Despite the high prevalence of chronic low back pain (CLBP) and osteoarthritis (OA), few estimates of the economic cost of these conditions in England have been published. The aim of the present analysis was to characterise the economic burden of moderate-to-severe pain associated with CLBP + OA and CLBP alone compared with general population-matched controls without CLBP or OA. The primary objective was to describe the total healthcare resource use (HCRU) and direct healthcare costs associated with the target patient populations. Secondary objectives were to describe treatment patterns and surgical procedures.  This was a retrospective, observational cohort study of patients receiving healthcare indicative of moderate-to-severe chronic pain associated with CLBP, with or without OA. We used linked longitudinal data from the Clinical Practice Research Datalink GOLD and Hospital Episode Statistics (HES). Patients (cases) were matched 1 : 1 with controls on age, sex, comorbidity burden, GP practice, and HES data availability. p < 0.0001). By 36 months after indexing, the mean (SD) per-patient total direct healthcare cost in the CLBP-alone cohort was £5081 (£5905) for cases and £1809 (£4451) for controls (p < 0.0001); in the CLBP + OA cohort, the mean (SD) per-patient total direct healthcare cost was £8819 (£7143) for cases and £2428 (£4280) for controls (p < 0.0001).  The CLBP-alone cohort comprised 13 554 cases with CLBP and 13 554 matched controls; the CLBP + OA cohort comprised 7803 cases with both OA and CLBP and 7803 matched controls. Across all follow-up periods, patients with CLBP alone and those with CLBP + OA had significantly more GP consultations, outpatient attendances, emergency department visits, and inpatient stays than controls (all  Moderate-to-severe chronic pain associated with CLBP—with or without OA—has a substantial impact on patients and healthcare providers, leading to higher HCRU and costs versus controls among people with CLBP alone or together with OA. Lower back pain and osteoarthritis (OA) are common musculoskeletal conditions and major causes of chronic pain and disability in the UK. Chronic pain was reported by 34% of respondents in the 2017 Health Survey for England, with the most commonly reported being musculoskeletal, including the back, hips, and legs , respectAn estimated one in 10 adults in the UK has symptomatic, clinically diagnosed OA.  Between Co-occurrence of low back pain (LBP) and OA is common. Gore and colleagues analysed data from patients who were newly prescribed selected pain medicines , cyclooxygenase-2 inhibitors, paracetamol, tramadol, and weak or strong opioids) in The Health Improvement Network UK database. They identified OA in 9.2–24.7% of patients with a diagnosis of CLBP and LBP in 7.4–21.9% of patients with a diagnosis of OA . In a stManagement of pain due to CLBP or osteoarthritis is complex and generally includes a combination of pharmacological and nonpharmacological approaches, with varying results , 14. Phast January 2007 to 31st December 2009  [Despite the high prevalence of CLBP and OA, to our knowledge, there are few recent published estimates of the economic cost of these conditions in the UK, and existing evidence predates published guidance for the care and management of this patient population , 20. The < 0.05) . General < 0.05) . Histori < 0.05) . ExistinThe aim of the present analysis was to characterise the economic burden of patients in England receiving healthcare indicative of moderate-to-severe pain associated with CLBP + OA, and those with CLBP alone, compared with general population-matched controls without CLBP or OA.This retrospective, observational cohort study of patients presenting to primary care with an episode of moderate-to-severe chronic pain associated with CLBP, with or without OA, and matched controls without CLBP or OA was conducted using linked data from the CPRD and Hospital Episode Statistics (HES). The study design is shown in Patients with an existing diagnosis  code) of LBP, either with or without OA, were indexed between December 2009 and November 2017 on a moderate-to-severe pain event occurring within a period of chronic pain. To be included, patients were required to be aged ≥18 years at index, to be eligible for linkage to HES data, to have ≥12 months of data before indexing and ≥12 months of data after indexing, and to have data of acceptable research quality as defined by the CPRD .A chronic pain episode was defined as a series of pain-related GP consultations relating to pain symptoms associated with CLBP or OA and/or a pain-related specialist consultation  in the secondary care setting, where gaps between visits were ≤12 months. The patient's first/earliest date of a moderate or severe pain event documented within the CPRD determined the index date.Moderate-to-severe pain events were defined as any of the following: a referral to/attendance with a pain specialist; a surgical or nonsurgical invasive procedure relating to the treatment of CLBP or OA ; two or more prescriptions for NSAIDs, including at least two different NSAIDs or opioids within a 3-month period; or a pain-related emergency department (ED) visit, with a pain-related GP follow-up within 14 days.Each patient within the study cohort (cases) was index matched 1 : 1 to a general population control within CPRD  on year of birth , sex, lifetime Charlson Comorbidity Index (CCI) score, GP practice, and linkage eligibility. The CCI is a score calculated based on the presence of a number of prespecified chronic conditions; the lifetime CCI score is the score calculated across the patient's entire medical record. Inclusion criteria and medical codes were reviewed for clinical relevance and appropriateness by RDK, AJD, and DAW. Each matched control patient was assigned a pseudoindex date equal to the index date of the case patient with whom they were matched.The CPRD GOLD primary care database is a longitudinal, anonymised research database of computerised medical records held by GPs across the UK. Over 650 primary care practices in the UK, covering 11 million people, participate in the CPRD, with clinical records for over 12 million individuals; an estimated 5.5 million people are actively registered. Data are broadly representative of the UK population . AvailabApproximately 75% of English practices contributing to CPRD are linked to the HES dataset, which provides data on all inpatient and outpatient contacts, including ED visits, occurring at NHS hospitals in England, with diagnoses recorded using ICD-10 codes.The primary study objective was to describe total healthcare resource use (HCRU) and direct healthcare costs associated with the target patient populations . Secondary study objectives were to describe CLBP/OA treatment patterns and surgical procedures.The key study outcomes were HCRU and direct healthcare costs. Components of resource use included GP appointments, outpatient appointments, hospitalisations, ED attendances, medicine use, and total direct healthcare costs . Use of physiotherapy and other outpatient services was limited to services provided in the secondary care setting. Pharmacological management included nonopioid analgesics , opioid analgesics , and adjuvant medicines . Pharmacological treatments assessed in this study were driven by the scope of NICE guidelines (NG59 and CG177) , 20, witUnit cost data were transformed into direct healthcare costs using appropriate unit cost data. GP consultation costs were sourced from Unit Costs of Health and Social Care, compiled and provided by the Personal Social Services Research Unit . For medThe study was conducted in accordance with legal and regulatory requirements and followed generally accepted research practices described in the Guidelines for Good Pharmacoepidemiology Practices issued by the International Society for Pharmacoepidemiology  and Goodst, 2019). Institutional review board approval was not required; no study participants were put at risk during the study, and confidentiality was maintained by use of data from deidentified electronic medical records provided by the CPRD.This study was approved by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulation Agency , 25th and 75th percentiles, minimum, and maximum values were reported for numeric variables.p < 0.05 was used for comparison of cases and controls. No corrections were made for multiple comparisons.All statistical tests were two-sided in nature; a significance level of Analyses were performed using Stata .st, 2008 and November 30th, 2018 , and an equal number of matched controls . Not all of these comorbidities were included in the CCI, upon which cases and controls were matched. Comorbid mental health conditions, including anxiety and depression, were also more common in cases compared with controls . The mean length of follow-up was 43.6 months in the CLBP-alone cohort and 39.9 months in the CLBP + OA cohort.Patient demographic and clinical characteristics are shown in p < 0.0001) (p < 0.0001); 26.7% of cases used pain management outpatient services during the same period compared with 0.2% of controls . Similar findings were observed during 0–6, 0–24, and 0–36 months of follow-up , patients with CLBP alone had significantly more GP consultations, outpatient attendances, ED visits, and inpatient stays compared with matched controls  . Orthopaollow-up .p < 0.0001). The mean (SD) length of stay over the 36-month follow-up was 0.82 (2.86) days in cases and 0.58 (4.49) days in controls (p < 0.0001).By 36 months after indexing, cases had a mean (SD) of 35.09 (26.94) GP consultations, 13.12 (14.44) outpatient attendances, 1.44 (2.91) ED visits, and 2.22 (4.57) inpatient stays compared with 14.32 (17.61), 4.15 (8.69), 0.56 (1.17), and 0.66 (5.62), respectively, in controls  number of treatment lines received was 9.0 (5−18), and the mean (SD) was 13.1 (12.3). Among cases, prescribing of paracetamol (9.9–20.9%) and topical NSAIDs (4.9–8.8%) increased substantially from line 1 to 10  had fusion surgery, 248 (2.1%) had disc replacement surgery, 1692 (14.0%) had medial branch block, and 334 (2.8%) had radiofrequency denervation.p < 0.0001) , patients with CLBP + OA had significantly more GP consultations, outpatient attendances, ED visits, and inpatient stays compared with matched controls  .p < 0.0001); 18.8% of cases used the pain management outpatient service during the same period compared with 0.3% of controls .The cumulative inpatient length of stay was almost three times longer for cases compared with controls in the first 12 months of follow-up (mean (SD) 2.52 (9.03) vs 0.90 (7.13) days; Similar findings were observed during 0–6, 0–24, and 0–36 months of follow-up . By 36 mth and 75th percentiles) number of treatment lines received was 11.0 (6–20), while the mean (SD) was 14.8 (12.5). Prescribing of paracetamol (19.2–32.3%), topical NSAIDs (9.1–15.6%) increased substantially from line 1 to 10 in cases with OA + CLBP, whereas the prescribing of systemic NSAIDs (23.8–27.9%), weak opioids (11.3–11.3%), and strong opioids (26.3–30.3%) remained relatively consistent. Use of antidepressants (12.3–26.5%), antiepileptics , and anxiolytics (6.5–13.3%) increased substantially from line 1 to 10 , 197 (2.6%) had fusion surgery, 188 (2.5%) had arthroscopy , 122 (1.6%) underwent osteotomy , and 70 (0.9%) had disc-replacement surgery. A further 698 cases (9.3%) had a medial branch block, 150 (2.0%) had radiofrequency denervation, and 2044 (27.2%) had an intraarticular injection.Among the 7520 incident cases, i.e., those without any moderate-to-severe chronic pain associated with CLBP prior to indexing, 1844 (24.5%) had a total joint replacement  (p < 0.0001). Individual cost elements for each healthcare resource used were also significantly higher for cases compared with controls. The contribution of inpatient stays to total costs was higher for cases (49–55%) versus controls (41–43%) across all time periods. GP consultations and outpatient attendances were other substantial contributors to the total costs .NHS England total healthcare costs incurred through cases during the 0–6, 0–12, 0–24, and 0–36 months of follow-up were 4, 3.5, 3, and 2.8 times higher, respectively, compared with matched controls  . By 36 mMedication costs were numerically lower in cases versus controls. They accounted for 2-3% of total costs in cases (£26 of £1271 at 0−6 months to £131 of £5081 at 0−36 months) and 7-8% of total costs in controls (£24 of £319 at 0−6 months to £127 of £1809 at 0−36 months).p < 0.0001) (p < 0.0001). Individual cost elements for HCRU were significantly higher for cases compared with controls.Total costs incurred by cases during the 0–6, 0–12, 0–24, and 0–36 months of follow-up were 5, 4.4, 3.8, and 3.6 times higher, respectively, compared with matched controls  . By 36 mp < 0.0001). GP consultations and outpatient attendances were other substantial contributors to the total costs .Inpatient stay costs accounted for approximately 60−66% of total costs for cases and 42−44% for controls  versus 6–8% of the total cost in controls (£24 of £415 at 0–6 months to £123 of £2428 at 0−36 months).This retrospective, longitudinal cohort study with matched controls is, to our knowledge, the first to provide a detailed analysis of HCRU and costs incurred by patients in England who have CLBP, with or without OA, and who experience moderate-to-severe pain. A total of 13734 patients with moderate-to-severe chronic pain associated with CLBP were identified, of whom 7803 (57%) also had a diagnosis of OA. Moreover, we identified 21357 patients with moderate-to-severe chronic pain associated with CLBP, of whom 7803 (37%) also had a diagnosis of OA. These estimates of OA as a comorbidity in patients with CLBP are higher than reported elsewhere , 12, mosPatients with moderate-to-severe pain associated with CLBP alone used significantly more healthcare services and incurred greater direct healthcare costs than their age-, sex-, geography-, and comorbidity-matched controls. The total direct cost of treating this patient cohort over 36 months was approximately £35 million (mean direct cost per patient of £5081 over 36 months), a considerable cost bearing in mind the relatively small size of the patient cohort (6724 patients with data at 36 months). Importantly, these direct costs represent a small proportion of the overall cost associated with CLBP, as our analysis did not take into consideration indirect costs, such as sickness absence and reduced productivity, and the cost of informal care, such as self-care and family care, not provided by the NHS. Inpatient stays were the main drivers of costs incurred in this patient population.Similarly, patients with moderate-to-severe pain associated with CLBP with concomitant OA used significantly more healthcare services and incurred greater direct healthcare costs than their matched controls. The total direct cost of treating these patients over 36 months was almost £31 million, with each patient incurring costs that were almost twice as much as those incurred by a patient with CLBP alone, primarily driven by inpatient stays and outpatient appointments. Almost one-quarter of patients in the CLBP + OA cohort underwent total joint replacement during the follow-up period, most commonly knee and hip replacement, considerably adding to the cost of their management. A small proportion of patients in both the CLBP-alone and CLBP + OA cohorts underwent procedures that were not recommended in the most recent guidelines for CLBP management (NICE low back pain and sciatica treatment guidelines published in 2016 and updated in 2020 ). Use ofOthers have reported similar HCRU trends in patients with CLBP compared with matched controls. In a US study of data from a managed care system, Mapel and colleagues observed that patients with CLBP were three times more likely to be hospitalised and had longer average lengths of stay—incurring greater costs—than their matched controls . In an aThe use of some analgesic medicines, including paracetamol and topical NSAIDs, increased across treatment lines in both cohorts of cases. Use of strong opioids remained consistent across lines in the CLBP cohort, at approximately one-third of patients. Since 2016, NICE guidelines for managing pain in people with chronic LBP advise against the use of most opioids, whereas the 2020 update to the OA management guidelines recommend opioids use with caution , 20. NotSome limitations of the study, many of which are inherent in real-world data analyses, should be considered. Diagnoses were identified using ICD-10 and Read codes, which are subject to potential miscoding. Secondary data sources are liable to have incomplete, missing, or low-quality data; the absence of a specific diagnosis or drug code was required to be interpreted as the absence of disease and medicines, respectively, resulting in potential misclassification bias. The CPRD is, however, widely considered a gold standard in healthcare event reporting, and missed diagnoses or prescriptions are likely to be rare. The requirement for 12 months of follow-up data following the index date introduces potential survivorship bias to the study. The chronic pain end date may not truly indicate the date when the chronic pain episode ended, as some patients may instead have decided not to use the NHS further and/or self-manage despite minimal improvement (if any) in their chronic pain.Not all HRGs have a national tariff, as some prices are negotiated locally; therefore, direct healthcare costs are likely to have been underestimated in this analysis as missing costs were not imputed. Our data were captured before changes in the recommended pharmacological treatment for people with LBP, specifically the use of opioids, and therefore might not reflect current pain management practice. Medicines bought over the counter, such as paracetamol and some NSAIDs, which have been reported to account for an annual spend of £600 million, and those administered through hospital pharmacies are not captured, and there is no national individual-level hospital prescribing database for England . This maSome analgesic medications have multiple indications; therefore, it is unknown if the medicine was prescribed to specifically treat CLBP or OA pain, or other pain and nonpain conditions. The definition of the study cohort and the involvement of clinical experts in the development of the protocol and statistical analysis plan meant that analgesics were likely to have been prescribed to treat the chronic pain associated with CLBP. The costs described in this study represent direct costs only; additional self-care and private care costs, plus societal and indirect employment costs, were not captured in this analysis but are likely to substantially increase the overall cost of chronic pain associated with CLBP.A key study strength is the real-world nature of the data. The linked CPRD and HES datasets have broad coverage, encompassing 75% of patients in English GP practices. Consequently, our findings are likely to be generalisable as an accurate representation of adults with CLBP alone and adults with OA + CLBP in England.Moderate-to-severe chronic pain associated with CLBP with or without OA has a substantial impact on patients and healthcare providers. We have shown that CLBP and OA are commonly comorbid and that healthcare utilisation and costs are increased for people with CLBP alone or comorbid with OA. This increase in healthcare utilisation and costs is largely associated with hospital admissions and outpatient attendances. Current costs for analgesic medicines are relatively low, but improvements in medical management have substantial potential to reduce resource utilisation if they can abrogate the need for more intensive care. Future research may look to describe resource use in patients with mild chronic pain and CLBP, to explore the indirect economic burden in this patient population. Further, with the establishment of integrated care boards (ICBs) and as the NHS becomes more data-driven, opportunities for similar research to use data derived from a broader breadth of aspects of care, such as from hospital pharmacies, may arise.


Complementary and integrative medicine may be effective for postoperative outcomes. This study aimed to determine the effect of lemon inhalation aromatherapy on pain, nausea, and vomiting and neurovascular assessment in patients for lower extremity fracture surgery.This is a randomized clinical trial study. Ninety patients who had undergone lower extremity fracture surgery were randomly assigned to the intervention (lemon aromatherapy) and control groups. Lemon aromatherapy was started in the morning of the surgery and extended at two-hour intervals until the end of the surgery, in the recovery room, and 16 h after surgery. Numerical pain and nausea and vomiting scales, the Rhodes Index of Nausea, Vomiting, and Retching, and the WACHS Neurovascular Observation Chart were used to assess the outcomes before and after the intervention . The data were analyzed using the Wilcoxon test, ANCOVA, and Repeated Measure ANCOVA.P < 0.001) and nausea and vomiting (P = 0.001) during the study period. Moreover, a significant difference was found between groups as to the frequency and severity of nausea, vomiting, and retching. The amount and duration of postoperative vomiting and nausea were significantly lower in the intervention group compared to the control group. In addition, lemon inhalation aromatherapy decreased the frequency of anti-emetic drug administration in the recovery room (P = 0.04) and 16 h post-surgery (P = 0.03).A significant difference was observed between the groups in terms of the intensity of pain .This study was registered in the Iranian Registry of Clinical Trail  ( Lower extremity fractures are associated with severe disability, recovery, and long-term treatment and require the most surgical procedures . It was Postoperative nausea and vomiting are among the common post-surgery side effects. Literature showed that one third of postoperative patients experienced moderate to severe nausea and vomiting following general anesthesia . Nausea Swelling and pressure on the muscles and arteries after a fracture are dangerous and may cause complications such as compartment syndrome . NeurovaAs previously stated, pain, nausea, and vomiting are common, and so are neurovascular complications; thus, providing some complementary and integrative health (CIH) may be essential for these patients. The effectiveness of aromatherapy in the treatment of postoperative nausea and vomiting was reviewed in many studies , 12. In As mentioned, complications such as pain, nausea and vomiting, and neurovascular impairment are common in patients with lower extremity fractures. Therefore, CIH may relieve postoperative pain and subsequently improve physiological parameters, rehabilitation, and initial mobility, reducing the need for analgesics. Previous studies on the effect of inhaled lemon aromatherapy in patients with fractures are limited ; therefohttps://www.irct.ir/trial/57331).This is a clinical trial study with a parallel group. The study was registered in the Iranian Registry of Clinical Trail  , participated in previous studies, received complementary and alternative interventions such as aromatherapy, meditation, relaxation, massage, acupuncture, etc. a week before the intervention, and had COVID-19 were excluded. Moreover, the patients who had compartment syndrome before the intervention were excluded.At first, one hundred patients participated in this study. Nine patients did not meet the inclusion criteria, and one of them was unwilling to participate, so 90 patients participated and were randomly assigned to the intervention and control groups. All of them continued the study and finished it Fig. .Fig. 1FlThe sample size in this study was based on a pilot study. Based on pain severity μ1-μ2 = 1.7, SD = 0.9 and drop rate = 20%, the sample size was estimated 90 patients (45 in each group). Moreover, based on nausea and vomiting severity μ1-μ2 = 4, SD = 3 and drop rate = 15%, the sample size was determined 52 patients (26 in each group). Therefore, regarding the higher sample size required, it was determined as 90 patients (45 in each group).As to randomization, the following were performed: Firstly, Rajai and Namazi hospitals were selected as two separate strata. Then, using WinPEPI software and balanced randomization of separate strata, a list of random allocations was set for 90 patients. Therefore, according to the list in each stratum , 45 patients were randomly divided into the intervention or control groups. A statistician who was not one of the research team generated the random allocation sequence using WinPEPI software and made sequentially numbered containers. A researcher assistant assigned the participants to the intervention based on random sequence that was in sequentially numbered containers.In order to conduct blinding, the assistant researcher who collected the data as well as the statistician who analyzed them were blinded to the groups and the assignment of individuals in the groups. Moreover, clinicians and nurses in the orthopedic clinical treatment rooms, and recovery and operation rooms were blind to the groups.The outcomes of this study were pain, nausea, and vomiting and neurovascular index. The variables were measured before the intervention, on entering the recovery room, 4, 8, 12, and 16 h after entering the orthopedic surgery ward. Pain intensity was assessed by a numerical rating scale. It numbered 0 to 10, which represented “no pain” to “the worst pain ever possible”, respectively. In this study, the test–retest score of the scale was found to be 0.94.Post-operative nausea and vomiting were measured using a numerical rating scale and the Rhodes Index of Nausea, Vomiting, and Retching. A numerical rating scale was used to rate the itemsfrom zero to 10. Higher scores indicated a higher intensity of nausea and vomiting. The Rhodes Index of Nausea, Vomiting, and Retching also measured the severity  and frequency  of these variables. This index measured the amount of vomiting , large (2–3 cups), and very large (3 cups and more)) and the duration of nausea  . This inThe WACHS Neurovascular Observation Chart was used to assess vascular, neurological, and compartment syndrome signs in the lower extremity under surgery. In vascular assessment, skin color and temperature, capillary refill times, and distal pulse were observed. For neurological assessment, movement, and sensation of the lower extremity under surgery were observed. In compartment syndrome assessment, the lower extremities under surgery were assessed for “pain on passive movement, increasing pain not relieved by analgesia, pain at rest, and edema”.In the intervention group, 5 drops of lemon essence was put on the patient's surgical facemask when the patients were in orthopedic clinical treatment rooms until he/she was transferred to the operation room. In the operation room and during orthopedic surgery, it was poured on a cotton ball and attached to the participants’ clothes with a distance 20 cm from the patient's nose. In the recovery room or post-anesthesia care unit (PSCU), it was poured on a cotton and inserted in the upper and right edge of oxygen mask which covered the patients’ nose and mouth. In the control group, bitter almond oil, which was odorless, was used in a similar way to the intervention group. A researcher assistant conducted the intervention. In fact, aromatherapy was done continuously. That is, the essential oil was poured on the surgical mask or cotton in each of the groups and inserted in the desired location. Cotton or surgical mask was replaced every two hours with essential oil aromatherapy. Aromatherapy was started in the morning of the lower limb fracture surgery and extended at two-hour intervals until  the end The lemon essence was a product of Barij Essence Pharmaceutical Co. and the certificate of decomposition of it was approved and delivered by the quality control unit. In fact, the production and analysis process of lemon essential oil was conducted by Barij Essence Pharmaceutical Co. To analyse lemon essential oil, we used a gas chromatography–mass spectrometry device (Agilent technologies model 6890). Analysis of lemon essential oil showed that the major components consisted of limonene, β- terpinene, γ terpinene, β-caryophyllene, neral, α-terpineol, neryl acetate, geranial, and geranyl acetate.Limited information has been reported on the side effects of lemon essence. It was reported that distilled sour lemon essence was not phototoxic. Unsolved essence irritated rabbits and mice moderately. However, a previous study showed that lemon essence had a lower risk of phototoxicity and that it was not allergenic . In a stThis study has been approved by the Research Ethics Committees of the School of Nursing and Midwifery, Management and Medical Information Science at Shiraz University of Medical Sciences . The informed consent form was signed by all the participants. The patients were informed about the objectives, duration of the study, and side effects. They also were ensured that participating or not participating in the study was optional and that they could withdraw from the intervention whenever they wanted.The data were analyzed using SPSS software version 26. In this study, the type of anesthesia , site of fracture, use of analgesics in pre-, intra-, and post-operative stages, use or non-use of anti-emetic drugs in vomiting in recovery and in the post-operative ward were considered as confounding variables. The data were analyzed using the Wilcoxon signed-rank test, ANCOVA, Chi-square, and Repeated Measure ANCOVA.Ninety patients participated and were randomly assigned to the intervention and control groups. All of them continued the study and finished it. The patients participated in this study before the intervention, on entering the recovery room, 4, 8, 12, and 16 h after entering the orthopedic surgery ward. No side effect, harm, or unintended effects were reported because of the intervention.The mean age of the patients was 38.06 (SD = 13.98), and 43.77 (SD = 14.16) in the intervention and control groups, respectively. Moreover, 38 (84.4%) patients in the intervention and 37 (82.2%) in the control groups were male. Moreover, 23 (51.1%) and 25 (55.6%) participants in the intervention and control groups underwent spinal anesthesia, respectively, and the others underwent general anesthesia. In the intervention group, 3 (6.7%), 24 (53.3%), 15 (33.3%), and 3 (6.7%) had ankle, tibia, femur, and hip fracture, respectively. In the control group, 5 (11.1%), 22 (48.9%), 15 (33.3), and 3 (6.7%) had ankle, tibia, femur, and hip fracture, respectively. This study showed both groups were homogenous regarding the age, gender, types of anesthesia during surgery, and site of fracture.p = 0.17). Also, no significant difference was found between the two groups with regard to pain intensity 8 h after entering the orthopedic ward . On the other hand, a significant difference was indicated between the two groups with respect to pain intensity upon entering the recovery room and 4, 12, and 16 h post-surgery. Repeated measure ANCOVA showed a significant difference between the groups in terms of pain intensity during the study period  . This variable was not different between the intervention and control groups in the recovery room and 16 h after entering the orthopedic ward (p < 0.05)  and dose of pethidine administration     Table .Table 2Cp > 0.05)  before the intervention. Moreover, the neurovascular observation scale was not different between the groups during the study period  Tables  and 4.TaThis study showed that lemon inhalation aromatherapy reduced pain intensity in patients with lower extremity fractures upon entering the recovery room and at 4, 12, and 16 h post-surgery. In a mouse model study, the flavonoid eriocitrin in lemon fruit was found to have an antinociceptive effect on postoperative pain. This effect may be mediated by opioid and GABA receptors . A systeThis study found that lemon inhalation aromatherapy reduced the severity and frequency of nausea, vomiting, and retching in patients who have undergone surgery for lower extremity fractures. This intervention also reduced the frequency of anti-emetic drug administration in postoperative lower extremity fracture patients. The clinical and important findings were that no patient in the lemon inhalation aromatherapy group needed anti-emetic drugs in the recovery room or 16 h postoperatively, respectively. Similarly, it was revealed that using aromatherapy with lavender, peppermint, ginger, and lemon reduced the number of orthopedic patients’ needs for anti-emetic drugs and their dose of anti-emetic administration . In anotAs a cost-effective intervention, lemon inhalation aromatherapy might reduce pain, nausea, and vomiting in patients after lower extremity surgery. Therefore, this intervention had implications in practice.The strength of this study was that the use of lemon essential oil was continued from the morning of the lower limb fracture surgery and extended at two-hour intervals until the end of the surgery, in the recovery room, and 16 h after surgery. Researchers’ assistant carefully carried out this intervention. Considering inclusion and exclusion criteria carefully minimized the effect of confounding factors, which was another strength of current study. To reduce the other confounders, ANCOVA was used and the type of anesthesia , use of analgesics in pre-,intra-, and post-operative stages, use or non-use of anti-emetic drugs in vomiting in recovery and in the post-operative ward were considered as confounding variables. Using random allocation and large randomized clinical trial was also another strength of this study.Although the patients with lower extremity orthopedic surgery who underwent lemon essential oil indicated lower pain intensity, kind and dose of anesthesia medications might affect the pain feeling in the patients. As it was not possible to control all of these covariates, it was one of the limitations of this study. The second study limitation was related to inclusion criteria that patients with lower extremity fracture surgery  participated in this study. These various types and sites of fractures might affect the symptoms and treatment. Therefore, other studies are recommended to be conducted on one site of fracture, e.g., the hip, femur, tibia, ankle, and heel which received one type of treatment, e.g., open and close reduction and internal and external fixation of the foot.This study indicated that lemon inhalation aromatherapy reduced the pain intensity, post-operative frequency, and severity of nausea, vomiting, and retching. Moreover, this intervention reduced the amount of postoperative vomiting and duration of nausea. In addition, lemon inhalation aromatherapy decreased the frequency of anti-emetic drug administration in the recovery room and 16 h postoperatively. Therefore, using lemon inhalation aromatherapy, as a pain reliever and a reducer of nausea and vomiting, is suggested for lower extremity fracture cases who have undergone surgery. Conducting further studies to support evidence-based practice regarding pain, postoperative vomiting, and neurovascular and compartment syndrome of fractured patients who have undergone surgery is recommended.


Objective: Pain is one of the most common symptoms of cancer patients. Patients with advanced stages of cancer are always transferred to primary medical institutions or treated with home medication due to their specific pathophysiological characteristics. Studies have shown that continuous pharmaceutical care can improve the effectiveness and safety of drug therapy for cancer pain patients in primary care, but no relevant research has been conducted in China. Based on the Delphi method, this study aims to construct a pharmaceutical care mode for cancer pain patients and analyze its effect in drug therapy treatment in primary care in China.Methods: A pharmaceutical care mode for cancer pain patients in primary care was developed through two rounds of expert consensus. A total of 200 cancer pain patients from January 2022 to January 2023 in Nanjing Drum Tower Hospital were recruited and divided into an intervention group and control group. The self-developed pharmaceutical care mode in primary care was conducted in the intervention group, while the traditional pharmaceutical care mode was conducted in the control group. Comparisons between the groups were performed in terms of pain assessment rate, reasonable rate of pain assessment, pain score, and incidence of adverse reactions.Results: The initiative of experts in the two rounds of consultation was 100%, with an authority coefficient of 0.83. The coordination coefficient of the second round was higher than that of the first round, indicating that the consistency of expert opinions was enhanced. There were 100 cases in each group, and 12 and 8 were lost to follow-up in the intervention group and control group, respectively. Compared with the control group, the intervention group had a significantly higher pain assessment rate, a reasonable rate of pain assessment, and a significantly lower pain score and incidence of adverse reactions.Conclusion: Under the scientific and reasonable mode of pharmaceutical care for cancer pain patients at the primary level, standardized drug therapy could significantly enhance the efficacy of treatment, thereby improving the quality of life of patients. Malignant tumor remains a crucial and life-threatening public health issue in the 21st century. The latest global cancer statistics reveals that China accounts for 24% and 30% of new cases and fatal cases of cancer all over the world, respectively . Pain isIt is necessary for patients with cancer pain to receive quality pharmaceutical care to control the pain. However, malignant tumor progression indicates that most cancer pain patients are no longer suitable for active anti-cancer treatment in third-grade class-A hospitals but should be transferred to primary medical institutions or take medication at home. Due to the lack of a standardized pharmaceutical care mode and pharmaceutical care capacity, there appear many drug-related problems (DRPs) in the treatment of cancer pain in primary healthcare institutions in China. In addition, there remain insufficient effective connections between superior hospitals and primary medical institutions, resulting in a higher risk of medication among patients after referral, thereby restricting the effect of cancer pain management at the primary care and increasing the incidence of inadequate analgesia or adverse reactions. Masami et al.  providedBased on the abovementioned analysis, this study first constructed a pharmaceutical care mode for cancer pain patients at the primary care level in China based on the Delphi expert consensus in order to focus on the continuity and quality of pharmaceutical care after referral from superior medical institutions to primary healthcare institutions. Second, this study carried out a prospective interventional study to investigate the effect of such modes so as to provide reference for promoting standardized and scientific practice of cancer pain pharmaceutical care at the primary care level.To ensure professionalism, the research team consisted of four members, including three senior clinical pharmacists and one master majoring in pharmacy. The main tasks included the preliminary construction of a pharmaceutical care mode for cancer pain patients at the primary care level, development of expert consultation questionnaires, determination of inquiry experts, distribution and collection of questionnaires, and statistical analysis.In this study, we recruited people from different positions in the field of cancer pain management, including clinical, pharmaceutical, and nursing experts, hospital administrators, pharmaceutical administration, health management research experts, and officials of health administration departments. The inclusion criteria were as follows: 1) more than 3 years of work experience in the field of cancer pain management, 2) bachelor’s degree and above, 3) medium-grade professional title and above, 4) and the ability to cooperate and complete two rounds of expert consultation.We searched related articles on continuous pharmaceutical care, cancer pain pharmaceutical care, and primary pharmaceutical care in the past 10 years on PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and Wangfang databases. On the basis of practical work experience, the research team summarized the key elements of the working mode and preliminarily set up a consultation questionnaire, including three first-level items and 16 second-level items. The questionnaire was composed of four parts: instructions, basic information of experts, construction index of the pharmaceutical care mode for cancer pain patients at the primary care level, and judgment basis and familiarity of experts. The Likert 5-level scoring method was used to determine the importance of indicators, and an open-ended supplementary suggestion column was set under each item, where experts could modify, supplement, or delete the corresponding items.Questionnaires were distributed by the “Wenjuanxing” platform and were collected within five working days for each round of consultation. The initiative of experts was expressed as the response rate of the questionnaires. We used the authority coefficient (Cr) to quantify the authority level among experts in the consultation, and the Cr was calculated as the average of familiarity with the questionnaire (Cs) and judgment coefficient (Ca). Kendall’s coefficient of concordance was used to evaluate the degree of coordination among experts, and the mean and standard deviation (SD) of each indicator reflected the concentration degree of experts’ opinions. Indicators were screened with the standard of the mean of importance assignment ≥3.5 and the coefficient of variation ≤0.3. Combining with supplementing and deleting the indicators according to the textual opinions of experts, the second round of consultation was formed. Based on the results of two rounds of consultation, a set of pharmaceutical care modes for cancer pain patients at the primary care level was obtained.The institutional review board of Nanjing Drum Tower Hospital approved this study (No. 2022-664-02), and all participants signed informed consent. In our study, an effect size of 0.5 and a power of 0.9 were applied . Considen = 100) and control group (n = 100). A study on the control group was carried out first, followed by the intervention group after some preparations, such as standardized cancer pain pharmaceutical care training.Patients were divided into an intervention group  pain score: numerical rating scale (NRS) was used to evaluate the pain status after pharmaceutical care for 1 month, with 0 point indicating painless, 1–3 points indicating mild pain, 4–6 points indicating moderate pain, and 7–10 points indicating severe pain ; 2) paint-test for continuous variables. The threshold for significance was p = 0.05. Excel 2021 software was used for data input. All statistical analyses were conducted using SPSS version 25.0 .Variables were expressed as mean ± standard deviation (x ± s) and counts (proportion) for continuous and categorical variables separately. Numerical differences between the two groups were assessed by the chi-squared test for categorical variables and the There were 24 experts in each round of expert consultation, and their basic information is shown in p < 0.01), indicating a statistically significant difference , tumor type, and other general information, with all Pain assessment was conducted after 1-month implementation of the cancer pain pharmaceutical care mode. As shown in Pain scores were collected at 1–3 months after the implementation of the cancer pain pharmaceutical care mode. As shown in Adverse reactions were recorded after 3 months of the implementation of the cancer pain pharmaceutical care mode. As shown in As a mature and reliable method that has been widely applied in the field of health services, the Delphi method is often used in the formulation of models and standards . On the It is of great importance for the Delphi procedure to select experts with higher attainments based on strict inclusion criteria . In thisThe response rates of the questionnaire in both rounds were 100%. In addition, the experts put forward a number of constructive suggestions, reflecting the high initiative and support of experts for this study . The resPain assessment is the first step in the management of cancer pain. Only by making a reasonable dynamic pain assessment and understanding the characteristics of pain degree, site, nature, and psychological state can the corresponding medication regimen be formulated so as to improve the treatment effect of cancer pain and the quality of life of patients. Most pain assessment in the community among cancer pain patients in developed countries is completed by pharmacists . At presPharmaceutical care in the management of cancer pain medication abroad includes the assessment of pain control, number of acute pain attacks, adverse drug reactions, formulation of medication regimens, and management of medication adherence . Some stPain scores were analyzed at 1–3 months after the implementation of the cancer pain pharmaceutical care mode. No significant difference between the intervention and control groups was found in the 1-month follow-up, which might be related to the low degree of cooperation and trust between patients and family doctors. However, at 2-month and 3-month follow-up, the intervention group had a significantly lower pain score compared to the control group, proving that the self-developed mode could improve the effectiveness of cancer pain control. The majority of patients prefer to visit hospitals because of their concerns about the service level of primary medical care. Under the standardized pharmaceutical care mode, family doctors gradually penetrate into the process of patient diagnosis and treatment, so patients can experience the same service from primary care as hospitals and will be more willing to seek cancer pain management from family doctors. The intervention group in our study had a significantly lower incidence of adverse reactions compared to the control group after 3 months of the implementation of the cancer pain pharmaceutical care mode, noting that such modes could remarkably increase the safety of cancer pain drug treatment. Standardizing the path of pharmaceutical care and clarifying the responsibilities and workflow of family doctors is conducive to timely detection of drug-related events and adjustment of medication regimens, thus conducting individualized management of cancer pain.Medication adherence remains an influencing factor for the effect of cancer pain medication. In our study, both the intervention and control groups had more than half of patients with moderate adherence, without statistical difference. However, compared with the control group, the intervention group had significantly more patients with good adherence and less with poor adherence. The abovestated results demonstrated that through standardized pharmaceutical care for cancer pain at the primary care level, regular medication evaluation records and medication education for patients could improve their medication adherence.There are some limitations in this study. First, 20 of the 24 experts in consultation were from Nanjing, Jiangsu Province, which had regional characteristics. Thus, the pharmaceutical care mode constructed in this study may need to be adjusted and improved according to the actual situation in the future. Second, empirical research was a single-center study with a relatively small sample size and short follow-up time, which might lead to bias. We expect to expand the research scope and sample size in the process of promotion and application in the later stage and to add the research on the influence of the application of this mode on patient medication adherence and economics so as to further confirm the application effect of this mode in cancer pain management in the primary care level.Through two rounds of Delphi expert consensus, this study developed a set of pharmaceutical care modes for cancer pain at the primary care level, which standardized the management process of cancer pain medication for patients referred to primary medical institutions or at home. The empirical research results of this model indicated that our pharmaceutical care mode could reduce the risk of drug use in cancer pain patients, as well as improve the quality of cancer pain management at the primary care level. We recommend further promoting and applying this mode in clinical practice in order to achieve continuous improvement and optimization.


Morton’s neuroma (MN) is a compressive neuropathy of the common plantar digital nerve, most commonly affecting the third inter-digital space. The conservative approach is the first recommended treatment option. However, other different approaches have been proposed, offering several options of treatments, where, several degrees of efficacy and safety have been reported. We treated five consecutive patients affected by MN through three indirect ultrasound-guided injections of type I porcine collagen at weekly intervals. All patients were assessed before the treatment, after the treatment and up to 6 months after the last injection via AOFAS and VNS scores for pain, in which the function and pain were evaluated, respectively. In all patients, both analyzed variables progressively ameliorated, with benefits lasting until the last follow-up. The trend of the scores during the follow-up showed significant statistical differences. No side effects occurred. To our knowledge, this is the first study on injections of type I porcine collagen for the treatment of Morton’s neuroma. Future research is needed to confirm the positive trend achieved in this MN mini-series. Morton’s neuroma (MN) is a compressive neuropathy of the common digital plantar nerve (CDPN). It often causes significant pain that limits footwear choice and weight-bearing activities. This condition was first described anatomically by Civinini in 1835 . TherefoNon-surgical interventions for MN are a recommended treatment option before surgery . HoweverSurgical treatment can be performed with two different approaches: dorsal or plantar. Both appear to have no negative impact on the clinical outcome of the MN patient, while appearing to only impact the aesthetic effect ,21. AlcoThere are several conservative proposals in the literature, but none can be considered the gold standard . The useFive consecutive patients  were admIndeed, the five enrolled patients had not undergone previous infiltrative or surgical treatments, had not undergone physical therapies in the last 3 months and did not change their footwear during the time-frame observation period. All of them had already treated the foot pain limiting weight-bearing activities. The patients reported a variable degree of pain during walking, paresthesia in the toes and pain when subjected to axial compression. Based on medical history and physical examination, compressive neuropathy of the common plantar digital nerve was suspected in all patients. As a whole, considering anamnestic information, all five subjects were classified as Morton’s neuroma (MN) patients  through We decided to treat the patients with a series of three injections of 2 mL of type I porcine collagen added with 2% lidocaine hydrochloride at weekly intervals, using an indirect US-guided (IUSG) approach. After a full and clear description of the study, the patient was invited to sign informed consent. Injections were performed by a single doctor with years of experience in ultrasound-guided infiltrative treatment. Each patient was confined to a bed with his knee flexed and his foot on the bed. The injection site was identified by using the US at the II or III interdigital space on the dorsal face of the foot; then, a 26G (13 mm) needle was inserted into the location identified, and the collagen was slowly injected. All the injections were performed at the point of maximum pain .The porcine type I collagen was obtained in the following formulation: a single vial with a 2 mL final volume containing porcine type I collagen, Colocynthis, NaCl and sterile water. The product is classified as a medical device , available as MD-NEURAL.MD-NEURAL  is a medical device designed to reduce neuropathic and muscular associated pain, counteracting physiological and pathological joint deterioration. Previous clinical evidence has been reported on both the efficacy and safety of MD-NEURAL in cases of the following neuropathic accuracies, neuralgia and associated neuropathic pain ,27,28.Patients’ timelines were established during the inclusion in the present study. All patients received three injections at a weekly interval, following a recent protocol . The cliThe AOFAS score ranges from 0 to 100 points; the best results are associated with higher scores. The VNS was used to assess pain both at rest and during weight-bearing activities. It ranges from 0 to 10; 0 represents the absence of pain, while 10 represents the maximum describable pain. The trends of collected values are illustrated in the following t-test was also performed. We acquired significant statistical data according to the p < 0.05.In order to evaluate the significant statistical differences among all MN patients and their cognate treatments, ANOVA analyses (using Dunnett’s multiple comparers test) were performed. In addition to assessing the effectiveness of treatment for all patients, the paired The follow-up was positively closed in all patients. The three scores were assessed for each patient at all the times established above in the p < 0.0001). The t-test also revealed a significant statistical difference by comparing the T0 vs. T5 treatment (p = 0.0089). In particular, the treatment protocol seemed to have an effect of stratification on the patients, in terms of the SD between T0 and T5 .According to the criteria established above, the results of the AOFAS questionnaire are reported in Regarding the analysis of the VNS ratings, the results were divided into two different lists, with the first reporting the quantification of pain at rest, while the second included the quantification of pain during weight-bearing activities. In both cases, the analyses revealed a positive trend for the two evaluation groups.p < 0.0001). Indeed, the t-test also revealed a significant statistical difference, comparing the T0 vs. T5 treatment (p = 0.0004). In this case, the results suggest a homogeneous positive effect, because the SDs between T0 and T5 were very close to each other .Nonetheless, the VNS showed a similar trend observed for the AOFAS questionnaire, in which it is mandatory to remark that the positive effect of treatment is associated with a depletion in the score. Here, we obtained the same significant final benefit . The meap < 0.0001). Indeed, the t-test also revealed a significant statistical difference, comparing the T0 vs. T5 treatment (p = 0.0009). In this case, the results do not suggest a homogeneous positive effect or the stratification of the patients, because the SD between T0 and T5 seemed to be different . However, the Delta VNS (VNS/T0–VNS/T5), showed a mean value equal to 5.20 points.Nevertheless, the VNS scale regarding the data acquired during the stimulation after treatment showed a significant final benefit for all patients . LookingNon-operative treatment is the first approach to Morton’s neuroma; surgical options should be considered when conservative treatments do not have enough of an effect . There aIn this framework, we treated our patients with type I collagen through indirect ultrasound-guided injections (IUSGIs) ,31. Our Previous preclinical studies demonstrated that collagen type I compounds could induce an anabolic phenotype in tenocytes by stimulating tenocyte proliferation and migration and COL-I synthesis , maturatConversely, the structural and mechanical effects provided by the collagen and biological matrix could function as an effective natural scaffold to support cell growth, while also providing a framework for cell–cell interactions by redirecting reinnervation /reorganiThe infiltrative use of porcine type I collagen could be contemplated as a promising non-surgical therapy against MN less than 10 mm in size.The procedure is safe and easy to perform.The combined indirect US-guided injection (IUSGI) approach can allow a more precise subministration of medical devices, where the point of application fits perfectly with the point of maximum pain.The proposed approach places itself exactly between the conservative approach and nerve-ablative treatments, as well up-front surgery and alcohol injection.Collagen treatment could play an important pivotal role in the positive modulation of the inflammatory process as well as steroid treatments but avoid their side effects (probably) physically acting on the fibrosis process.The present study should recapitulate the list of principal take-home messages:The use of collagen-based medical devices seems to have not been described before in a mini-series of MN patients. Indeed, the positive clinical and functional results and the absence of side effects allow us to propose collagen injections as an option for the treatment of MN. Future studies, especially if validated by larger cohorts of subjects and longer follow-ups, will need to confirm these findings.


Significant differences were found for neck disability (p < 0.047), immediately post-treatment, in favor of the DDN group. Moreover, there were significant differences for pain during the intervention (p < 0.002), in favor of the DDN group (4.54 ± 2.21) versus the PE group (6.54 ± 2.27). PE and DDN appear to have similar short-term effects. PE proved to be a more painful treatment than DDN. Clinical trial registry: NCT04157426.Deep dry needling (DDN) and percutaneous electrolysis (PE) provide the benefit of the mechanical effect of the needle, and PE adds the potential advantages of the galvanic current it incorporates in myofascial trigger points (MTrPs) therapy. The aim of this study was to compare the short-term efficacy between PE and DDN on active MTrPs of the levator scapulae by considering pain intensity. A simple-blind randomized controlled trial was carried out, recruiting patients suffering from non-specific neck pain lasting more than 3 months and with active MTrPs in the levator scapulae muscle (n = 52). Patients were divided into intervention  and control  groups and received one treatment session on the active MTrPs of the levator scapulae. Patients were assessed for pain intensity, pressure pain threshold (PPT), cervical range of motion (CROM), neck disability and post-needling soreness, immediately after treatment, at 72 h and at 14 days. In addition, pain during treatment was recorded after the procedure. There were no significant differences for pain intensity, post-needling soreness and PPT. We found significant differences in CROM, immediately after treatment ( Non-specific chronic neck pain (NCNP), also called mechanical pain, is defined as neck pain with or without irradiation whose origin is unknown. In NCNP, there is no underlying structural pathology and it lasts more than 3 months ,2,3. It To date, the pathophysiology is still not clearly known. However, in recent years, different studies have linked this condition to myofascial pain syndrome (MPS), establishing the presence of myofascial trigger points (MTrPs) as a relevant clinical sign in subjects with cervical spine disorders ,7,8. ThuNon-invasive methods such as ultrasound or manual therapy  have beeThe efficacy of DDN in relation to pain reduction has been widely demonstrated, especially in relation to immediate effects, comparing it with other types of manual therapy, sham or no treatment ,14. TherPE has been attributed to advantages over DDN such as producing a greater number of LTRs, with fewer punctures, in addition to generating post-needling soreness and greater regenerative effects . PE has A randomized, controlled and single blinded clinical trial was carried out between 28 September 2021, and 1 January 2022, involving two groups. This study was prospectively registered at ClinicalTrials.gov  and approved by the ethics committee of the Hospital Clínico San Carlos (C.P.-C.I.13/021) following the regulations of the declaration of Helsinki. No funding was received to avoid conflict of interest.Patients with NCNP were asked to participate in the trial. All of them were recruited from the Physiotherapy and Podiatry clinic FISIOFUENLA, located at C/Francia 34 bajo A (Fuenlabrada) 28943 Madrid, Registration No. CS5583, of the Community of Madrid, and gave written informed consent before participating in the study.From the 62 patients recruited and who agreed to participate, 54 were finally selected as they met all the eligibility criteria. The first requirement was to have both active MTrPs in one of the levator scapulae muscles, and the principal investigator was responsible for identifying them by clinical examination as determined by Travell and Simons . In spitt-test for a normal distribution with a two-tailed test, with an α level of 0.05, a 95% confidence interval, a desired statistical analysis power (1 − β) of 80% (error β = 20%) and an effect size of size of 0.8. Therefore, 26 participants were required in each group.Sample size was calculated with the G*Power 3.1.4.9.4 software  and was obtained according to the difference between two independent groups. The differences between the two independent means were sought using the independent Student’s In the pretreatment assessment, first the principal investigator was in charge of the physical examination and of marking the two active MTrPs. Then, a second investigator, who remained blind to group assignment, was in charge of data collection  and baseline assessment: pain intensity, pain after puncture, neck disability, pain threshold to pressure (PPT) and cervical range of motion (CROM). Immediately afterwards, the principal investigator was in charge of performing the interventions, DDN or PE, as well as recording any adverse effects that might result from the treatments. The secondary investigator then remeasured the same variables, adding the recording of perceived pain during treatment. Similarly, at 72 h and 14 days, pain intensity, post-needling soreness, neck disability, PPT and CROM were recorded again. Participants were instructed not to disclose their group assignment. The participants reported their current pain intensity using the modified visual numeric pain scale (VNPS) adapted to Spanish. This is a version of the visual analogue scale (VAS), developed by González, VM. et al. , to whicThe Northwick Park Pain Questionnaire (NPQ) is a self-administered questionnaire for measuring neck disability, which was developed by Gonzalez, T. et al. , validatThis version is a feasible, reliable and valid tool whose test–retest reliability on the total score measured by the ICC is 0.63 . MoreovePPT was measured with an analogic pressure algometer . The pressure gauge was applied perpendicular to the surface of the active MTrP and was gradually increased at a uniform rate of approximately 1 kg/s. Patients were asked to alert the investigator when they started to feel any discomfort or pain, at which point the pressure was paused and the instrument was immediately withdrawn to read the PPT. Changes in PPT are considered clinically significant when the increase is >15%, compared to baseline . The algA universal goniometer was used for the measurement, which was placed on the top of the patient’s head. The participants were seated and asked to move their head as much as possible by performing a maximum active ipsilateral rotation towards the affected side. A minimum detectable change of 5° is required for CROM in subjects with neck pain . The uni2)) were assigned to the DDN group and 27 subjects  were assigned to the PE group. Equal numbers of participants were randomly allocated using the GraphPad statistical and epidemiological analysis software system  to each group: 27 subjects  for healthcare centers, both in taking measurements and in carrying out interventions. This protocol included the obligatory use of masks and hydroalcoholic gel for patients and physiotherapists, and permanent ventilation and disinfection of the room as well as all of the equipment and materials used with each patient.The study was performed following the COVID-19 safety protocol established by the Community of Madrid  and a high frequency 12L-RS, 5–13 MHz probe. The patients were placed in prone position and the physical therapist performed the following protocol [®, Madrid, Spain), with a guide tube in the DDN group; and then, needle insertion in the active MTrP until LTR is obtained, which Hong [The treatments were performed in the two active MTrPs, on the right or left side, marked in the previous assessment. Both protocols were ultrasound guided, with a portable LOGIQ e BT11protocol : disinfeich Hong  considerich Hong  showed rAfter the first LTR, the “Hong’s  fast-in ® equipment  was employed. Once the first LTR was obtained and following the protocol described by Valera and Minaya [To carry out this treatment, a Physio Invasivad Minaya , the phyAt the end of the process, in both groups, the needle was removed, the point was compressed for 30 s and the same procedure was repeated in the second active MTrP.p > 0.05. In addition, the independent Student’s t-test for parametric data for the variables that were adjusted to normality (p > 0.05) or the U Mann–Whitney nonparametric test for the variables that did not conform to normality (p < 0.05) were performed to assess any systematic differences between groups. For these analyses, a p value < 0.05 with 95% CI was considered for statistically significant differences. Furthermore, the effect size for outcome measurement differences between both groups was determined by Cohen’s d using the formula d = 2t/√gdl, and interpreted as very small if d was lower than 0.20, small if d varied from 0.20 to 0.49, medium if d varied from 0.50 to 0.79 and large if d was equal of higher than 0.80 [Statistical analyses were performed using SPSS software IBM SPSS Statistics . For quantitative data, mean, standard deviation (SD) and lower and upper limits of the 95% confidence interval (CI), as well as median were calculated, and normality analysis was performed using the Kolmogorov–Smirnov test for sample sizes >50, where the data were considered normally distributed if han 0.80 .Sixty-two patients were initially recruited to participate in the study. Of all participants, 8 patients were excluded because they did not meet the inclusion criteria. In addition, there were two losses during the study for reasons related to Coronavirus disease (COVID-19). Therefore, there were finally 52 participants who completed it, 26 in each group . None ofp > 0.05 in all cases  at VNPS for pain intensity between groups, before and immediately after treatment, at 72 h and at 14 days . Cleland et al. [d et al.  reportedp > 0.05) at VNPS for post-needling soreness between groups, before and after treatment . Immediately after treatment, the score in the VNPS scale were similar in both groups. At 72 h, in the PE group the score was 0, while in the DDN group, the score was 0.8. At 14 days, post-needling soreness had disappeared in both groups.p < 0.05) at VNPS for pain intensity during intervention, showing a lower score in patients who received DDN .p > 0.05; mean difference = 5.90; d = 0.61), but immediately after treatment there are significant differences (p < 0.05): patients who received DDN showed a lower percentage of disability . The relevance of the NPQ improvements immediately after treatment is limited because they did not reach the MCID [p > 0.05; mean differences = 0.4 y 1.7; d = 0.04 y 0.15 respectively).the MCID , but at p > 0.05) between groups, on PPT at central MTrP  and insertional MTrP , before and after treatment. In addition, the relevance of the PPT improvements obtained in both groups is limited because they did not reach the MDC, 0.45–1.13 kg/cm2, [ kg/cm2,  for neckp > 0.05; mean difference = 3.27; d = 0.49), but immediately after treatment  and at 72 h , there are significant differences (p < 0.05), showing a greater ipsilateral maximum active rotation movement for patients who received PE in both measurements. The relevance of the CROM improvements obtained in the present study is limited because they did not reach the MDC for the CROM rotation [rotation .Contrary to what we hypothesized, we found no statistically significant differences between groups in terms of pain intensity. To the best of our knowledge, we have not found any studies comparing both techniques in cervical musculature, but in the study conducted by Valera-Calero et al.  on the rIf we analyze similar studies, but with a longer follow-up period, the study by López-Martos et al.  on the lIn view of the results, the mechanical effect of the needle was more important than the effect of the galvanic current. Perhaps, as we pointed out in our study, a greater number of sessions and longer follow-up time are required to obtain more evident differences between the two techniques ,18. We tWe found an important limitation caused by the Coronavirus disease, which caused difficulties in finding the sample for the study, losses during the evaluations as well as the requirement for incorporating special security measures. In addition to the scarcity of scientific literature on PE, and more specifically, of studies comparing both interventions, DDN and PE, as well as the short follow-up time and the single treatment session could have contributed to the absence of differences between groups in some outcomes. Indeed, future analysis should include the efficacy of each technique separately. It provides new insight into the therapeutic approach’s effectiveness, especially in myofascial pain, which still needs to be better understood. In addition, the lack of a control group that did not receive treatment may be a limitation, as there may be patients who improved naturally over the days. Moreover, as in this study the interventions were ultrasound-guided, this could have led to higher positive patient expectations. Despite our sample size calculation justifying the used sample in our study, a prior systematic review and meta-analysis  claimed The protocol  used for


Patients affected by neurological disorders can develop stomatognathic diseases (SD) related to decreased bite force and quality of mastication, bruxism, severe clicking and other temporomandibular disorders (TMD), which deeply affect patients’ swallowing, masticatory and phonation functions and, therefore, their quality of life. The diagnosis is commonly based on medical history and physical examination, paying attention to the temporomandibular joint (TMJ) range of movements, jaw sounds and mandibular lateral deviation. Diagnostic tools such as computed tomography and magnetic resonance imaging are used instead in case of equivocal findings in the anamnesis and physical evaluation. However, stomatognathic and temporomandibular functional training has not been commonly adopted in hospital settings as part of formal neurorehabilitation. This review is aimed at describing the most frequent pathophysiological patterns of SD and TMD in patients affected by neurological disorders and their rehabilitative approach, giving some clinical suggestions about their conservative treatment. We have searched and reviewed evidence published in PubMed, Google Scholar, Scopus and Cochrane Library between 2010 and 2023. After a thorough screening, we have selected ten studies referring to pathophysiological patterns of SD/TMD and the conservative rehabilitative approach in neurological disorders. Given this, the current literature is still poor and unclear about the administration of these kinds of complementary and rehabilitative approaches in neurological patients suffering from SD and/or TMD. The stomatognathic system (SS) is defined as a functional complex including craniofacial structures with musculoskeletal and ligamentous components, the temporomandibular joint (TMJ), oral cavity, neck and masticatory muscles . PatientDespite the presence of SD in neurological patients, functional training for SS and TMJ has not been commonly adopted in hospital settings as part of formal neurorehabilitation. Generally, the non-pharmacological treatment for SD and TMD aims to decrease pain, induce muscle release and stabilize muscle function and joint mobility through physical therapy (PT) and/or manual techniques (MT) . Among tThe review was carried out by searching on PubMed, Google Scholar, Scopus and Cochrane Library using a combination of keywords that we have reported in Search terms were defined according to the PICO model  . The popThen, the inclusion criteria were (i) neurological patients affected by SD/TMD; (ii) pain topic; (iii) English language; and (iv) publication in a peer-reviewed journal. We excluded articles that described theoretical models, methodological approaches, basic technical descriptions as well as animal studies and conference proceedings.n = 264), 149 papers were initially screened, and only 32 were found eligible for a full assessment. Finally, only 10 articles fulfilled the inclusion criteria, as reported in the new PRISMA flowchart  according to title, abstract, text and scientific validity. The agreement assessment was performed using Cohen’s kappa coefficient . In caselowchart  17]..n = 264)The risk of bias in controlled studies was assessed through a revised Cochrane risk of bias (RoB 2) , while cWe analyzed the 10 selected pieces of evidence dealing with the presence and treatment of SD/TMD in patients affected by neurological disorders. The agreement of the judge’s decision for the inclusion of the studies was Cohen’s k = 0.82, which means a perfect agreement. In particular, we classified the studies according to the association between neurological disorders and TMD and its rehabilitation treatment, reporting a summary of results in a tabular form see .The risk of bias assessment of randomized controlled trials, cross-sectional studies and case-control studies was evaluated, respectively, with RoB 2  and NOS The general quality of the included studies ranged from low ,25,27,28The etiology of SD and TMD is linked to a wide range of functional, psychological and environmental factors, especially in neurological disorders in which the underlying pathology is complex. People affected by multiple sclerosis (MS) are more susceptible to developing TMD disorders ,31. IndeWhen orofacial pain occurs, patients commonly consult dentists or gnathologists, although osteopaths or physiotherapists can primarily identify a TMD during a physical examination and manual treatment . In factAn in-depth anamnesis is the first fundamental step to guide the clinician to carry out the most relevant physical examination and diagnosis. A comprehensive history for a patient with orofacial pain includes the main complaint, medical history, dental history and psychosocial history. The patient should provide the dentist with a full description of the symptoms and the reason why the patient is seeking care. In this context, clinicians should investigate the quality of pain , which movements or activity exacerbates the pain and how long it has been present. In addition, clinicians should ask patients to indicate their pain point(s) with their fingers, figuring out the pain localization . To moreFurthermore, clinicians should observe the patient’s head and neck alignment with the whole body, hemifacial asymmetry, paying attention to abnormal mandibular movements, decreased joint range of motion and jaw sounds , which can be related to anterior disc displacement  or to recapture the displaced disc  . In partA static occlusal examination includes detecting teeth rotation, spacing, overjet and overbite see  includi from theActually, physical examination also includes palpation, following the direction of muscle fibers causing pain that can radiate into neighbor areas  . The palMultidisciplinary management with a focus on conservative and complementary therapies is currently recommended for patients who present TMD or orofacial pain. However, evidence about cranial–temporomandibular and stomatognathic rehabilitation (CTS-R) in patients affected by neurological disorders is still lacking see .Conservative and rehabilitative management should aim to decrease orofacial pain and muscle contractures/spasms, improving TMJ function, despite the variety of TMD and SD types that clinicians could find in the population of neurological patients. Notably, Zapata-Soria et al.  identifiIndeed, specific coordination exercises, including open-close or lateral mandibular movements , can be Actually, the use of the occlusal splint to treat TMD is common in dentistry. In fact, these devices promote the correction of vertical dimension, TMJ realignment and repositioning, also providing cognitive awareness . The mecInterestingly, Umay et al.  performeAnother conservative and complementary approach that needs to be mentioned is the psychological management of pain, which should be included in the multimodal rehabilitation approach of TMD patients . In factAs far as we know, this is one of the few reviews ,60 that Understanding the loading of SS and the existence of myofascial tension, articular dysfunctions and parafunctions such as bruxism are fundamental in delivering the most tailored functional evaluation and training in these patients. In fact, in neurological patients, it is not easy to address the right diagnosis due to patient compliance and the common overlapping between neurological disorders and SD or TMD. Physical examination should be meticulously performed, investigating patterns of occlusal contacts, mandibular opening movement and muscle tenderness. In this way, clinicians can collect indispensable information for planning primary and tempestive treatment.Additionally, Botox injection and dry needling have been suggested to manage orofacial pain in myogenous TMD, especially when other strategies have already failed . In partToday, clinicians and therapists should consider the whole person as a unique and global system in which muscular and fascial components can influence body posture, SS and its functions , which are almost impaired in neurological patients. Some authors stated ,78 that Consequentially, an altered pattern of movements in TMJ may cause an overload in masticatory muscles . These alterations have repercussions on the upper trapezius and contralateral sternocleidomastoid, which determine flexion and side deviation of the head, also involving the ipsilateral shoulder  and spine muscles (such as gran dorsi and iliopsoas) that have insertions on the lumbar tract and ileum. In this way, the cranial–mandibular structures could influence lower body extremity, not only in static posture but also during gait ,81. HoweFurthermore, a multidisciplinary approach is strongly recommended, as patients can benefit from complementary therapies, including OMT, posture re-education, physical exercises and occlusal splint therapy, for SD and TMD. Finally, a co-work among gnathologists (or even dentists), physiotherapists, osteopaths and neurologists is extremely important in achieving better outcomes and avoiding unnecessary treatments.-Parafunctional activities, such as bruxism and day clenching, have been found in PD and MS patients ,19,22,23-Reduction in TMJ movements due to painful muscle contractions is a common TMD feature in neurological conditions, especially in OMD, PD and SCA ,35,37,38-Muscle weakness and reduced TMJ functions were found in post-stroke survivors as a result of the acute onset of the brain damage ,26,27,28Since a standardized protocol for the evaluation and treatment of SD/TMD in neurological disorders is still lacking, herein, we have reported some evidence-based clinical advice about the administration of multidisciplinary conservative approaches for neurological patients who have SD/TMD:To summarize, although SD and TMD in neurological patients do not seem to be uncommon, a standard diagnostic or rehabilitation approach is still lacking. Clinicians and therapists should consider the role of SS and TMJ structures during functional training, given their fundamental role in swallowing, chewing, breathing and speaking. To better manage SD/TMD, neurological patients should be seen as a single unit, in which the stomatognathic complex works together with the cervical spine and lower extremity in maintaining body posture and spinal alignment. Future studies are needed to fill this existing gap in the individuation and treatment of SD and/or TMD in the neurorehabilitation field.


Previous studies have assessed different aspects concerning the applications of i-PRF in the oral cavity. However, nothing is known regarding patients’ perceptions of the injection of autologous platelet-rich fibrin (i-PRF).To investigate patients’ perceptions after injecting platelet-rich fibrin (i-PRF) in the course of retracting upper canines.Twenty-one patients, whose treatments required extractions of both upper first premolars, were recruited. Extraction side was randomly allocated to the intervention or control sides. After the alignment phase, i-PRF was injected twice with a one-month interval on the buccal and palatal aspects of the extraction sites (intervention side). Patients’ perceptions were evaluated with two questionnaires: the first was used to assess the level of pain, discomfort, swelling, eating and swallowing difficulties as well as jaw movement restriction after 1 h (T1), 2 h (T2), 6 h (T3), 24 h (T4) and 48 h (T5) of the second injection; the second questionnaire was used to assess the acceptance of the i-PRF injection and overall satisfaction with this technique at the end of canine retraction phase. Visual Analogue Scale (VAS) was adopted for this purpose. Wilcoxon Signed Rank Test was used to compare between both sides at all time points while Friedman’s Test was the selected test for detecting variables’ changes over time. Post-hoc Wilcoxon Matched-Pairs Signed-Rank Tests were applied when any of the results were significant. As to the multiplicity of tests, Bonferroni Correction was implemented.P < 0.05), whereas they declined sharply and went back to almost normal values at T4 (after 24 h). At T5 they were 0. Discomfort and difficulty in mastication on intervention sides were significant only at T1 and T2. Pain, swelling, and chewing difficulties were significant (P < 0.001) during the 4 assessed time points. The increase was insignificant regarding swallowing difficulties and jaw movement limitations at all time intervals.Pain and swelling levels were significantly higher on the experimental compared to the control sides at T1, T2, and T3 (Injecting autologous (i-PRF) during orthodontic canine retraction is a well-perceived and well-tolerated method due to the limited discomfort which significantly diminishes 24 h afterwards.ClinicalTrials.gov (Identifier Number: NCT03399422. 16/01/2018). The true efficacy of any treatments under question is something of great importance, definitely. However, it is not only the efficacy of the intervention but rather also the resulting Quality of Life (QoL) that matters. The higher related QoL levels mean that the procedure will meet the patients’ acceptance and the healing will be promoted. Patient-Reported Outcome Measures (PROMs) are real authentic manifestations of the QoL concept, representing the resulting interaction between the patients and the techniques or materials used.Orthodontic treatment of adult patients is frequently challenging because of their higher expectations regarding aesthetics and comfort. Moreover, fast completion of the orthodontic treatment is one of priorities of adults , 2 especAlthough injectable platelet-rich fibrin (i-PRF) is considered to be a promising biomaterial , the sciIt was a randomized split mouth clinical trial with 1:1 allocation ratio to intervention and control sides conducted in the Department of Orthodontics at the Faculty of Dentistry, Damascus University. The study was approved by the institutional review board (IRB) and ethical review committee of Damascus University (N. 2473). The CONSORT  statement was followed as a guide for this study which was registered at Clinicaltrials.gov with the identifier number (NCT03399422). The recruited study participants were patients presenting to the Department of Orthodontics, Faculty of Dentistry, Damascus University. Patients’ inclusion and follow-up is shown in the CONSORT flow chart  requiring bilateral maxillary first premolars extractions; crowding ≤ 3; OJ < 10; no tooth loss except third molars; normal to vertical growth pattern; no transverse discrepancy; no systemic diseases; good oral hygiene  [and Löe) , and norExclusion criteria were: patients taking anticoagulants or medications that interfere with orthodontic tooth movement , smokers, bony defects observed radiographically, previous history of orthodontic treatment.The purpose and methods of the study were comprehensively clarified to the potential participants who met the inclusion criteria. After ensuring the patients’ compliance and acceptance, the patients and/or their legal guardians for those who were under 18 years old, were asked to sign an informed consent.Computer-generated random numbers were used for randomization of the right and left extraction sides to either the experimental side (i-PRF) and control side (non i-PRF), with a 1:1 allocation ratio. The randomization was done by a research assistant who was not involved in this trial. Blinding was only applicable in the data analyses phase.The intervention was an injection of i-PRF on one of the extraction sides in a predetermined moment of the standardized orthodontic treatment, which comprised; fixed orthodontic appliances with MBT.022 inch slot , initial archwire sequence was: 0.014-in NiTi (or 0.016-in NiTi depending on the amount of crowding), 0.016*0.022-in NiTi, and, 0.017*0.025-in NiTi; extraction of the maxillary first premolars just before the insertion of 0.019*0.025-in SS archwire; canine retraction was achieved with closed nickel-titanium coil springs with 150 g of force per side Fig. . No medind i-PRF injection.Two questionnaires (Q1 and Q2) were administered following a comprehensive explanation of the purpose of the survey: the Q1 aimed to record the levels of pain, discomfort, swelling, difficulties in mastication, difficulties in swallowing and jaw movement restriction using a 100-mm Visual Analogue Scale (VAS) – Fig. The Q2 questionnaire consisted of 3 questions aiming to assess patient’s satisfaction with the procedure and a probability to recommend this procedure to patient’s family and/or friends. The Q2 was administered at the end of canine retraction phase Table . A 100 mStatistical analysis was accomplished using the IBM SPSS version 25 , probability values equal or less than 0.05 were considered significant. The analysis was performed by one of the researchers who was blinded to study results. Non-parametric tests were used to analyse the data that were not normally distributed and in particular Wilcoxon Signed Rank Test to compare the levels of pain, discomfort, swelling and chewing difficulties between the two sides. Friedman’s Test was the selected test for detecting variables’ changes over time. The Post-hoc Wilcoxon Matched-Pairs Signed-Rank Tests were applied when any of the results were significant. Bonferroni Correction was adopted for the purpose of multiplicity of tests.nd month of the retraction period (an acceleration rate 31.7%), while there were no differences in the rate of canine movement on intervention and control sides in the remaining months of retraction phase [Twenty-one patients aged 16–28 years  participated in this study. There were no changes to the study protocol after trial commencement. The main outcome measure—the time of canine retraction—was described in our previous study. In summary, i-PRF injection failed to reduce the duration of canine retraction because it significantly accelerated upper canine retraction only during the 2on phase .Descriptive statistics of responses to the Q1 questionnaire are shown in Tables  and 3. PP < 0.001, P = 0.002, and P = 0.023, respectively) and swelling levels , while discomfort and chewing difficulties were different between sides at T1 and T2 only . At T4 the differences between both sides were not statistically significant (P > 0.05). No significant differences were found in terms of age and gender relationships with pain and discomfort after the implementation of Spearman Correlation Coefficient and Kruskall-Wallis Tests respectively  according to Friedman’s Test. Post-hoc pairwise comparisons with Bonferroni’s adjustment of alpha level for values that showed significant differences are presented in Table P-value > 0.05)  changes of variables between the 4 time-points, the levels of pain, discomfort, swelling, and difficulty in chewing were significantly different between points in time (5) Table .Table 5SSatisfaction levels of the injection were promising and decent enough (75.71 ± 27.85) as shown in Table The application of platelet rich fibrin to facilitate orthodontic tooth movement has not been thoroughly investigated regarding its effect on patients’ daily activities. To the best of our knowledge, there were no previous studies that evaluated patients’ perceptions associated with i-PRF injection during orthodontic treatment. Hence, in this study we assessed pain, discomfort, swelling, and difficulty in mastication and swallowing as well as limitation in jaw movement after application of i-PRF during retraction of the upper canines. Moreover, we evaluated patients’ satisfaction with the procedure. We used VAS to measure the variables that are subjective in nature because it is a very reliable and easy method in addition to its wide usage in other previous studies , 32, 33.The low-speed centrifugation protocol (700 rpm within 3 min) was adopted to obtain the i-PRF , 34, 35 PRF is the second generation of platelet concentrates that has the advantage of gradual release of growth factors that last up to 28 days , 40, 41.Patients’ responses regarding pain, discomfort, swelling, and difficulty in mastication and swallowing as well as limitation in jaw movement after the second injection were used for analysis because we wanted patients to have prior experience with injection. In this way, we wanted to reduce the role of stress during the response, especially immediately after the injection. By analysing the responses after the second injection, we obtained more reliable information about how patients felt. Additionally, none of the participants used any kind of analgesics what ensured the reliability of the answers.P < 0.05). Nevertheless, “unpleasantness” caused by pain at T1 was judged as relatively mild. In general, increased pain level could be related to the gingival trauma after injection as well as the simultaneous application of orthodontic force – we used coil springs to move canines—that might cause some irritation and discomfort [Despite the differences between the experimental and control sides in the perception of injection-related “stress” for most variables and at most assessment timepoints, the mean values of the studied variables were relatively low even 1 h after injection (T1). For example, our data demonstrated that the levels of pain on the experimental side were statistically significantly higher than on the control one at T1, T2, T3  than the control, then decreased sharply after 24 h and this might be attributed to the oedema associated with the injection and the submucosal accumulation of the material that diminished gradually. This is consistent with Liou’s study [Swelling levels were greater on the experimental side within the first six hours . However, the slightly elevated values during the first two hours were explained by the correlated pain and discomfort that quickly faded away, and to the conservative nature of the process unlike the cortical bone puncturing techniques that cause serious amounts of annoyance and require some time to be healed when compared to the injection only.Our findings regarding swallowing and jaw movement limitations demonstrated that there were no statistically significant increases at all time intervals (Satisfaction rates were recorded after the second injection as the patient had a complete perception of the injection procedures and was accustomed to the presence of the coil springs. Fairly good incidence of satisfaction has been reported (75.7%) amongst participants, and this can be attributed to the little-invasive approach which resembles the infiltrative nature of the anaesthesia and is of limited aggressiveness. Eighty-one percent of the patients admitted that extraction of the premolars was more annoying than the injection itself. Our findings were in line with Ganzer et al.’s study who stated that patients’ pain perception after premolar extraction was more negative when compared to the application of miniscrews . PatientThe split-mouth design and not having placebo injections might be considered as the main limitations of this study that could somehow confound our findings. Still, that placebo option would have been unethical and would have caused possible unjustifiable pain from a therapeutic point of view, had it been applied, and hence it was abandoned. Long-term effects of the injection on patients’ perceptions could be addressed when having prolonged follow-up periods, however, all values dropped down to zero at the fifth evaluation time point. Apparently, blinding was only ensured when analysing the results because it was not possible to be employed whether to the main investigator who conducted the research or to the patients who received the injections.Injectable platelet-rich fibrin (i-PRF) doesn’t cause high levels of discomfort within the first day following the injection and it can be considered as a non-invasive technique that causes minimum side effects.Platelet-rich fibrin injections are accompanied initially by low to medium pain, discomfort, swelling, eating and swallowing difficulties, jaw movement restriction only 6 h post application.Patients treated with this method can get back to their normal life on the second day and the associated values of pain and discomfort drop down to zero by that time meaning that the unfavourable effects of the injection are temporary.The results of this study support the following findings: