorders Methodology  were traThe questions asked the patients concerning the indicators of stress—somatic and psychological sensations in the last month. According to Dworkin and LeResche , somaticThe study group was divided according to the diagnostic criteria for TMD (DC/TMD) proposed by Schiffman et al. in 2014  Table 2Table 2.We also used another questionnaire developed by a team of two orthodontists, two maxillofacial surgeons, and two prosthetic surgeons to evaluate the objective and subjective symptoms of TMD. It consists of manual functional analysis of TMD according to Bumann et al.  and palpThe number and frequency of intra-articular injections were based on the recommendations of other researchers. All publications known to the authors of this paper proposed a series of up to 5 intra-articular HA injections. These observations are consistent with the analysis of literature on the administration of drugs to the temporomandibular joint cavity conducted 10 years ago by Mountziaris et al. , who ideFor the purpose of this study, a protocol was developed for each of the 5 visits. On the first one, subjective and physical examinations were carried out on the basis of a questionnaire to qualify the patient for intra-articular injections. Viscosupplementation with HA was performed on each of 5 visits. During the last (fifth) visit, the injection was followed by subjective and physical examinations based on the questionnaire. Those patients who did not come for the fifth appointment—and so were not surveyed twice—were not included in the study. This inclusion criterion was met by 40 patients.Out of the group of 40 patients who were present at the first and fifth appointments, 27 did not miss any of the appointments and received 5 HA injections. Ten patients canceled one of the visits  and were given four intra-articular injections. The remaining three patients were only present at three appointments, and so received only three HA injections. The total absenteeism rate was 8%. In most cases, it resulted from unexpected events or satisfactory effects of treatment, which reduced the motivation to attend all five procedures.The puncture site was determined in accordance with the protocol proposed by O’Connor et al. . After dThe pain was determined on the basis of a clinical trial. Its presence was recorded for each of the patients in the preliminary and final questionnaires. Then, according to the protocol proposed by Skeie et al. , the paiThe opening pathway was evaluated in the preliminary test and after viscosupplementation. It is shown in a simplified Farrar’s diagram according to the protocol presented by Gorzałek and Kulesa-Mrowiecka . In our In the study group, muscle pains were present in 36 patients before viscosupplementation and 14 patients after the treatment, which means a 61% effectiveness of the therapy in this regard . Joint pain was present in 25 patients before the HA injections. At the end of the therapy, only 3 patients complained about this type of pain—it was not reported by 22 out of 25 (88%) patients. These data are presented in In 23 patients, muscle and joint pain coexisted before injection. The presence of both types of ailments after viscosupplementation was found in one patient. In 22 out of 23 people (96%), at least one of the types of pain disappeared. A person in whom both muscular and joint pain were present after the end of HA therapy was a 34-year-old woman who had reported the presence of pain in the right temporomandibular joint for about a month before the start of HA injections. She had not been treated previously for temporomandibular joint ailments. That patient reported no concurrent diseases, and on the basis of a questionnaire, we determined exposure only to moderate stress . During the clinical examination, the patient was diagnosed with a dislocation of the joint disc with reduction, characterized by clearly limited mobility of the mandible: the opening amplitude was 32 mm, the protrusive and lateral movements were about 2 mm. HA viscosupplementation did not improve mandible mobility. The patient was qualified for further diagnostics, manual therapy, and possible treatment with the use of a repositioning splint.The analysis of diagrams showing the movement of the mandible in the coronal plane allowed us to assess the influence of HA viscosupplementation on the opening pathway. In 5 patients, the anomalies of mandibular movement in the coronal plane did not exceed 4 mm. During the initial examination, the remaining 35 patients had pathological opening pathways (88% of the study group). Of these 35 subjects, an S-shaped opening pathway occurred in 26 patients and deflection in 9 patients. After completion of the intra-articular HA injection therapy, the mandible mobility in the frontal plane was normalized in 22 out of 35 patients (63%). Out of 26 patients with the S-shaped pathway, 16 (62%) patients showed satisfactory improvement at the end of treatment, and the remaining 10 (38%) patients maintained an alteration of at least 4 mm. In the group of 9 persons diagnosed with deflection, the therapy resulted in 6 (67%) patients obtaining a normal opening pathway during the final examination, while the remaining 3 patients (33%) showed no significant improvement.The treatment resulted in an increase in the amplitude of mandibular movements in all planes. The mean opening movement in the study group was 40.1 mm. After HA injections, it increased by 4.5 to 44.6 mm, i.e., by 11%. The applied therapy had the greatest influence on the protrusion, which increased from 5.4 to 7.2 mm (by 31%). The range of lateral movement was 7.8 mm to the right and 8.0 mm to the left before the start of HA injections. It improved by 0.7 (by 9%) and 0.9 mm (by 11%), respectively, reaching 8.5 and 8.9 mm. Negative correlations were observed between the differences in the initial and final amplitudes and the initial amplitudes of individual extreme movements of the mandible. They indicate a weaker therapeutic effect of HA injections in cases of high initial mandibular mobility. The data discussed are presented in A correlation was also observed between the presence of pain before treatment with HA and the severity of stress experienced by patients. For the purpose of this report, pain was rated on a scale from 0 to 2, where 0 meant no pain, 1—muscle or joint pain, and 2—concurrent muscle and joint pain. Exposure to stress was determined on the previously mentioned scale from 0 to 4, resulting from an interview based on the questionnaire by Dworkin and LeResche . The patAs indicated by Panek and Maślanka , as wellPainful ailments resulting from masticatory system disorders have a very complex nature. Harper et al.  attempteMeticulous diagnostics of pain etiology allows us to take optimal therapeutic action. The method of treatment of muscle pain was proposed and examined by Pihut et al. . These aIn our study group, out of 36 people complaining of muscle pain, only 61% reported its total disappearance following HA viscosupplementation. This significantly lower therapeutic efficacy of intra-articular HA injections compared to intramuscular botulinum toxin administration is associated with the fact that intra-articular therapy only has an indirect effect on the masticatory muscle system. Similar effectiveness of HA viscosupplementation in the treatment of muscle pain was observed by Pihut et al. , where, With regard to joint pain, our results showed 88% effectiveness of HA viscosupplementation. It is difficult to put these results in perspective because, in the available literature, only Pihut et al.  identifiIn the treatment of pain resulting from TMD, intra-articular HA injections are used as a viable alternative to rinsing the joint cavity. However, the lack of a uniform protocol of management in TMD patients has resulted in various modifications of the treatment. These two methods are proposed to be used separately, and there are also recommendations for combining them. De Riu et al.  examinedWidening the joint cavity by the mechanical displacement of the condylar processes downwards is also possible to achieve by conservative methods using various types of occlusal splints. However, their therapeutic effect is difficult to evaluate. Raphael and Marbach , in a stIn our own study group, there were 6 patients whose complaints persisted as a result of previous therapies, and the effectiveness of viscosupplementation with HA in terms of pain relief was 83%. In this context, it is worth considering splint therapy as a preliminary treatment in sudden pain and unknown etiology. This approach was used by Shoush et al. , who comn = 25). However, those authors admitted that during the first three months, they did not observe any significant effects of treatment with occlusal splints. It was only after 12 months of observation that the 88% success rate of the therapy was determined.Akbulut et al.  showed mAkbulut et al.  defined The method proposed by Kijak et al. —based onr = −0.68. The significantly higher HA viscosupplementation efficiency for lower initial mandibular opening amplitudes in our study is shown in Lewandowski  also shox is the initial amplitude of the mandibular opening and y is its increase following HA viscosupplementation. The mean final opening calculated using this formula would be 36.7 mm in the group of patients examined by Fonseca et al. [The trend line shown in a et al. , which ix is the initial amplitude of mandibular opening, and y is an increase in the amplitude of the opening following joint lavage. In the discussed material, the final amplitudes of mandibular opening after joint cavity rinsing were, on average, as much as 5 mm higher than the expected results of treatment of the same group of patients who were treated only with intra-articular HA injections. The results of treatment by rinsing the joint cavities and HA viscosupplementation are presented in The improvement of mandibular mobility expressed as an increase in the amplitude of opening was also determined in groups treated with joint rinsing. In an analysis of 7 publications by the authors listed below, the relationship between the initial value of mandibular excitation and its increase in the course of therapy was also observed for joint cavity rinsing. It may be presented by the following formula:Gouveia et al.  demonstrWhile the influence of HA viscosupplementation on the mandibular opening has been confirmed by numerous authors, data on the activity of the mandible in the transverse plane are very limited. These are presented by Chandrashekhar et al. , based oThe possibility of combining joint rinsing with HA viscosupplementation should also be considered. In a unique study by Gurung et al. , the higThe influence of HA viscosupplementation on the degenerative changes of the articular fossa and head is also worth mentioning. In our own examination, radiological assessment of joint surfaces was performed on the basis of orthopantomograms and functional radiographs of temporomandibular joints. Degenerative changes on these surfaces were found in 8 patients before the treatment. Among them, remodeling was observed in only one patient who had previously been diagnosed with osteophytes. In the remaining 7 patients who were diagnosed with various resorption lesions before the treatment, no noticeable improvement in the condition of joint surfaces was observed. Similar observations were presented by Sun et al.  who injer = 0.30), which indicates a tendency for pain to coexist with increased stress. Indirectly, this result may also prove the participation of psychological components in the process of initiation and evolution of TMD.Many authors have emphasized the significant influence of psychological components on the development of TMD. For example, in our study, we found a positive correlation between muscle and joint pains and stress (Pearson’s correlation coefficient TMD is often discussed in the context of somatic diseases, but also stress and mental disorders. For example, Czerwińska-Niezabitowska and Kulesa-Mrowiecka  discusseAccording to the results of our own research and the literature analysis, the high short-term effectiveness of HA viscosupplementation should be taken into consideration when treating pain and functional limitations related to TMD. Although it was most effective in reducing joint pain, good results were also observed for muscle pain. HA viscosupplementation positively influenced the mandibular opening pathway and amplitude. It also increased mandibular mobility in other directions. The verification of late treatment effects of hyaluronic acid viscosupplementation requires a continuation of the research.


The opioid epidemic has emerged as a major health and social problem over the last few decades. An increasing number of patients with opioid use disorder are presenting for perioperative management. These patients are either on buprenorphine or methadone for the maintenance and treatment of opioid addiction or chronic pain. In the settings of acute pain, the optimal management of patients with opioid use disorder is challenging, and recovery can be jeopardized secondary to the unique pharmacology of these agents. The purpose of this narrative review is to summarize the existing studies on the perioperative management of patients who are using buprenorphine and methadone and provide guidance for the management of patients with opioid use disorder during the perioperative period. In 2016, an estimated 50 million adults in the United States struggled with chronic pain. .Medications such as long-acting synthetic opioid methadone and partial opioid agonist buprenorphine have been found to be the effective treatments for OUDs. These medications aim to decrease the illicit opioid use and relapse and increase treatment engagement ,5. It isBuprenorphine is a derivative of thebaine, which is a mixed opioid receptor modulator. It is highly lipophilic and has a large distribution volume . Its actBuprenorphine’s half-life is widely variable and depends on the route of administration. It is poorly absorbed by the gastrointestinal system; hence, it is administered via sublingual, dermal, and parenteral routes. Its half-life is three hours when it is administered via intravenous (IV) route and can be 24-60 hours when it is administered sublingually . It is mMethadone is a long-acting synthetic opioid that is a full mu receptor agonist. It has been used both as an analgesic in severe pain and in the treatment of OUDs. When used for the treatment of OUD, the oral stock solution is often mixed with orange-colored solution or cherry syrup to prevent the aberrant use through the parenteral route. It is rapidly absorbed following oral administration, and its effects start between 15 and 45 minutes with a maximum plasma concentration of 2.5-4 hours after administration. Methadone is widely distributed in the body and it is highly bound to protein leading to cumulative effect and slow elimination . It has An effective daily dose of methadone for OUDs varies between 60 and 120 mg/d . The purCurrent studies related to the use of buprenorphine and methadone for patients with OUDs presenting for surgery are mostly retrospective reviews, case reports, case series, and expert opinions. Buprenorphine has several advantages over methadone for the treatment of OUDs. It was shown to have less potential for abuse, provides greater flexibility in prescribing, and can be managed as an office-based treatment option . TherefoThere are several strategies proposed to treat severe pain in patients on buprenorphine maintenance treatment. When planning to continue buprenorphine during the perioperative period , it is advised to use the different types of oral opioids and/or IV opioid analgesics with the use of patient-controlled analgesia (PCA) titrated for adequate pain control ,22. A stA multimodal pain management approach with the use of dexmedetomidine, remifentanil, and ketamine perioperatively has shown success in providing adequate pain control among patients taking buprenorphine for OUD ,26. The Researchers have proposed algorithms for managing patients on methadone presenting for elective surgery. If the patient can tolerate oral medication, then it is advised to continue oral methadone on the morning of surgery and throughout the perioperative period ,21,27. IThe perioperative management of patients with OUD is complex. These patients may have underlying medical, psychiatric, surgical conditions, and psychosocial problems in conjunction with their medication treatment. The management of their pain in the acute setting following surgery can be challenging and, often times, their OUD is not addressed. This may result with the worsening of their medical condition, readmission rates, overdose, and relapse. These patients require specific considerations and planning to prevent poor outcomes.The stigma associated with OUDs may foster a negative judgment of the patient. These patients can be perceived as drug-seekers if their pain is poorly controlled. In this regard, patients worry about receiving inappropriate care in terms of pain control with the possibility of relapse and withdrawal symptoms.It is recommended that these patients be evaluated preoperatively to obtain a full pain history, physical examination, and assessment for other psychiatric and medical comorbidities . It is iIt is important to understand that patients receiving maintenance therapy with buprenorphine and methadone do not receive adequate analgesia from these opioids in the setting of acute pain. The analgesic and addiction profile treatment differ as well as the associated neuroplastic changes associated with long-term opioid exposure, that is, tolerance and hyperalgesia may effectively diminish their analgesic properties . For exaThe patient’s baseline addiction treatment needs to be addressed during the treatment of acute pain while taking maintenance buprenorphine and methadone therapy. It is imperative to have a plan for aggressive pain management . The undIf the decision is made to continue the use of methadone and buprenorphine, then it is important to continue the patient’s usual dose to avoid the worsening of pain symptoms due to increased pain sensitivity associated with opioid withdrawal . AdequatRegarding methadone, if the patient is unable to receive oral medications, then methadone dose can be administered via IV, intramuscular (IM) or subcutaneous (SC) routes. The dosing methadone via IV, IM and SC routes should be administered as half to two-thirds of the maintenance dose divided into two to four equal doses .The high affinity of buprenorphine to the mu receptor makes pain treatment more complicated than methadone. The most effective approach comes with the clinical experience of the provider with buprenorphine. The upward titration of a short-acting full opioid agonist to effect is recommended if the decision is to continue buprenorphine in the perioperative period. The buprenorphine dose can also be increased in patients who are not on a maximal dose to 24-32 mg daily . StrategIn conclusion, the increasing utilization of buprenorphine and methadone as a maintenance therapy for OUDs continues to grow to fight against the opioid epidemic. As a result, these patients face challenges in acute pain management during the perioperative period. These complex patients have altered the neural responses of tolerance and hyperalgesia that may alter and worsen the pain experience. Management with a traditional dosing of mu receptor opioid analgesics may be inadequate during the perioperative period. Moreover, patients may require higher doses of opioids with an inherent risk of precipitating patient cravings and subsequent relapse. Therefore, multimodal strategies should be employed as a part of the aggressive pain management to mitigate anxiety and allow for the successful treatment of pain. The author’s recommendation to continue buprenorphine and methadone was based on the strength of evidence and personal experience. However, providers should be cognizant of the fact that pain is subjective and treatment needs to be individualized.


Knee osteoarthritis (KOA) is a common degenerative disease associated with joint dysfunction and pain. Ultrasound-guided radiofrequency (RF) may be a promising therapy in the treatment of chronic pain for KOA patients.  To evaluate the efficacy and safety of ultrasound-guided RF treatment for chronic pain in patients with KOA. Setting. We examined the studies evaluating the clinical efficiency of ultrasound-guided RF on chronic pain in KOA population.  A systematic review was conducted, and a meta-analysis was carried out when possible. I2 statistic and the potential sources of heterogeneity by subgroup and metaregression analyses, respectively.  A systematic review for the efficacy and safety of ultrasound-guided RF treatment for pain management of KOA patients was carried out in PubMed, EMBASE, Cochrane Library, Web of Science, Wanfang Data, and China National Knowledge Infrastructure (CNKI) from the date of inception to February 2020, and a meta-analysis was conducted. The primary outcomes of pain intensity  and knee function [the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)] were evaluated from baseline to various follow-up times by random-effects model. Heterogeneity was assessed by Limitations. There were some limitations in the study. Firstly, the small number of relevant studies limited the confidence level of the meta-analysis. Also, the significant heterogeneity may not be explained due to the limited data. Secondly, the direct comparison of two different guidance methods (ultrasound vs. fluoroscopy) for RF therapy is lacking. In addition, the outcomes were blindly assessed in the meta-analysis from all studies according to evaluation of bias, which could affect the reality of the data. Finally, most of the studies only provided short follow-up times, so we could not analyze the long-term effectiveness of ultrasound-guided RF in the treatment of patients with KOA.  Eight publications with 256 patients were included in the meta-analysis. RF could relieve pain with −4.196 of pooled mean difference and improve knee function by decreasing 23.155 points in WOMAC. Three patients had ecchymosis, two with hypoesthesia and one with numbness after the procedure, and improved within 6 months. Furthermore, study design and treatment target were the sources of heterogeneity by subgroup and metaregression analyses, accounting for 37% and 74% of variances, respectively. Target of genicular nerve achieved better pain relief than intra-articular or sciatic nerve. Sensitivity analysis showed that removal of any single study was unlikely to overturn the findings.  Ultrasonography is an effective, safe, nonradiative, and easily applicable guidance method for RF in pain relief and functional improvement in KOA patients. Knee osteoarthritis (KOA) is a very common joint disease and associated with diverse factors including age, obesity, metabolic bone diseases, acute or chronic joint injuries, etc. . The preRecently, minimally invasive RF has been extensively used in the treatment of different stages of KOA and has achieved convincing therapeutic benefits. However, conventional RF is routinely guided by X-rays, so it may increase the risk of radiation exposure to the patients and health care providers . Thus, mA systematic review was conducted, and a meta-analysis was carried out when possible.We systematically searched several electronic databases including PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, Wanfang Data, and China National Knowledge Infrastructure (CNKI) via strategies developed using the appropriate Medical Subject Headings (MeSH) terms from the date of inception to February 2020. Keywords such as “knee osteoarthritis,” “ultrasound guided,” “radiofrequency therapy,” “genicular nerve,” “intra-articular,” and “chronic knee pain” were used. No date, language, or country limitations were applied to the searching.The inclusion criteria for the meta-analysis were as follows: (1) human clinical trials with or without control groups and cointervention were allowed if the trial was performed equally to both arms; (2) patients were diagnosed with KOA and suffered from chronic pain without satisfying pain relief by conservative therapies; (3) patients received RF therapy such as pulsed radiofrequency (PRF) or radiofrequency ablation (RFA); (4) minimally invasive procedure was completed under the guidance of ultrasound; and (5) necessary evaluation index was provided before and after RF therapy, for pain intensity and knee function including visual analogue scale (VAS), numerical rating scale (NRS), Oxford Knee Score (OKS), or Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and for quality of life including 36-Item Short-Form Health Survey (SF-36).The exclusion criteria for the meta-analysis were as follows: (1) full text is not available; (2) patients received total knee arthroplasty (TKA) or other knee surgery; (3) case report; (4) studies with insufficient data or uncompleted RCT; and (5) studies with doubtful data such as illogical outcomes without reasonable explanation.After targeted publications were found from different databases, the duplicates were removed first by two experienced investigators independently. Next, irrelevant studies were excluded by further scanning the title and abstract of publication by the inclusion criteria, and then the full text of remaining study was carefully screened to identify eligibility according to the exclusion criteria. Any uncertainty or disagreements were finally resolved via discussion between the two investigators and consulted with the third investigator to reach consensus.Two investigators independently extracted relevant data from each study including the first and corresponding authors, year of publication, country, study design, sample size, demographic characteristics (age and gender), grade of radiologic KOA (Kellgren–Lawrence grading system), follow-up time, type of RF, ultrasound transducer parameter, treatment targets and controls, primary outcomes such as the scores of pain intensity (VAS or NRS) and knee function  at baseline and available follow-up times, complications or adverse effects, conclusion, and limitations. We contacted the first and/or corresponding authors of study to verify any unclear information and data by e-mails, and the data were considered to be irretrievable without a reply from the authors. All the information was recorded in a prepared spreadsheet, and data were fully analyzed after collection.The quality and risk of bias for each study were independently assessed by at least two examiners. Additional investigators were consulted when discrepancies were present. RCTs were assessed by the criteria from the Cochrane Handbook for Systematic Reviews of Interventions . The potI2 statistics to measure the degree of data inconsistency as I2 > 50% being statistically significant between studies. Data were also analyzed with the random-effects model for high heterogeneity. Subgroup analysis was conducted for study design (RCT vs. prospective vs. retrospective study), treatment target (intra-articular vs. genicular vs. sciatic nerve), the performance of DNB, and follow-up period . Metaregression analyses were performed to evaluate the sources of heterogeneity based on all the covariates including age and gender in subgroup analysis. Sensitivity analysis was conducted to evaluate the impact of every single study on the pooled mean difference (MD). In addition, the publication bias was evaluated by Begg and Mazumdar rank correlation test and Egger's regression test [One of the primary outcomes from the studies was the pain intensity of patients as reported as the VAS (0–10 or 0–100 mm) or NRS (0–10) in different studies. To standardize the pain scale, the VAS (0–10 cm) was equivalent to the NRS (0–10) and transformed the scale from 0–10 cm to 0–100 mm. The 95% confidence interval (CI) for the difference in means was used to measure the scores of pain and knee function (WOMAC). For each analysis, the heterogeneity test was performed with ion test , 22. ComA total of 157 publications were identified from six electronic databases and 117 studies for further screening after removing 40 duplicates. Eighty-four irrelevant studies were removed through screening the titles and abstracts of publications, and 25 additional studies were excluded by exclusion criteria via full-text screening. Finally, eight eligible publications were included in the study of meta-analysis including 3 RCTs, 3 prospective trials, and 2 retrospective studies –30. The The included studies were conducted in five countries including Spain 3, Turkey 2, Egypt 1, India 1, and China 1, and the published date was from 2013 to 2019. The studies had 256 patients in total, with 61 males and 195 females, and the mean ages ranged from 60.0 to 72.5 years. The characteristics of studies were presented in P < 0.001; I2: 97.894%) compared to that of pretreatment (baseline) in patients with OA  after the treatment of ultrasound-guided RF compared to that of baseline in patients with OA.As shown in in Ultrasound-guided RF induced adverse events were uncommon and not serious; 3 patients were reported with ecchymosis at the site of procedure in the study by Santana Pineda et al.  and two As mentioned previously, two different methods were used to evaluate the risk of bias. For RCTs, the risks of selection, performance, attrition, report, detection, and other bias were determined by the criteria from the Cochrane Handbook for Systematic Reviews of Interventions . The risP=0.332 and P=0.274 for pain relief and P=0.245 and P=0.226 for functional improvement .No publication bias was found for the primary outcomes  of RF therapy in patients with OA. The results showed P < 0.01 and P < 0.001, resp.). However, there was no significant difference in pain relief whether DNB was administrated or not before RF therapy and among different follow-up periods (P > 0.05).Subgroup analysis was performed to confirm the sources of heterogeneity for pain intensity associated with study design (RCTs vs. prospective vs. retrospective studies), treatment targets (intra-articular vs. genicular vs. sciatic nerves), administration of DNB before treatment (applied vs. unapplied DNB), and time of follow-up , and the results are presented in Furthermore, we also performed a metaregression analysis based on all the covariates in subgroup analysis including age and gender to verify the sources of heterogeneity, and the results are shown in The results in P < 0.01) before and after RF therapy for both Lysholm and SF-36 scores [P < 0.05) [Moreover, the total time spent on the procedure for ultrasound-guided RF was recorded and compared to that of fluoroscopy-guided RF in the study by Sarı and colleagues . The dur6 scores . In addi6 scores , 30. San < 0.05) . The OKSKOA is a very common disease and has become a huge economic burden on our society , 4. PatiRecently, RF has been widely used to relieve intractable pain in KOA patients as a novel minimal invasion technique , 33. ChoIn the study of meta-analysis, 8 articles with a total of 256 patients were analyzed to evaluate the effect of ultrasound-guided RF on pain relief and knee functional recovery in patients with KOA. The main results revealed that all the patients suffered from intractable knee pain before treatment, and pain intensity and knee function were significantly improved from baseline (pretreatment) to different follow-up times after RF therapy. In an RCT for comparison of the efficacy of ultrasound- and fluoroscopy-guided RF in KOA patients by Sari et al. , ultrasoFor the meta-analysis, the patients with previous TKA used only as control were excluded from the calculation according to our exclusion criteria in the study by Erdem and Sir . In the The application of ultrasonography is rapidly increased for guidance of RF in pain management and knee function improvement in KOA patients. Over the last few years, more and more patients with KOA have used ultrasonography instead of fluoroscopy in RF therapy. Perrine et al. found that ultrasound- and fluoroscopy-guided RF therapy achieved the same effects on pain relief and functional improvement in KOA patients . Kim et I2 was more than 50 by subgroup analysis and metaregression analysis for potential sources of heterogeneity. In addition, the outcomes were blindly assessed in the meta-analysis from all studies according to evaluation of bias, which could affect the reality of the data. Finally, most of the studies only provided short follow-up times, so we could not analyze the long-term effectiveness of ultrasound-guided RF in the treatment of patients with KOA.There were some limitations in the study. First of all, we have only 8 enrolled studies with 256 patients for the meta-analysis. The small number of relevant studies and enrolled patients limited the confidence level of the meta-analysis. Secondly, another major problem is lacking high-quality RCTs to directly compare the two different guidance methods (ultrasound vs. fluoroscopy) for RF therapy in patients with KOA. Thirdly, high heterogeneity was observed in the studies. For example, study design and treatment targets were of the major between-study variances as accounted for 37% and 74% of variances, respectively; and Although there were some limitations in the studies, the results still provided clear evidence that ultrasound-guided RF therapy was effective and safe in the treatment of KOA patients for pain relief and knee function improvement. Numerous uncompleted RCTs related to the meta-analysis were found from the Cochrane Library, indicating that researchers and physicians have paid more attention to the application of this novel technique. However, there are still some questions needed to be answered. Ultrasound-guided RF therapy to target genicular nerve has only been widely used in recent few years. There are no detailed criteria or recommendations for this procedure such as RF type and treatment targets currently. The long-term effectiveness of ultrasound-guided RF in the treatment of KOA is still needed to be defined due to limited data. Nevertheless, ultrasonography is an effective, safe, dynamic, easily applicable, and nonradiative guidance method for RF therapy to achieve satisfying pain relief and functional improvement in KOA patients who failed conservative treatment. However, the efficacy and safety of ultrasound-guided RF in the treatment of KOA requires further investigation for clinical validation by high-quality multicentric, randomized controlled trials with large sample size.