Trigeminal neuralgia is a chronic pain condition associated with sharp, shock-like pain in one or more divisions of the trigeminal nerve. For patients who do not respond well to pharmacotherapy, there is growing evidence that Botulinum toxin type A injections into the trigeminal ganglion provide pain relief for several weeks up to several months at a time. One option is to administer injections into the trigeminal ganglion in Meckel’s cave by inserting a needle through the Pterygopalatine Fossa using fluoroscopy to guide and confirm the proper needle placement. However, there is evidence that Botulinum toxin travels across nerve synapses; thus, injecting directly into the trigeminal ganglion may not be necessary. We present two patients with a confirmed diagnosis of trigeminal neuralgia who were treated by injecting Botulinum toxin type A intraorally into the mental foramen which resulted in 6 months or longer of pain relief. Injections into the mental foramen are much easier to administer than those administered directly into the trigeminal ganglion, and both patients treated with this technique experienced comparable results to what can be expected from traditional fluoroscopy-guided botulinum toxin injections. Though more research is needed, these cases potentially imply that a less-invasive injection may be sufficient in managing trigeminal neuralgia-related pain. Trigeminal neuralgia (TN) is a chronic neurological disorder characterized by sharp, shock-like pain in one or two of the three main divisions of the trigeminal nerve: namely, the frontal V1), maxillary V2), and mandibular V3) nerves [, maxilla, and man nerves ,5.The first line of treatment includes pharmacotherapy, usually with anticonvulsants and antispasmodic agents, although this management is frequently associated with side effects and variable success . Other iA literature review showed a paucity of studies testing the efficacy of injecting BTX-A into a peripheral foramen rather than the trigeminal ganglion itself to treat trigeminal neuralgia. Botulinum toxin is known to travel along the peripheral nervous system to the trigeminal ganglion, mediated by axonal organelles that travel via microtubules . In one A PubMed search conducted on 7 July 2022 using MeSH terms including “Trigeminal Neuralgia”, “Botulinum Toxin Type A”, and “Pain Relief” showed only one article where the terminal end of the V3 branch was injected via the mental nerve to manage trigeminal neuralgia. Although the researchers described this study as quasi-experimental, they observed a statistically significant decrease in VAS and frequency of attacks, with 19 of 20 patients experiencing significant pain relief and only 1 patient experiencing minor inferior labial weakness which improved after 2 months , it is pThe injection site is identified initially by assessing the exact location of the mental foramen on a cone-beam computed tomography (CBCT) or panoramic radiograph. Most frequently, the foramen is situated between the apices of the first and second lower premolars or just below the apex of the lower second premolar.The patients are then assessed intraorally and the correlation with the radiograph is determined. The BTX-A syringe is then prepared using the dilution of 1 cc of non-preserved sterile saline into 50 units of Botulinum toxin A, which is then drawn up into a 1 cc tuberculin syringe with a 27–30-gauge needle. Each 0.1 cc of solution represents 5 units of BTX-A; hence the patient will receive 0.4 cc (20U).The lower lip on the injection side is retracted gently and the foramen is then identified using a dental syringe and needle or directly with the tuberculin syringe and 30 gauge needle. Lidocaine 1% plain may be injected prior to the BTX-A, depending on the patient’s preference. The 0.4 cc of BTX-A is injected at a 45–60-degree angle to the mandible, and the needle is initially advanced 2–3 mm, at which point, it usually contacts the bone of the mandible. Once the foramen is located, the needle can be further advanced an additional 2 mm just beyond the opening of the mental foramen. The BTX-A is then injected slowly to avoid pain or potential nerve injury see . Even wiImportant to note is the potential confounding variable of using both lidocaine and BTX-A in assessing the efficacy of BTX-A for the management and resolution of trigeminal neuralgia-related pain. In both cases, a diagnostic block using lidocaine plain was performed in the initial consultation to assess if, by eliminating the mandibular division of the trigeminal nerve (V3) as a source, the pain improved only while numb, and as soon as the lidocaine plain wore off 30–60 min later, the pain returned in the exact same intensity and frequency. Performing nerve blocks is crucial in the diagnosis of traumatic trigeminal neuralgia especially . BecausePatient 1 is an 82-year-old female who presented to our clinic for a consultation regarding trigeminal neuralgia which was diagnosed by her neurologist in 2019 based on her clinical signs and symptoms as well as a computed tomography angiography (CTA) of the brain confirming the superior cerebellar artery pulsating over the trigeminal root entry zone. The patient reports that the pain is intermittent in nature, but she rates it as a 10/10 on the visual analog scale (VAS) and describes the pain as “a strike of lightning” in her lower left jaw, beginning at the canine area and extending posteriorly. The patient has a 16-year history and cannot recall any inciting events or trauma to the area. She did have multiple dental extractions in the lower left mandible after the symptoms began because of a misdiagnosis on the part of the dentist. Her primary care physician prescribed 300 mg of gabapentin per day, which provided minor relief but gave her a systemic rash, so she was then referred to a neurologist who prescribed 300 mg of carbamazepine per day, which provided only moderate relief. She is unable to tolerate higher dosages of carbamazepine due to the increased severity of the side effects she experiences, namely, severe malaise, lethargy, and confusion. She reports feeling pain in the region of the inferior alveolar nerve as well as in the lingual division, with the lingual branch presenting with a tingling sensation with no alteration in taste sensation.Due to the classic symptoms described by the patient as well as the positive CTA findings, we agreed with her diagnosis of trigeminal neuralgia. She was made aware of the various management options including continuing with carbamazepine, cryotherapy, neurovascular decompression, gamma knife therapy, trigeminal ganglion nerve blocks, or BTX-A injections. She elected to return to her neurologist to discuss the side effects of the medication and persistent chronic pain.Nine months later, the patient returned, requesting BTX-A injections as her neurologist was unable to find an optimal dosage for her with pharmacotherapy treatment to minimize pain without resulting in increased side effects. The patient was informed that the use of BTX-A is not an FDA-approved procedure but that there is a growing body of literature supporting BTX-A for the management of TN. The patient was also informed that the injections with local anesthetic usually are placed into the trigeminal ganglion under fluoroscopy; however, we would be injecting BTX-A into the mental foramen on the left and assessing the response. After obtaining informed consent and reviewing the most recent cone beam computed tomography scan to determine the precise location of the mental foramen, one cc of 2% lidocaine plain was administered into the left mental foramen. Once it was confirmed that the patient was anesthetized, twenty units of BTX-A were then administered to the mental foramen. The patient endorsed diminished pain with numbness to the appropriate nerve distribution. This treatment provided 6 weeks of complete pain relief, and at approximately 7 weeks, the patient reported the return of a shock-like pain in the V3 distribution, though with lower intensity and less frequency. It was decided to repeat the BTX-A injections, and following this round of injections, the patient experienced 10 weeks of pain relief. The third treatment provided 5 months of pain relief, and after the fourth treatment, it has been 18 months since the patient received her last BTX-A injection, and she is currently pain-free with no intermittent attacks and is currently not on any medication for TN.Patient 2 is a 34-year-old female who presents for a second opinion for neuralgia-type pain on the left following the surgical removal of an impacted wisdom tooth. Noteworthy diagnoses in the patient’s medical history include multiple sclerosis with slight motor weakness of the lower limbs which is more pronounced on the left side and optic neuritis on the right side, which is what led to the diagnosis of MS by her neurologist.She developed a slight pericoronitis on her lower wisdom teeth, which coincided with her starting treatment for her MS. On preoperative x-ray, it was determined that the lower left wisdom tooth was vertically impacted, and the apices of the wisdom tooth were noted to be intimately associated with the IAN. At the time of the extraction, the oral surgeon packed the lower left extraction socket with bovine bone xenograft. The patient contacted her surgeon 48 h postoperatively, informing them that she had persistent numbness on the lower left lip and chin. The surgeon reassured her that the tooth was very deep and that this was to be expected. At her one-week follow-up, the patient was informed that the sockets were healing well, and despite the V3 on the left being anesthetic, she was told the sensation would return after a 3–6-week period.She continued with the surgeon over the subsequent 3-month period, and despite the patient being numb, she reported the onset of significant shock-like pain emanating from the center of the anesthetic side, but the surgeon once again reassured her. They informed her that it was related to her MS, resulting in unpredictable recovery.She sought a second opinion 4 months post-surgery, and she was found to have anesthesia on the left distribution of IAN with intense shock-like pain, consistent with anesthesia dolorosa because of probable IAN damage. The CBCT showed that the xenograft was packed into the base of the socket, which was in direct contact with the IAN, and thus mineralized bovine bone was found to be completely compressing the nerve in the wisdom tooth area see . We discWe administered an IAN block with 2% lidocaine plain and observed the reduction in the pain proximal to the injection site as well as her V2 pain; however, the intense shock-like pain distal to the injection site in the lower lip on that side remained. Once full sensation had returned, we then gave her a mental nerve block on that side with lidocaine and this resulted in immediate cessation of pain in both V2 and V3, which suggested a diagnosis of a peripheral mediated pain, though extension into V2 was inconsistent with this. We then proceeded to inject Marcaine with Kenalog into the mental nerve on the left to determine if this would provide any longer-term relief.The patient returned for a 2-week follow-up where she explained that she only had pain relief for as long as the Marcaine was effective. We discussed consulting with her neurologist to change her pregabalin to gabapentin, but she mentioned that the gabapentin made her very light-headed and lethargic. We then discussed that BTX-A has shown positive results when used in managing chronic neuropathic pain. We requested a clearance from her neurologist and discussed her diagnosis since she is presenting with signs and symptoms of both neuropathic pain due to nerve injury as well as TN.The neurologist saw the patient and they diagnosed her with TN of the V3 and V2 as well as iatrogenic trigeminal neuropathic pain in the V3. They agreed with the BTX-A injections and wished to change her pregabalin to Tegretol, although the patient did not agree to change at that stage. The patient was informed by our service that BTX-A has shown benefits in managing TN, although most of the literature has demonstrated efficacy when injected into the trigeminal ganglion and not into a peripheral branch. When performing the procedure, the mental foramen was located using available radiographs and a dental syringe, and she was given lidocaine plain followed by 20 units of BTX-A into the mental nerve. The patient tolerated the procedure well. At her two-week follow-up appointment, the patient reported that it took 1 week after the procedure for her pain to diminish and subsequently cease. She continued taking her pregabalin during this time.This pain relief lasted for 5 months, at which point, the patient returned for the exact same regimen of 20 units of BTX-A injection into the left mental foramen. At her 2-week follow-up, the patient indicated that she responded better to the injections this time and that all her pain had gone. She also informed us that her MS had deteriorated significantly, and as a result, her neurologist was starting a whole new management protocol.The patient was seen at 8 weeks after her second treatment with BTX-A and she remained pain-free, although she also remained anesthetic on the left side with no improvement. She has had this management for 18 months now and has definite benefits; however, her MS has progressively deteriorated which, according to her neurologist, has exacerbated her TN flare-ups.Both patients reported a similar decrease in the frequency and intensity of shock-like pain attacks from a mean of 16 per day pre-treatment to no more than 4 post-treatment. The intensity of the pain also significantly decreased from a mean of 10 on the VAS pretreatment to between 2 and 3 post-treatment. This was followed by a period of complete cessation of pain, with patient 2 requiring two weeks as opposed to one week for patient 1.Irrespective of etiology, the period of pain relief seemed to increase after each consecutive treatment. At the most recent follow-up appointment, both patients reported an improvement in pain and quality of life, which they indicated was significantly better than any other treatment they had previously received. The patients stopped their prescribed TN medication under the supervision of their neurologist after receiving this treatment.This case report is organized with both cases together because, despite the patients presenting very different etiologies of their trigeminal neuralgia-like pain, the BTX-A toxin appeared to be effective in offering pain relief for both.When comparing the response to treatment between the patients, the patient with neurovascular compression-related TN responded quicker after each treatment and seemed to experience a far higher quality of life and overall more consistent pain relief. The patient with MS-related TN and iatrogenic neuropathic pain also required two treatments with BTX-A before reducing and stopping medication for pain as opposed to patient 1 who reduced and stopped medication after one BTX-A treatment.Significantly, none of the patients reported any prolonged alteration in the mental nerve distribution following injecting BTX-A into the mental foramen. Patient 1 reported paresthesia for 48 h, while patient 2 reported no change as they were already anesthetic from the initial wisdom tooth extraction and bone graft.These results are consistent with what has been reported in the literature for traditional BTX-A injections into the trigeminal ganglion; however, these patients were treated with an easier, less-invasive technique and were spared from additional radiation exposure to achieve a similar outcome.The method of action of BTX-A traveling along the nerve is not entirely understood, though recent animal models provide new insights. These studies reveal that the BTX-A can travel in either retrograde  or anterIt is also uncertain how BTX-A acts to reduce pain when injected into a nerve ending. Regardless of the mechanism of action, the analgesic effects of BTX-A are well-documented ,30. A poIn the second case, it is important to emphasize that the patient manifested symptoms of TN and MS prior to the IAN damage; however, after the nerve damage was sustained, she experienced more intense TN-like pain with the added numbness from the injury. Thus, it appears that the nerve damage exacerbated her TN.What was noted when comparing the efficacy of this treatment between the two patients was that, despite the effectiveness of this treatment for both patients, the patient with MS and iatrogenic nerve injury was far more variable in her response. There also seemed to be a correlation between the patient’s MS flare-ups and alterations in her MS medication, which may pose a confounding variable in determining their response to BTX-A. Despite the variability in patient 2′s case, it may be that this treatment is effective not only for trigeminal neuralgia but also for trigeminal neuropathy, although far more research is needed in this area.While double-blind studies are needed to suggest the efficacy of this technique, these two patients report effective pain relief. The current literature and our experience, though both limited, indicate that this treatment modality is safe and effective with no local or systemic adverse effects. For these two patients, the regimen described in this report is fast-acting and long-lasting; however, this is an evolving technique, and additional research is necessary to identify the optimal dosage, the timing of each injection, and its effectiveness when compared to existing treatments for different causes of TN.


Severe postoperative pain not only is a considerable burden for patients but also leads to overprescription of opioids, resulting in considerable health concerns. The remarkable development of new technologies in the health care system provides novel treatment opportunities in this area and could exploit the additional placebo effect, provide added value for patients, and at the same time support hospital staff. We aimed to test the pain- and opioid intake-reducing effects of enhanced postoperative pain management by boosting pain medication by using a technical application and/or augmented physician rounds.In a four-arm, randomized clinical trial, 96 patients (24 patients per group) scheduled for a total knee replacement (TKR) were randomized into four groups for four postoperative days: an “application” group (APP) with information via an iPad-based application; a “doctor” group (DOC) with augmented physician rounds; a combination group (APP+DOC), which received both interventions; and a “treatment as usual” group (TAU) as a baseline with no additional intervention besides the standard care which consists of standardized medication, regular physician rounds, and physiotherapy. Postoperative pain and opioid requirements pre- and postoperatively until hospital discharge were recorded.P=.02, partial η2=.10). APP+DOC experienced greater postoperative pain relief than DOC  and TAU , respectively, the difference compared to APP  was not significant. Opioid consumption differed significantly between groups . APP+DOC (72.9 mg) and DOC (75.4 mg) consumed less oxycodone than APP (83.3 mg) and TAU . APP+DOC consumed significantly less oxycodone than DOC (d=0.2–0.4). There were no significant group differences in NSAID and Morphine sulfate consumption. Patients in APP+DOC were more satisfied with their treatment than patients in TAU .The difference between post- and preoperative pain was significantly different between the groups . The study was registered at DRKS.de (identifier: DRKS00009554).The online version contains supplementary material available at 10.1186/s12916-022-02638-0. Severe postoperative pain not only is a considerable burden for patients but also leads to overprescription of opioids, resulting in considerable health concerns , 2. GiveOpioid overuse usually starts immediately after surgery . HoweverDigital devices offer patients the advantage of access to important information related to their health and pain status; this can support the efficacy of their medication intake. Digital medical devices could potentially integrate the concept of “open medication” into the clinical routine . Open meExploiting the additional placebo effect is especially important after surgeries from which patients experience severe postoperative pain. Total knee replacement (TKR) surgery is usually followed by severe pain for 15–30% of patients . To dateOur aim was to improve the postoperative pain experience and to reduce opioid consumption in patients with postoperative pain after TKR. Based on findings from the research field of open medication, we investigated whether openly administered medication implemented through a newly developed digital application (app) combined with augmented physician rounds leads to greater pain relief (primary outcome), reduction in oxycodone consumption, and an increase in self-rated treatment satisfaction with postoperative medication (secondary outcomes).This randomized controlled clinical trial (RCT) included three treatment groups and one therapy as usual control group . These groups comprised 96 patients (24 patients per group) undergoing TKR at a German hospital center in Hamburg.The study was conducted in accordance with the principles of the Declaration of Helsinki, and the protocol was approved by the local ethics committee of the ethical commission of the German Psychological Society . The study was registered at DRKS.de (identifier: DRKS00009554).Patients 18 years of age or older were eligible to participate in the study if they were undergoing TKR due to knee osteoarthritis. Patients were excluded if they were cognitively impaired, had insufficient command of the German language, had a diagnosed mental disorder ), when All patients included in the study received the standard operating procedure of anesthesia and postoperative pain management, which included general anesthesia or spinal local anesthesia, physician rounds, postoperative physiotherapy, and postoperative pain medication according to the German Guidelines . Anesthesia was standardized and equal between groups. The patients were able to self-determine their pain medication intake within predetermined maximum limits, and the medications included conventional NSAID/COX-2-selective inhibitors, paracetamol, and opioids and morphine sulfate. However, patients had the option to deviate from this regimen on an individual basis and take less medication if pain was less severe. In the case of insufficient pain relief, patients had the option to request more analgesics. In consultation with the physician, NSAIDs and oxycodone intake could then also be increased on an individualized basis (PRN) and was therefore defined as the second outcome. In our study, all groups received the same type of anesthesia  received written and visualized information about their pain medication via the newly developed digital app Fig. . The appIn the second treatment group (DOC), the same information, but without any visualization, was conveyed via the physician for five minutes daily. He was a staff member of the clinic where the TKR was performed and the study physician of our research team. During his enhanced physician rounds with the patients in the DOC, he responded emphatically and individually to the patients and encouraged them to ask any questions, including questions about their surgery and pain medications.In the third treatment group (APP+DOC), information was conveyed via the app and the responsible physician (augmented physician rounds). In this group setting, the physician provided information about pain medication tailored to individuals and visualized its pain-reducing effects by using the prognostic curve of the iPad app. Moreover, he responded emphatically to patients’ annotations and encouraged them to ask further questions.In contrast, patients in the control group received medication through standard hospital procedures; this involved the use of a medicine dispenser of the standard hospital medicine dispenser labeled “morning,” “midday,” and “evening.” The patients received standard physician rounds without tailored information. TAU was used to provide a baseline against which the additional benefit of the investigated intervention could be determined.The course of the study can be comprehended in more detail in the study protocol Doc . EligiblAll patients were randomly assigned to one of the four groups. Group assignment was performed by an independent researcher who was not related to the study and who randomly drew pieces of paper from four piles that were stratified by age and sex ((1) female and ≤ 70 years of age; (2) male and ≤ 70 years of age; (3) female and > 70 years of age; and (4) male and > 70 years of age). To eliminate unintended bias, all the pieces of paper were folded and were identical from the outside. The group allocation was communicated to the researcher after the baseline assessment. Regardless of their group allocation, all patients received the usual care, which included hospitalization for 4 days after the surgery, analgesics according to medical guidelines, standard physician rounds, and physiotherapy. The healthcare staff  of the clinical routine care were not informed and therefore not aware of the group allocation. Patients in the APP groups  were asked at the fourth day after the surgery if they made use of the information system.We tested the interventions with patient-related outcome measures. The primary outcome was self-documented average postoperative knee pain for 4 days following the TKR rated on a numerical rating scale . Hence, the course of pain based on the pain ratings  for four consecutive postoperative days was analyzed. Additionally, pain relief was assessed by calculating the difference between the pain level one day prior to the surgery (directly after admission) and the pain level experienced on the fourth postoperative day. This outcome measure was chosen because preoperative pain influences postoperative pain and the desire for pain relief. Hence, postoperative pain is not independent of preoperative factors and should be analyzed in accordance with that context. Baseline pain values should be assessed to have an indicator against which potential treatment effects can be assessed .Secondary outcomes were postoperative oxycodone consumption and self-reported treatment success regarding expectation fulfillment. The daily course of oxycodone prescription (in mg) was evaluated to assess oxycodone consumption. Additionally, NSAID and morphine sulfate consumption was analyzed. Treatment satisfaction was analyzed through self-reported treatment expectations before the surgery and with the Stanford Expectations of Treatment Scale (SETS) and questions about treatment satisfaction after the surgery .F test was used to adjust the degrees of freedom for deviations from sphericity. Hence, the results revealed the interactive effect of time (postoperative days) and group. For significant main and interaction effects, exploratory post hoc analyses for significant results were derived from Fisher’s least significant difference (LSD) tests. Hence, we were interested in comparing all studied groups with each other. For the primary outcome, the multiple imputation method for missing observations was conducted after assessing whether the data were missing at random. For all performed analyses, two-sided P values of P<.05 were considered statistically significant. To account for multiple comparisons, Bonferroni corrections were applied. Analyses were performed with IBM SPSS Statistics software, version 27.0 .The statistical analysis can be reproduced in more detail in the statistical analysis plan Doc . A powern=24 patients per group) at the Centre for Orthopedics and Trauma Surgery in Schoen Clinic Hamburg Eilbek were randomly enrolled into four groups . The relief of postoperative knee pain assessed on an NRS (0–10) significantly differed between groups . Specifically, the patients in APP+DOC had a significantly greater reduction in pain than the patients in DOC (P=.04) and TAU . However, on the second day , third  and fourth day , the groups with physician support (DOC and APP+DOC) consumed significantly less oxycodone than the groups without physician support (APP and TAU) .The course of oxycodone consumption significantly differed between the groups in the four postoperative days  and APP+DOC . Moreover, APP+DOC showed lower total oxycodone consumption than DOC, with an effect size of Cohen’s d=0.2.The medication schedule provided up to a maximum of 20 mg of oxycodone daily . The post hoc tests revealed a significant difference between APP+DOC and TAU (P=.03), with APP+DOC patients indicating higher satisfaction with their treatment than TAU. Novalgin =0.95, P=.46), Celebrex =1, P=.40), and morphine sulfate =0.58, P=0.77) did not differ significantly between groups.A trend a significant interaction between group and time was shown in the ratings for treatment expectation  that enhanced open medication and influenced medical treatment expectations with insightful care from the physician to reinforce treatment expectations, establish a relationship based on trust, and clarify uncertainties. The face-to-face, personal contact contributed to an interactive improvement in treatment outcomes and, by combining the strength of the digital tool and patient-oriented doctor contact, improved treatment.Additional file 1: Doc S1. Outcome with Five Groups.Additional file 2: Doc S2. Study Protocol (References: [erences: –70).Additional file 3: Doc S3. Statistical Analysis Plan (References: [erences: –70).Additional file 4: Doc S4. CONSORT Checklist.


We aimed to investigate clinical benefits and economic costs of inhaled methoxyflurane when used by ambulance staff for prehospital emergency patients with trauma. Comparison is to usual analgesic practice (UAP) in the UK in which patient records were selected if treatment had been with Entonox® or intravenous morphine or intravenous paracetamol.Over a 12-month evaluation period, verbal numerical pain scores (VNPS) were gathered from adults with moderate to severe trauma pain attended by ambulance staff trained in administering and supplied with methoxyflurane. Control VNPS were obtained from ambulance database records of UAP in similar patients for the same period. Statistical modelling enabled comparisons of methoxyflurane to UAP, where we employed an Ordered Probit panel regression model for pain, linked by observational rules to VNPS.Overall, 96 trained paramedics and technicians from the East Midlands Ambulance Service NHS Trust (EMAS) prepared 510 doses of methoxyflurane for administration to a total of 483 patients. Comparison data extracted from the EMAS database of UAP episodes involved: 753 patients using Entonox®, 802 patients using intravenous morphine, and 278 patients using intravenous paracetamol. Modelling results included demonstration of faster pain relief with inhaled methoxyflurane . Methoxyflurane’s time to achieve maximum pain relief was estimated to be significantly shorter: 26.4 min (95%CI 25.0–27.8) versus Entonox® 44.4 min (95%CI 39.5–49.3); 26.5 min (95%CI 25.0–27.9) versus intravenous morphine 41.8 min (95%CI 38.9–44.7); 26.5 min (95%CI 25.1–28.0) versus intravenous paracetamol 40.8 (95%CI 34.7–46.9). Scenario analyses showed that durations spent in severe pain were significantly less for methoxyflurane. Costing scenarios showed the added benefits of methoxyflurane were achieved at higher cost, eg versus Entonox® the additional cost per treated patient was estimated to be £12.30.When administered to adults with moderate or severe pain due to trauma inhaled methoxyflurane reduced pain more rapidly and to a greater extent than Entonox® and parenteral analgesics. Inclusion of inhaled methoxyflurane to the suite of prehospital analgesics provides a clinically useful addition, but one that is costlier per treated patient.The online version contains supplementary material available at 10.1186/s12873-022-00664-y. Acute pain is present in over 70% of those attended by Emergency Medical (ambulance) Services  for trauStandard care, termed hereafter usual analgesic practice (UAP), for prehospital trauma pain includes non-drug measures  and a balanced analgesic approach depending on the cause of the pain: UAP for moderate to severe pain due to trauma includes morphine , paracetamol (intravenous) and Entonox®  . Other aBarriers to adequate pain relief in the prehospital setting include poor pain assessment, limited analgesic choice or delivery routes and contraindications to effective drugs , 6. MorpMethoxyflurane , a volatile fluorinated hydrocarbon anaesthetic, has analgesic properties in sub-anaesthetic doses . AlthougA number of recent open-label randomised controlled trials (RCTs) conducted in Emergency Departments (EDs) have found that methoxyflurane relieves pain more quickly or more effectively or both compared with usual analgesia . In the A rapid review suggested both methoxyflurane and Entonox® are safe and superior to placebo for reduction of moderate pain in the ED but found no evidence that either agent was better compared with each other . A recenIn this study, we aimed to evaluate the benefits and economic cost of adding methoxyflurane to prehospital care for adults with pain from traumatic injury. In particular, we focussed on the speed and degree of pain relief from use of methoxyflurane and the addition to costs if it was introduced into UAP.All methods were carried out in accordance with relevant ethics guidelines and regulations.Supplementation of UAP with methoxyflurane was implemented by the East Midlands Ambulance Service National Health Service Trust (EMAS), a large English regional ambulance service, over an evaluation period running from December 2018 to November 2019. When a patient was administered methoxyflurane their episode data plus additional paramedic-recorded data were acquired for analysis.Control episode data were extracted from the EMAS database of episodes of UAP care carried out under standard protocols, covering the same period as the methoxyflurane evaluation. Three distinct groups were constructed depending on the record of treatment: Entonox®, intravenous morphine (Morphine IV), intravenous paracetamol (Paracetamol IV). In addition, inclusion into each group required the patient match methoxyflurane’s indication on age, trauma, level of consciousness and severity of initial pain. Furthermore, for an episode to be included at least two pain scores must have been recorded with the first taken on or before the time of analgesic administration and the remainder taken during its period of effect.We used a non-randomised, model-driven design to compare patients administered methoxyflurane with those treated with Entonox®, Morphine IV, Paracetamol IV, and, in each case, a prespecified hypothesis for test that methoxyflurane relieved pain faster than its comparator.Originally devised in November 2017 as a cluster randomised clinical trial (“MAPIT protocol version 1.0 221117.pdf”) and registered on 10/11/2017 ISRCTN #24016440 [In the meantime, methoxyflurane, being licensed for use by ambulance clinicians, was evaluated by EMAS from December 2018 to November 2019, the first NHS ambulance trust to do so. With EMAS making available to us their evaluation data plus UAP data obtained from their database of episodes of care, we designed, in December 2019, a retrospective observational database study (“MAPIT protocol version 1.3 031219.pdf”) that no longer required informed consent for the purpose of research from patient participants. Ethics approval for our retrospective observational database study was received from University of Lincoln Human Ethics Committee in December 2019 (“UoL Ethics_Letter091219.pdf”). In this paper we report on both the EMAS evaluation as well as our conduct of the approved retrospective observational database study.Staff from four EMAS ambulance stations were recruited to volunteer to take part in training to administer methoxyflurane. Training sessions lasting one hour took place between October and December 2018. The first half of the session provided information about the drug, how it works, when to use it, who to use it on and contraindications. The second half was practical, using drug demonstration packs to show how to prepare the methoxyflurane delivery “whistle” and administer the drug to a patient. Trained staff received a laminated risk minimisation checklist  patients with moderate to severe traumatic pain from suspected single or multiple fracture, other injuries, and/or burns were eligible for recruitment if able to give verbal consent to treatment prior to methoxyflurane administration. Patients were ineligible if they had a medical contraindication to inhaled methoxyflurane, or lacked mental incapacity precluding informed consent. If it was deemed clinically appropriate or methoxyflurane was not effective, patients could be offered additional analgesia according to the scope of practice of the treating ambulance clinician. At conclusion, ambulance staff fitted patients with wristbands to enable ED staff to identify those patients that had received prehospital methoxyflurane and then at handover ED staff were issued with an information leaflet informing them that the patient had received methoxyflurane and what dose had been administered.Patients given methoxyflurane were asked to score their pain prior to administration, 5 min later, and at 30 min or on arrival at ED, whichever was sooner. A verbal numerical pain score (VNPS) was used according to a severity-increasing 0–10 integer scale used routinely in UAP. We also used a 4-point categorisation of pain: severe (VNPS 7–10), moderate (VNPS 4–6), mild (VNPS 1–3), none (VNPS 0).Descriptive statistics were used to summarise patient demographics, treatments administered and pain scores. Analgesic performance against pain was assessed using an Ordered Probit panel regression model for pain, linked by observational rules to VNPS. Hypothetical scenario analyses were used to compare durations under analgesia spent in severe pain and to compare treatment costs. Computational work was undertaken using STATA®, Mathematica®, mathStatica® and MS-Excel®. A complete description of the development of the statistical model, hypothesis tests and scenario analyses is available in the electronic supplement.From the perspective of the ambulance service, we contrasted the per patient cost of managing trauma pain with methoxyflurane against that of Entonox® and a weighted mix of parenteral morphine and paracetamol. The cost schedule upon which estimates are based is given in Table We assumed the cost of methoxyflurane was the product of its price per dose by its rate of use, thus allowing for dose wastage and second dosing. Next, we assumed that when managing pain with Entonox® that the average trauma patient uses half of the contents of a size ED cylinder (containing 700 L compressed gas when full). For parenteral morphine and paracetamol, we assumed single ampoules of both drugs were used along with, respectively, 3 and 2 ampoules of sodium chloride for flushing. In constructing the parenteral casemix we assume: 40% Morphine IV, 20% Paracetamol IV, 40% combined use of Morphine and Paracetamol IV. Finally, requiring additional on-scene crew to administer stronger analgesics (eg EMT crew requiring paramedic backup) was assumed to occur at the rate of one in every 50 patients and costed at the 2018/2019 NHS reimbursement rate.Overall, 96 clinicians were trained in administering methoxyflurane including 45 paramedics, 1 student paramedic and 50 EMTs. They prepared a total of 510 doses for administration to a grand total of 483 patients—10 doses from the overall supply of 520 were unallocated at the end of the evaluation period. A single dose was used by 458 patients, 21 patients used 2 doses (4.4%), and data on the usage or otherwise of one dose by 1 patient were completely missing. In total 9 doses (1.8%) were wasted comprising 3 doses which were unsealed, not used and discarded to waste, and 6 doses for which preparations resulted in failure at the first attempt at administration due to spillage or damage—these were replaced and a dose administered at the second attempt from available stock on hand. These details are depicted in Fig. Pain management was such that 217 of 479 patients used methoxyflurane and no other analgesic (45.3%). When it was used alongside other analgesics, methoxyflurane was first-line treatment for 89 patients and last in sequence for 142 patients. Clinicians prepared and administered most doses at the scene of the incident, yet 26 doses were prepared for administration during patient conveyance to hospital and 10 doses were initiated after arrival at hospital but before patient handover.License violations for methoxyflurane were observed in age and condition. There were 4 patients aged under 18 years of whom 3 were administered methoxyflurane while the prepared dose was not administered but discarded to waste for the fourth. Two patients were ineligible according to the evaluation protocol because of Glasgow Coma Scale (GCS) scores of 13 or lower and 7 had their scores either misrecorded or missing altogether; only one of these 9 was not administered methoxyflurane, where their dose was discarded to waste after being prepared. Free-text record entries revealed that the patient in this case questioned whether the hospital ED would accept them as a patient if they were treated with methoxyflurane. At presentation, 10 patients were not trauma-classified yet 9 were subsequently administered methoxyflurane. Finally, methoxyflurane was administered to 2 patients that had given initial pain scores of 3 (mild) as well as to 5 of 6 patients missing their baseline pain score.Ambulance crews used free-text entries to record patient compliance to inhalation instructions, to notify side effects and any discontinuations prior to completion of the dose. They recorded 13 patients (2.7%) nonadherent to instructions on use of the Penthrox® inhaler, 10 of whom were aged over 75 years. Despite their inhalation difficulties 6 patients persisted in trying to use their dose. Crews reported 36 occurrences of side-effects in 32 patients (6.7%) the severity of which forced 19 to discontinue methoxyflurane (4%). Table From an EMAS supplied database of over 500,000 episodes of attended emergency care over the period December 2018 to November 2019, we identified 22,422 episodes that matched the licensed patient indication for treatment with methoxyflurane. This was further reduced to 1,833 episodes after imposing the study inclusion/exclusion restrictions. These were: (i) record of at least two VNPS scores, where the first had to be taken either on or before the time of analgesic administration and the remainder taken during its period of effect; and (ii) the only analgesic used was either Entonox® (753 patients), Morphine IV (802 patients) or Paracetamol IV (278 patients). These details are depicted in Fig. The patient sample in the methoxyflurane evaluation was mainly female 64.8%) with average age 63.1 years. Over 95% of patients recorded a GCS score of 15 indicating conscious and fully awake. Almost half of the patient sample presented with either a limb injury or fall with possibly secondary soft tissue injury too. Half as many again presented with either suspected neck of femur fracture or other hip injury with possible secondaries of limb injury or soft tissue injury. Table .8% with In Table The baseline score For methoxyflurane patients their final pain score Selected estimates for the three modelling comparisons are given in Table p = 0.016) but otherwise not in the other two comparisons . Males reported significantly less initial pain than females for those patients that were treated with methoxyflurane and for those patients that were treated with Entonox®. Age did not differ significantly across the three comparisons  nor were any coefficients individually significant from zero. The joint test of trauma classifications showed no significant difference in coefficients in any comparison .Sex differed significantly in the Morphine IV comparison , there were significant reductions in pain for people presenting with head, neck or back injury or multisystem trauma.p = 0.899, 0.914, 0.877. However, there was a significant increase in pain when instructions on using the Penthrox® inhaler were not complied with. Occurrence of a side effect to methoxyflurane sufficient to cause its early discontinuation did not result in a significant increase in pain .Pain was not significantly influenced by usage of concomitant analgesics in the methoxyflurane arm, joint tests yielding p < 0.001 for the one-sided significance test), methoxyflurane relieved pain faster in each comparison. Estimates for duration to methoxyflurane’s trough pain averaged approximately 26.5 min . All comparator trough pain estimates—Entonox® 44.44 , Morphine IV 41.76 , Paracetamol IV 40.75  – were significantly larger.Support for equality of effect was minimal . The predicted pain pathway by treatment for each comparison, set for the scenario to begin in severe pain, are given in Table The duration of time until the level of pain was no longer classified severe was, for methoxyflurane, estimated to be a little over 10 min. Time to minimal pain (trough pain) is achieved at approximately 27 min for methoxyflurane. Figures We estimated the cost to the ambulance service of managing trauma pain with methoxyflurane to be £18.89 per patient, based on the overall usage rate observed in the evaluation (510 doses used by 483 patients). For Entonox®, added to breathing filter and mouthpiece we apportioned half, per assumption, the monthly bottle refill and rental charge to estimate the per patient cost as £6.60 (= £0.71 + (£4.84 + £6.93)/2). Managing trauma pain Morphine IV, we estimated the per patient cost to be £7.70, comprising single use of tourniquet, cannula and cannula pack, syringe, drawing up needle, 3 ampoules of sodium chloride and one ampoule of morphine sulfate per assumption; added too was provision for paramedic backup of £4.19 as per assumption (£209.38/50). Similarly, for Paracetamol IV we estimated the per patient cost to be £7.87. For the mix that combined use of Morphine IV and Paracetamol IV to manage trauma pain we estimated per patient cost to be £9.98. Finally, for the parenteral weighted casemix we estimated per patient cost to be £8.65.Comparing ambulance service costs for the scenario that sees trauma pain managed with methoxyflurane as opposed to Entonox®, the added benefits due to use of methoxyflurane are estimated to incur additional cost per treated patient of £12.30. For the second scenario that compares methoxyflurane to a parenteral casemix, our estimate of the additional cost per treated patient was £10.24.This is the largest pragmatic evaluation to date of prehospital methoxyflurane for adults with moderate or severe pain due to trauma. We evaluated the use, effect on pain and clinician reported adverse effects of methoxyflurane in a real-world prehospital ambulance setting, where the interventional drug was already licensed for use and where standard protocols and previous clinical experience and training meant that standard analgesic drugs could and would be used in conjunction with methoxyflurane. We found that methoxyflurane performed better than Entonox®, intravenous morphine or paracetamol in the extent and speed of pain reduction. The magnitude of reduction in pain was clinically important, particularly for those patients with initially severe pain and when compared to Entonox®. Methoxyflurane was the only drug administered for 45.3% of patients provided with this analgesic. Methoxyflurane was easy to administer in most patients and the rate of recorded adverse events was low.The faster and greater reduction in pain judged against Entonox® was similar to effects observed in a previous study where methoxyflurane used in ED in one study was compared indirectly with Entonox® used prehospitally in another, where each included study used placebo as a comparator . This stThe advantages of methoxyflurane in achieving faster pain reduction was consistent with findings from a number of recent open-label RCTs . This inA further randomised, double-blind, placebo-controlled trial in EDs in France, comparing methoxyflurane vs placebo, both combined with usual analgesia . showed In the prehospital setting comparing methoxyflurane with intramuscular tramadol in a cluster randomised cross-over trial for people with moderate to severe pain due to musculoskeletal trauma in Singapore, methoxyflurane was superior to tramadol in efficacy, speed of onset and administration, but with more minor adverse effects .Adverse effects were uncommonly reported in this study. Recent RCTs of methoxyflurane recorded adverse effects including headache, dizziness and sleepiness . There aWe were able to account for use of other drugs using carefully constructed statistical models, considering the most likely confounders including age and sex, in adults who had suffered traumatic injury. We accounted for the nature of the injury but there may have been other unknown confounders that led to the differences we found. Because ambulance clinicians were not blinded to assessment of outcomes it is possible that pain scores were affected by knowledge that methoxyflurane was being used. To mitigate this, the importance of accurate pain assessment based on pain scores reported by the patient was emphasised during training.The cost analyses and comparisons were based on reference and local costs, but these were presented transparently so that they can be reviewed and revised considering differences or future changes in costs of methoxyflurane or the comparators.Our findings suggest that methoxyflurane provides an effective prehospital alternative to Entonox® and intravenous options for moderate to severe pain in patients with trauma and can be safely used by paramedics and EMTs. This study points to methoxyflurane acting earlier and with a greater reduction in pain than Entonox® or intravenous paracetamol and also acting more quickly with a similar reduction in pain compared with intravenous morphine.The more rapid is analgesia may be particularly helpful in the prehospital environment where speed of stabilisation and transfer of patient is important, where cannulation may be difficult or where some ambulance personnel may not be trained to cannulate or administer intravenous analgesics. This will have implications for prehospital guidance in trauma in the UK and Europe which have been updated in the UK  to incluFurther research, using randomised controlled designs would be needed to confirm the relative benefits of methoxyflurane compared to intravenous morphine or paracetamol for pain due to trauma in adults in the prehospital setting. Other potential benefits, for example on speed of delivery to the ED and patient reported experience should also be investigated .Additional file 1: Supplement 1. Estimation sample and outputs for methoxyflurane against each comparator: main sample. Additional file 2: Supplement 2. Estimation sample and outputs for methoxyflurane against each comparator: per protocol license indication sample.Additional file 3: Supplement3. Statistics.


Severe pain is prevalent in cardiac surgery patients and can increase cardiac complications, morbidity and mortality. The objectives of the study were to assess perioperative pain intensity and to assess predictors of pain post-cardiac surgery, including clinical characteristics and depression.A total of 98 cardiac surgery patients were included in the study. Pain intensity was assessed using a Numerical Rating System. Pain was measured one day pre-operatively and recorded daily from Post-operative Day 2 to Day 7. Clinical data were recorded and depression scores were assessed using the Center for Epidemiological Study of Depression (CES-D).p = 0.01 pre-operatively). Patients with severe pain (NRS 7–10) had significantly higher levels of white blood cells (WBC) compared to patients with no pain-moderate pain (NRS 0–6), (p = 0.01). However, CES-D scores were only weakly correlated maximum WBC levels perioperatively.Pain intensity increased significantly during hospitalization from pre-operative levels, surging at 2 days post-operatively. Predictors of high pain intensity were high pre-operative CES-D scores, female gender, cardiac function, smoking and high body mass index (BMI). Significantly higher pre-operative CES-D scores were found in patients with severe pain compared to patients with no pain to moderate pain (18.23 ± 1.80 vs 12.84 ± 1.22, Pain intensity significantly increased following surgery, and was associated with depressive symptoms, female sex, cardiac function, BMI, and smoking. These factors may serve as a basis for identification and intervention to help prevent the transition from acute pain to chronic pain. Depression post- cardiac surgery is highly prevalent , and is There is increasing evidence that pain and depression share common mechanisms. Recent studies have found similarities between neuroplasticity changes induced by pain and by depression , 11. In Perioperative pain is also a major risk factor which can lead to the development of chronic pain, increased cardiac complications, increased morbidity and increased mortality –17.Current data is limited on the coexistence of both pain and depressive symptoms in cardiac surgery patients , 7. CurrHowever, whether pre- and post-operative depression is associated with perioperative pain in cardiac surgery patients is not well studied.The objectives of the current study are to assess the peri-operative pain intensity, and to determine whether perioperative depression scores and clinical characteristics are predictive of post-surgical pain intensity.A prospective study was conducted to investigate the relationship between reported pain scores and depressive symptoms throughout the perioperative period. Pain was measured one day pre-operatively and recorded daily from Post-operative Day 2 to Day 7.using a Numerical Rating System throughout hospitalization. Depression scores were assessed using the Center for Epidemiological Study of Depression (CES-D) at pre-operative, during hospitalization, and up to 10 days post-discharge. The study was approved by the institutional review board. Signed informed consents were obtained from all study participants.Adult patients undergoing cardiac surgery  at the Baruch Padeh Poriya Medical Center from March 2018 to June 2020 were included in this study.Inclusion Criteria: 1) patients eligible for cardiac surgery  2) patients ages 20 and older.Exclusion Criteria: 1) Patients under the age of 20; 2) patients with end-stage renal disease requiring dialysis; 3) presence of peripheral neuropathy; Glasgow Coma Scale score < 13) patient on chronic pain medication; and 5) patients with chronic inflammatory disease were excluded from the study.Clinical and surgical data were recorded from the electronic medical records. The following variables were recorded: Age, BMI, left ventricle ejection fraction (EF) less than 50%, white blood cell count, Working status, Smoking status, Diabetes, Residence, Education level, Marital status, Numeric Pain Rating, and CES-D depression scores.Pain was measured using a Numerical Rating System (NRS), which is an 11 point interval scale evaluating pain from 0-to-10, with 0 characterizing no pain and 10 characterizing maximum pain , 19. PaiThe Center for Epidemiological Study of Depression (CES-D) scale was used to measure depression scores in patients, as it has demonstrated acceptable reliability amongst various patient groups . The 20 Statistical analysis was performed using SPSS . Data was reported as mean ± SE or as percentages. One-way repeated measure analysis of variance (ANOVA) was performed to compare the pain intensity longitudinally across assessment time points. Pain severity was divided into 2 categories based on the NRS scores: no pain to moderate pain (score of 0–6), and severe pain (score of 7–10). The rate of pain  and the percentage of patients with pain  was calculated across assessment time points. One-way repeated measure analysis of variance (ANOVA) was performed to compare the depression scores longitudinally across assessment time points. Independent T-test analysis was performed to compare the CES-D scores at pre-operative, hospitalization, and 10 days post-discharge time points, between patients with no pain-to-moderate pain (NRS score of 0–6) and severe pain (NRS score of 7–10) post surgery.p-value of < 0.05 was considered significant.A univariate logistic regression was performed to examine the association between pain intensity category (severe pain or no pain-moderate pain) and the following variables: pre-operative CES-D, hospitalization CES-D, CES-D 10 day post-discharge, age, sex, diabetes, ejection fraction, BMI, and smoking status. Multivariable logistic regressions were performed forcing all covariates with statistical significance of < 0.175 into the model. Backward variable elimination was used to develop the regression model. Those variables with a statistically significant level of < 0.1 were retained in the final model. In addition, the differences in depression scores between patients with severe pain and patients with no pain-moderate pain were examined using an independent-samples t-test. A p-value of < 0.05 was considered significant. The association between pain scores, CES-D scores, and WBC levels were assessed at pre-operative and post-operative time points using the Pearson correlation coefficient.A 2-way repeated measure ANOVA was performed to assess levels of WBC longitudinally, comparing the 2 pain categories: no pain-moderate pain (NRS of 0–6) and severe pain (NRS 7–10) A 2. 70% of the patients had preserved ejection fraction (left ventricle EF higher than 50%) and 40% were active smokers. Baseline characteristics in patients with No pain- Moderate pain and patients with severe pain are presented in Table A total of 98 patients were included in this study. The mean age was 61 years old and there were 25% female patients. In this patient’s cohort, 36% of the patients were diagnosed with diabetes and the average BMI was 25.5 kg/mp < 0.0001). Pain intensity gradually decreased during the first week postoperatively 7 days of follow-up, but remained higher than the baseline levels (p < 0.0001). Although the percentage of patients with pain decreased gradually during the first week, the percentages of patients reporting moderate (NRS 4–6), and severe (NRS 7–10) pain remained high, with 83% of patients reporting moderate-severe pain on POD-2, 60% on POD-3, 41% on post-operative day- 4, 27% on post-operative day-5, 22% on post-operative day-6, and 19% post-operative day-7  2 p < 0.000. Pain inp = 0.01). There was a trend of higher CES-D scores in patients with severe pain compared to patients with no pain-moderate pain during hospitalization (22.60 ± 1.46 (95%CI 19.65–25.56) vs. 20.77 ± 1.36 (95% CI 18.05–23.49) and 10-days post discharge (17.30 ± 1.72 (95% CI 13.83–20.77) vs. 15.38 ± 1.27 (95% CI 12.84–17.92), but the levels did not reach significance.Significantly higher pre-operatively CES-D scores were found in patients with severe (NRS 7–10) post-operative pain compared to patients with no pain to moderate pain (NRS 0–6) Fig.  . Hospitalization and 10 days post-discharge CES-D scores were also weakly correlated with maximum white blood cell count perioperatively .A Pearson correlation indicates that pre-operative CES-D scores was weakly correlated with maximum pain intensity (p = 0.01)  had significantly higher levels of WBC compared to patients with no to moderate pain (NRS 0–6), (01) Fig. . In bothR2 = 0.40,χ2 = 35.1 p < 0.001).A univariate analysis revealed that pre-operative CES-D, female sex, and high BMI were significant predictors of pain intensity during hospitalization Table . In a muThe main finding of the study is that patients with severe post-surgical pain had significantly higher depression scores pre-operatively than patients with no pain to moderate pain.In our study, predictors of post-cardiac surgery pain intensity were pre-operative CES-D scores, smoking, high BMI, female sex, and ejection fraction (< 50%). The majority of these factors are modifiable. Studies have reported that cardiac surgery patients pain is more prevalent in depressive symptoms , 7. SincIn our patient population, pain peaked early in the post-operative period, which is consistent with current literature , 25. In Pain and depression have been noted to have significant comorbidity and both involve similar neural networks and similar neurotransmitter systems that influence neuroplasticity in the brain , 11. ImaPost-surgical pain may also be linked not only to depressive symptoms, but also to the trauma associated with the procedure and the elevated white blood cell (WBC) levels induced by the surgery , 31. In Pain intensity significantly increased post-cardiac surgery, and is associated with depressive symptoms, female sex, cardiac function, BMI, and smoking. These factors may serve as a basis for identification and intervention to help prevent the transition from acute pain to chronic pain. Moreover, physicians should anticipate higher levels of pain in patients with higher CES-D scores. The high depressive scores found post-operatively highlight the need to establish depression screening as part of the pre-operative patient management. Future research should investigate the effectiveness of post-cardiac surgery pain treatments and determine whether perioperative treatment with antidepressants medications can affect patient outcomes.


Moreover, patients who were given dexamethasone had lower pain scores at 6 h , 12 h , and 24 h  when compared with placebo. In conclusion, the systemic administration of dexamethasone increases the anesthetic success rate and improves pain management in patients with SIP.Inferior alveolar nerve block (IANB) has a high failure rate in subjects with symptomatic irreversible pulpitis (SIP). It has been suggested that drugs with anti-inflammatory activity could improve the efficacy of the anesthetic used for IANB. The aim of this study was to assess the effect of dexamethasone on the success of dental anesthesia in patients with SIP. An information search was performed using PubMed and Google Scholar. The risk of bias of the included studies was evaluated with the Cochrane Collaboration’s risk-of-bias tool. The anesthetic success rate, pain intensity (VAS), and adverse effects were extracted. Data were analyzed using the Mantel–Haenszel test and odds ratio or the inverse variance and standardized mean difference. Dexamethasone increased the anesthetic success in comparison with placebo ( Ial pulps , alteredal pulps —of the pAccordingly, various drugs that interfere with or reduce inflammation and/or pain—such as the supplementary administration of local anesthetics , as wellSome clinical assays have been carried out to determine the effect of dexamethasone on the success of dental anesthesia in patients with SIP, and interesting results have been found ,22,23,24This systematic review was developed in strict adherence to the guidelines for reporting systematic reviews and meta-analyses of studies that assess health care interventions (PRISMA) ,26,27. TOur research team posed the following question: How effective is dexamethasone compared to a placebo or a local anesthetic in terms of anesthetic success rate and post-endodontic pain management in patients with SIP?Population: Randomized, double-blind clinical trials.Interventions: Administration of dexamethasone in patients with SIP.Control: A group using placebo/a group with local anesthesia.Outcomes: Anesthetic success rate, anesthesia depth and duration, pain intensity using the visual analog scale (VAS), pain intensity evaluated through the Heft–Parker VAS, rescue analgesic medication, and adverse effects.These criteria were written according to the PICO recommendations .Clinical studies reporting a loss to follow-up of more than 20%.High risk of bias according to the Cochrane Collaboration’s risk-of-bias tool. The keywords used to perform PubMed and Google Scholar searches were “dexamethasone”, “corticosteroids”, “glucocorticoids”, “symptomatic irreversible pulpitis”, “active dental pain”, and “dental pain”. At least two keywords were used for the identification of articles, i.e., “dexamethasone” AND “symptomatic irreversible pulpitis”. In addition, three filters were employed in PubMed: article type , language (English or Spanish), and species (humans). The retrieved articles were saved for further assessment. Articles published up to 1 November 2021 were eligible. The Cochrane Collaboration’s risk-of-bias tool was employed ,30,31. EArticle ID data, design, treatments, sample size, dose, anesthetic success rate, anesthesia depth and duration, thermal or electric pulpal tests, pain intensity, rescue analgesic medication, and adverse effects were obtained.Yavari et al. 2019  reportedTwo independent assessors carried out the bias assessment and data extraction. Any disagreements between them were reviewed and decided by a third evaluator, when necessary.2 test. Funnel plots were used to represent the publication bias of the included clinical trials. The influence of the weight of each study on the results of the meta-analysis was evaluated through a sensitivity study. A p-value of ≤0.05 and odds ratio or a mean difference ≥ 1  within a 95% confidence interval was considered to be a statistically significant difference [The Review Manager 5.3 software for Windows was used for data analysis, forest plots, and funnel plots. All meta-analyses were conducted using the random-effects model. The anesthetic success was analyzed using the Mantel–Haenszel test and odds ratios (ORs). On the other hand, pain intensity was assessed with the inverse variance and standardized mean difference. The data heterogeneity was measured with the Ifference ,33,34,35In total, 17 clinical assays were found in both databases , of whicThe anesthetic success was evaluated across eight clinical trials that compared dexamethasone and placebo in patients with SIP ,17,20,21The pain control assessment was performed with six clinical assays. All of these clinical trials found that dexamethasone was more effective than placebo in patients with SIP ,19,22,23n = 249) [p < 0.08, n = 253) [n = 253, p < 0.003, n = 502). The overall anesthetic success rate of dexamethasone was 60.55%, while that of saline was 38.64% [p < 0.001, The local assessment of the anesthetic success rate of dexamethasone and placebo was performed using four clinical studies n = 249) ,9,11,16. ,9,11,16n = 253) ,17,20,21Moreover, no study reported that dexamethasone improved the depth of anesthesia, whereas one dexamethasone clinical trial  found ann = 302) [p < 0.001), 12 (p < 0.0001), and 24 (p < 0.0008) postoperative hours when compared to those who were given local anesthetics  ,22,23. Tsthetics .n = 58) [n = 436) [The number of patients who took rescue analgesics in the dexamethasone group was lower in comparison with controls, but a statistical difference was not found (n = 58) ,18. On tn = 436) ,14,20,22The sensitivity analysis did not show important changes in the results of either the anesthetic success index or the pain intensity meta-analyses. Moreover, the visual evaluation identified no publication bias using a funnel plot .The most important finding of this systematic review and meta-analysis is that systemic—but not local—administration of dexamethasone increased the anesthetic success rate when compared to systemic placebo in patients with SIP. However, the data trend shows a positive effect in favor of the local administration of dexamethasone, for which it is likely that increasing the sample size could achieve this statistical difference. Moreover, dexamethasone produced lower pain intensity scores at 6, 12, and 24 h when compared to the control group. On the other hand, the evaluation of depth and duration of anesthesia, along with the adverse effects of dexamethasone, was not possible, due to the small number of studies reporting these clinical data. No study reported an increase in anesthetic depth, while only one trial reported that dexamethasone prolonged the duration of anesthesia. Aksoy et al.  demonstrThe Cochrane Collaboration’s risk-of-bias tool showed that all items had a general result indicating a low risk of bias. The items with the highest risk of bias were blinding of patients and medical personnel (performance bias), and blinding of outcome assessment (detection bias) . MoreoveWaldron et al.  carried Some studies have been carried out to determine the adverse effects of dexamethasone in humans. Polderman et al.  reportedThe main advantages of this study include an adequate methodology, rigorous and conservative statistical methods, and the available evidence with a lower risk of bias to perform a powerful pooled analysis ,34,35,49In conclusion, this is the first systematic review and meta-analysis showing that the systemic administration of dexamethasone increases the anesthetic success rate and improves pain management in patients with SIP.


Chronic Pain is a complex condition. Our approach is to enable young people to function despite their pain. All patients are offered our Pain Education Workshop (PEW) based on pain education, self-management, and cognitive behavioural therapy. Pre-pandemic this was delivered face to face, and with social distancing guidelines in place we adapted virtually in response to patient need. We were interested to see if the children and young people were finding the intervention useful in their journey towards managing their pain. We hoped this would prove to a positive experience for our patients in a time of great uncertainty.Data was collected from patients who attended a weekday virtual PEW  at Evelina London Children’s Hospital between November 2020 and May 2022. All patient had an initial appointment in our multidisciplinary Paediatric and Adolescent Chronic Pain Clinic. Overall, the aims of the workshop are for patients to learn and recognize the link between psychosocial factors and the impact of boom and bust on pain intensity, whilst supporting patients’ ability to self-manage.Attendees completed a series of pre and post workshop self-report questionnaires. The questionnaires requested patients to rate their confidence in their understanding of pain and in using self-management strategies, using a 5 point Likert scale (1=Not at All to 5=Extremely Confident). Patients were then asked an open question to establish what they would like to gain from the workshop. Immediately post workshop patients were asked to re-rate their confidence in their understanding of pain and in using self-management strategies. They were also asked to report what they will do differently as a result of attending the workshop.A statistical comparison of the patients’ confidence in understanding chronic pain before and after PEW; and in self-management strategies were assessed with paired t-tests. Our null hypothesis being that no difference pre and post workshop would be found.A qualitative content analysis of the patient’s reported hopes for (pre-workshop) and what they took away (post workshop) was undertaken and key themes were identified.Since November 2020, a total of 140 patient were offered PEW, 107 of which undertook this intervention. Group sizes varied from 4-14 young-person and parent diads, over 17 sessions. Full data sets for pre- and post-intervention feedback were analysed on 56/107 patients. These patients’ average age was 14 (range 9-18); 47 female, 9 male.The mean patient self-reported understanding of chronic pain pre-workshop was 2.8/5 (range 1-5). Post-workshop scores increased to 4.0/5 (range 3-5). Patient’s confidence in managing their pain increased from 3.2/5 (range 2-5) to 3.9/5 (range 2-5). Paired T-tests on these scores showed a statistically significant difference in understanding chronic pain post PEW (P < 0.001), and in confidence in self-management post PEW (P < 0.001).Themes identified pre-intervention by the young people included:• Increasing understanding and knowledge of chronic pain• learning how to cope with pain• Improving access to treatmentTake home message themes:• relaxation techniques• pacing• goal setting.Analysis of the themes in combination with the patient reported scores demonstrated that outcomes as set by the young person were met by the intervention.The results from this study provide evidence for the effectiveness of PEW, in terms of delivering predefined workshop outcomes. It showed significant improvements in patients understanding of chronic pain, and patient’s confidence in using self-management strategies. Similarly, when asked what they took away from the intervention, patients reported wanting to practice using self-management strategies-reinforcing the assumption that PEW was effective in increasing patients confidence to self-manage. As a result, the findings are supportive of assumptions that CBT interventions combined with pain education can have a positive impact, increasing patient’s self-efficacy and increasing their confidence to self-manage.In conclusion, this study provides evidence for the effectiveness of a brief multidisciplinary biopsychosocial intervention for chronic pain.Previous research into the field has mainly focused on face-to-face interventions run over numerous weekly sessions. We have demonstrated similar effectiveness whilst using an online, one-off intervention. This demonstrates services can access patients and offer effective treatment whilst reducing the impact on resources. Moreover, we provided much needed virtual support for young people during and post pandemic.Limitations:• Small sample size. Larger sample is needed to fully assess the effectiveness of virtual PEW and to generalise to a wider population.• High attrition rate (33/140). Paediatric patients with chronic conditions are more likely to show persistent/chronic absences (school attendance <90%). Research has shown that psychoeducational interventions have been most effective when they are run on weekends to minimise the loss of school. Access to technology to participate in a virtual group may also be a factor.It is likely that further longitudinal studies are needed to assess the long-term effectiveness of PEW. We are unable to predict whether patients remained confident in using self-management strategies after the workshop or for how long. Since chronic pain is recurrent pain lasting longer than 3 months it is important to capture how effective PEW is in increasing patient’s confidence in managing their condition in the long-term. It is also necessary to assess the long-term effectiveness of PEW in increasing and improving patients understanding of pain. Studies have shown recall can improve 9-24 hours after new information is learnt. However, past 24 hours, recall of learnt information starts to decline if the information is not relearned continuously. Not being able to recall pain messages can affect patients’ abilities to utilise this knowledge to inform coping strategies and manage symptoms long term.


Transmasculine people are assigned female at birth but identify as male. These patients often are prescribed testosterone therapy as part of their transition. This treatment can affect ovulation and stop menstrual periods. Endometriosis is a common condition that causes pelvic pain in some people born with female pelvic organs. Not a lot is known about transmasculine people and how often endometriosis affects them. Testosterone should help treat if not reduce the incidence of endometriosis. This commentary looks at the current literature in order to help clarify existing knowledge gaps. Transmasculine patients who present for hysterectomy as a surgery to help them affirm themselves in their self-identified gender sometimes report pelvic pain symptoms as well. There are many reasons why patients report pain before surgery, and this can be related to endometriosis, even though this diagnosis is less expected in this group. Providers caring for transmasculine patients should be aware of this. Transmasculine individuals are assigned female at birth but some identify as male or choose to take on a masculine gender expression. Some patients choose to transition to their self-identified gender, and a proportion of these patients are prescribed long-term regimens of testosterone therapy. Testosterone therapy is known to cause cessation of ovulation and menses, and many of these patients report amenorrhea within months of starting testosterone. Very little data exist looking at the effects of short- and long-term testosterone use on ovarian and uterine function (MEDLINE Search 2000-2021). As clinicians treating this patient population, we have previously made assumptions about the low incidence of endometriosis in these patients; however, up until recently, very few publications have existed specifically looking at pelvic pain and endometriosis in transmasculine individuals and we do not know the prevalence of this condition in this patient population. This lack of knowledge can be attributed to the barriers many trans patients face when accessing care and their resultant underrepresentation in medicine. Therefore, the aim of this commentary is to review the literature on pelvic pain and endometriosis in transmasculine patients seeking hysterectomy.Hysterectomy is a common gender-affirming surgery that some transmasculine patients undergo. Some transmasculine patients also present for management of pelvic pain and describe endometriosis symptoms. Sometimes, patients seek hysterectomy for a combination of their pain and their desire to transition to their self-identified gender. For some surgeons, it is hard to decipher the true indication for hysterectomy, but among those who routinely care for this patient population, it is widely accepted that hysterectomy is a reasonable choice for most patients, as the removal of the pelvic organs helps patients feel more aligned with their self-identified masculine gender, which reduces their gender dysphoria. In order to undergo hysterectomy as gender affirmation surgery, providers are encouraged to follow the World Professional Association for Transgender Health (WPATH) Standards of Care , which oAs we know, endometriosis is most commonly diagnosed by visual inspection and identification of the disease. Specific to the transmasculine population, few studies have looked at and commented on the intraoperative findings of patients undergoing hysterectomy for gender affirmation, even in the setting of reported pelvic pain. In a study looking at adolescent patients, 35 transmasculine patients with mean age of 15 years presented with dysmenorrhea, and of those who were placed on testosterone therapy for gender affirmation, one in three had persistent pelvic pain symptoms (Very few pelvic organ pathology studies exist, looking at hysterectomy specimens in transgender men undergoing hysterectomy, and the reports that have been published show mixed findings. For example, The above finding could be attributed to aromatization of exogenous testosterone to estradiol in the peripheral tissues. There are no studies specifically looking at estradiol level trends in trans individuals using long-term testosterone. But it is very plausible that high levels of androgens may be converted to estrogen in this clinical scenario, leading to a hyper-estrogenic state in these patients. Endometriosis is considered an estrogen-dependent disease. And while the aforementioned hypothesis does not explain the mechanism by which endometriosis may occur in a higher proportion of trans individuals compared to their cisgender counterparts, it may explain why they may be symptomatic of their disease, even if they are amenorrheic.As many as 1 in 10 women suffer from endometriosis. However, the prevalence of incidentally diagnosed disease is even higher. For instance, 17% of women undergoing laparoscopic ovarian drilling were found to have endometriosis at the time of their laparoscopic procedure (Endometriosis is present in up to 87% of patients who present for management of chronic pelvic pain . In our The majority of the studies that currently exist are limited by their retrospective nature and the reliance on the electronic medical record to obtain data. Because of these methods, we are not able to draw conclusions about pain characterization in this patient population. For instance, it is not clear if all patients presenting with pain have ‘endometriosis’-specific type pain, or whether it is a combination of this type of pain with other pain syndromes. Again, the contribution of the gender dysphoria felt by patients presenting for surgical interventions also makes it hard to interpret with confidence some of the results presented in these studies. Some patients may confuse what some cis women may describe as ‘normal’ menstrual discomfort with actual pelvic pain, as the discomfort felt about their bodies may amplify their symptoms. Future research should focus on better defining pain symptoms, collecting pre- and postoperative pain scores, and also creating comparative cohorts with cisgender populations seeking the same interventions for pain. This would allow us to better characterize pain symptoms in each group, to evaluate if pain is resolved in the same way and also to determine if endometriosis is similar between patient groups.In summary, endometriosis exists in transmasculine individuals. Those seeking hysterectomy may present with reports of pain symptoms and some may only seek the procedure for gender affirmation. Either way, hysterectomy is a medically indicated procedure in individuals assigned female at birth seeking alignment with their self-identified masculine gender. In those with pain symptoms, providers should be aware that traditional management options may not always be appropriate for patients given their desire to virilize. Further, many patients feel favorable about having a hysterectomy for gender affirmation. Perhaps the newest piece of data we have now is that more patients than expected have incidental findings of endometriosis. Surgeons performing these procedures for this patient population should be aware of this and should be prepared in some cases to perform a more complicated hysterectomy.The author declares receiving authorship royalties from UpToDate, Inc.This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.


BackgroundAssessment of pain has always been subjective and is commonly assessed using a numeric pain scale (NPS) or Wong-Baker faces scale. The pain intensity score is not standardized and relies on individuals’ past experiences. The disadvantage of using such pain assessment scales and treating the numbers can lead to overdosing on analgesics leading to unwanted side effects. The Robert Packer Hospital/Functional Pain Scale (RPH/FPS) was developed as a tool for the objective assessment of pain and its impact on a patient’s function. AimThe study aimed to validate the RPH/FPS scale against NPS and Wong-Baker faces scale in medical, surgical, and trauma patients. The patients’ were also asked to rank the scales as one (1) being the most preferred to three (3) being the least preferred.DesignThis prospective, observational cohort study compares the two most common pain scales, the NPS and the Wong-Baker Faces, to the RPH/FPS.MethodsSpearman correlation was used to test for correlation between the three scales, and Wilcoxon rank-sum test was used to compare means between the RPH/FPS and NPS. The study participants were also asked to rate their preferences for the scales by rating the most preferred of the three scales as one (1) and the least preferred number three (3). ResultsThe RPH/FPS had a strong correlation with both the NPS and Wong-Baker Faces scales . As for preferences, the RPH/FPS was ranked first on 36.9% of the surveys followed by NPS on 35.9%, and the Wong-Baker Faces on 22.3%. There were 4.9% of the surveys missing the preference rankings.Conclusion level and the providers' observation of the patient.The results validate the RPH/FPS scale against the NPS and Wong-Baker Faces scales. This gives the clinicians a tool for objective assessment of pain and its effect on the recovery process, thereby minimizing the observed disconnect that sometimes happens between the reported pain intensity Pain is defined according to the International Association for the Study of Pain (IASP) as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage" .Pain is a subjective assessment determined primarily by a patient's self-report . Two of The NPS and Wong-Baker Faces scales have been used for many years and validated many times . HoweverThe aim of the phase 2 study was to validate this scale for general surgery, trauma, and internal medicine patients that have not seen the RPH/FPS scale prior to this admission. Our study shows a comparative data analysis of the RPH/FPS to NPS and Wong-Baker Faces scales. Implementing the RPH/FPS into the electronic medical records (EMR) should aid the providers in having a complete assessment of the patient and improve the patient experience.Patient populationIn accordance with institutional guidelines, Institutional Review Board approval (IRB#2007-51) was obtained prior to initiating the current study. All patients were prospectively enrolled in the observational cohort study after obtaining verbal informed consent. Inclusion criteria were set as adult patients with inpatient admittance. Exclusion criteria were set as <18 years of age, a prior diagnosis of cognitive impairment, a history of opioid abuse, and non-English speakers. All patients were identified through a daily admission report prospectively enrolled for this study without any changes to their quality of care if they refused to participate.Data collectionFor the purposes of the study, patient demographics and characteristics of hospitalization were collected, including age, gender, education, admitting service, and diagnosis. Patients were also asked to complete three separate health questionnaires that evaluated their pain. These questionnaires included the NPS, Wong-Baker Faces pain scale , and theThe NPS evaluates a patient's subjective pain level based on a scale of 0-10, with 10 being the worst pain and 0 being no pain at all. The Wong-Baker Faces scale was originally developed for the evaluation of pediatric patient scales but has since been used internationally for patients >3 years of age to evaluate their pain. The scale asks patients to evaluate their pain level based on a set of different faces associated with an objective number 0-10 , 13 surgical patients (12.8%), and 80 internal medicine patients (79.2%).Convergent validityPatients reported a mean NPS score of 7.75 ± 2.03, a mean Wong-Baker Faces score of 7.77 ± 2.01, and a mean RPH/FPS score of 6.08 ± 2.37  did not complete the preference survey  to glean information about how pain affects function. The care coordinator will also be able to find helpful information regarding the patient's ability to concentrate due to pain, i.e., "Is now a good time to discuss POC, or is the patient unable to concentrate due to pain." Auxiliary services are unable to find any of this information using the NPS or any other unidimensional pain scale. Further studies should expand the population in which the RPH/FPS is tested and compared to existing pain scales.