Low-Dose Methoxyflurane versus Standard of Care Analgesics for Emergency Trauma Pain: A Systematic Review and Meta-Analysis of Pooled Data.

PURPOSE: Undertreatment of trauma-related pain is common in the pre-hospital and hospital settings owing to barriers to the use of traditional standard of care analgesics. Low-dose methoxyflurane is an inhaled non-opioid analgesic with a rapid onset of pain relief that is approved for emergency relief of moderate-to-severe trauma-related pain in adults. This analysis was performed to compare the efficacy and safety of low-dose methoxyflurane with standard of care analgesics in adults with trauma-related pain. METHODS: A meta-analysis was performed on pooled data from randomized controlled trials identified via a systematic review. The primary endpoint was the pain intensity difference between baseline and various time intervals (5, 10, 15, 20, and 30 minutes) after initiation of treatment. RESULTS: The pain intensity difference was statistically superior with low-dose methoxyflurane compared with standard of care analgesics (overall estimated treatment effect=11.88, 95% CI=9.75-14.00; P<0.0001). The superiority of low-dose methoxyflurane was demonstrated at 5 minutes after treatment initiation and was maintained across all timepoints. Significantly more patients treated with methoxyflurane achieved response criteria of pain intensity ≤30 mm on a visual analog scale, and relative reductions in pain intensity of ≥30% and ≥50%, compared with patients who received standard of care analgesics. The median time to pain relief was shorter with methoxyflurane than with standard of care analgesics. The findings were consistent in a subgroup of elderly patients (aged ≥65 years). CONCLUSION: Methoxyflurane can be considered as an alternative to standard of care analgesics in pre-hospital and hospital settings for treatment of adult patients with acute trauma-related pain.

Non-interventional study evaluating exposure to inhaled, low-dose methoxyflurane experienced by hospital emergency department personnel in France.

OBJECTIVES: Low-dose methoxyflurane is a non-opioid, inhaled analgesic administered via the Penthrox inhaler and was recently licensed in Europe for emergency relief of moderate-to-severe trauma-associated pain in conscious adults. This non-interventional study investigated occupational exposure to methoxyflurane in the hospital emergency department (ED) personnel during routine clinical practice. SETTING AND PARTICIPANTS: The study was conducted in two hospital ED triage rooms in France over a 2-week and 3-week period, respectively. Low-dose methoxyflurane analgesia was self-administered by patients via the inhaler under the supervision of nursing staff, per routine clinical practice. An organic vapour personal badge sampler was attached to the uniform of the nurses working in the treatment rooms throughout an 8-hour shift (total of 140 shifts during the study period). Seven-day ambient air monitoring of each treatment room was also performed. Methoxyflurane levels adsorbed in each badge sampler were measured by a central laboratory. The primary objective was to evaluate methoxyflurane exposure experience by the hospital ED nurses during an 8-hour shift. RESULTS: In 138 badge samplers, the median (range) concentration of methoxyflurane present following 8-hour nursing shifts was 0.017 (0.008, 0.736) ppm. This level was almost 900-fold lower than the previously reported 8-hour-derived maximal exposure level of 15 ppm; methoxyflurane exposure approaching this threshold was not documented in any badges. There was no correlation between the number of applications of low-dose methoxyflurane administered during a shift (range 0-5) and the vapour exposure measured on the personal badge samplers. CONCLUSIONS: This study indicates that nurses working in hospital EDs experience very low levels of occupational exposure to methoxyflurane vapour during routine clinical practice. These real-world data can provide reassurance to healthcare providers supervising patients receiving low-dose methoxyflurane analgesia via a Penthrox inhaler; further studies may inform exposure in other hospital ED settings.

Evaluation of pain relief treatment and timelines in emergency care in six European countries and Australia.

PURPOSE: Inadequate relief of pain is common in prehospital and hospital emergency department (ED) settings. We investigated pain treatments and timelines in patients receiving pre-hospital and hospital ED care to provide insight into potential approaches to reduce the burden of trauma-related pain. PATIENTS AND METHODS: In this observational, retrospective chart review, patients had received emergency care for musculoskeletal trauma injuries and analgesic treatment for moderate-to-severe pain in Belgium, France, Germany, Italy, Spain or Sweden. As inhaled low-dose methoxyflurane (LDM) is used extensively in Australia but was not widely available in Europe at the time of this analysis, data from Australia were collated to provide insight into the potential utility of this analgesic in Europe. The primary endpoint was time to administration of first pain relief treatment following arrival of paramedic/ED care. RESULTS: Randomly selected physicians (n=189) collated data from 856 patients (Europe: n=585; Australia: n=271) via an online survey. Time to first pain relief treatment varied between countries and was significantly longer across Europe versus Australia (mean [SD] 38.1 [34.7] vs 29.9 [35.5] mins; P=0.0017). Patients from Australia who received LDM experience a shorter mean (SD) time to first pain treatment following arrival of emergency care versus patients who received other analgesics (propensity score matched [n=85] per group: 21.7 [24.2] vs 39.1 [43.0] mins; P=0.0013). Across all countries, mean (SD) time to first analgesic was shorter when treatment was administered by paramedics versus hospital ED staff (15.7 [14.7] vs 49.1 [38.4] mins). CONCLUSIONS: While there was a large variation in analgesia timelines across countries, mean times are shorter in Australia compared with Europe overall. In Australia, use of LDM was associated with a significantly shorter time from emergency assistance to first pain treatment compared with non-LDM treatments. Further studies are needed to investigate the utility of LDM in Europe.

The role of inhaled methoxyflurane in acute pain management.

Methoxyflurane is an inhaled analgesic administered via a disposable inhaler which has been used in Australia for over 40 years for the management of pain associated with trauma and for medical procedures in children and adults. Now available in 16 countries worldwide, it is licensed in Europe for moderate to severe pain associated with trauma in conscious adults, although additional applications are being made to widen the range of approved indications. Considering these ongoing developments, we reviewed the available evidence on clinical usage and safety of inhaled analgesic methoxyflurane in trauma pain and in medical procedures in both adults and children. Published data on methoxyflurane in trauma and procedural pain show it to be effective, well tolerated, and highly rated by patients, providing rapid onset of analgesia. Methoxyflurane has a well-established safety profile; adverse events are usually brief and self-limiting, and no clinically significant effects on vital signs or consciousness levels have been reported. Nephrotoxicity previously associated with methoxyflurane at high anesthetic doses is not reported with low analgesic doses. Although two large retrospective comparative studies in the prehospital setting showed inhaled analgesic methoxyflurane to be less effective than intravenous morphine and intranasal fentanyl, this should be balanced against the administration, supervision times, and safety profile of these agents. Given the limitations of currently available analgesic agents in the prehospital and emergency department settings, the ease of use and portability of methoxyflurane combined with its rapid onset of effective pain relief and favorable safety profile make it a useful nonopioid option for pain management. Except for the STOP! study, which formed the basis for approval in trauma pain in Europe, and a few smaller randomized controlled trials (RCTs), much of the available data are observational or retrospective, and further RCTs are currently underway to provide more robust data.

A Review of the Burden of Trauma Pain in Emergency Settings in Europe.

Trauma pain represents a large proportion of admissions to emergency departments across Europe. There is currently an unmet need in the treatment of trauma pain extending throughout the patient journey in emergency settings. This review aims to explore these unmet needs and describe barriers to the delivery of effective analgesia for trauma pain in emergency settings. A comprehensive, qualitative review of the literature was conducted using a structured search strategy (Medline, Embase and Evidence Based Medicine Reviews) along with additional Internet-based sources to identify relevant human studies published in the prior 11 years (January 2006-December 2017). From a total of 4325 publications identified, 31 were selected for inclusion based on defined criteria. Numerous barriers to the effective treatment of trauma pain in emergency settings were identified, which may be broadly defined as arising from a lack of effective pain management pan-European and national guidelines, delayed or absent pain assessment, an aversion to opioid analgesia and a delay in the administration of analgesia. Several commonly used analgesics also present limitations in the treatment of trauma pain due to the routes of administration, adverse side effect profiles, pharmacokinetic properties and suitability for use in pre-hospital settings. These combined barriers lead to the inadequate and ineffective treatment of trauma pain for patients. An unmet need therefore exists for novel forms of analgesia, wider spread use of available analgesic agents which overcome some limitations associated with several treatment options, and the development of protocols for pain management which include patient assessment of pain.Funding: Mundipharma International Ltd.

Prolonged-release oxycodone/naloxone reduces opioid-induced constipation and improves quality of life in laxative-refractory patients: results of an observational study.

BACKGROUND: Opioids are an effective treatment for moderate-to-severe pain. However, they are associated with a number of gastrointestinal side effects, most commonly constipation. Laxatives do not target the underlying mechanism of opioid-induced constipation (OIC), so many patients do not have their symptoms resolved. Fixed-dose prolonged-release (PR) oxycodone/naloxone (OXN) tablets contain the opioid agonist oxycodone and the opioid antagonist naloxone. Nal-oxone blocks the action of oxycodone in the gut without compromising its analgesic effects. AIM: To evaluate the effectiveness of PR OXN in patients with severe pain who had laxative-refractory OIC with their previous opioid. METHODS: The study was carried out in 13 centers across the UK and Ireland, using a bespoke online tool to capture patients' data. Patients were reviewed according to normal clinical practice of each center and rated any changes in their constipation and quality of life (QoL) since starting PR OXN. Any change in patients' laxative use was also recorded. RESULTS: One hundred and seven patients were entered into the database, and 81 went on to attend at least one review. Of these, 54 (66.7%) reported an improvement in constipation and 50 (61.7%) reported an improvement in QoL since starting PR OXN. Fifty-seven patients (70.4%) said they had reduced laxative intake; 48 (59.3%) only needed laxatives as required. CONCLUSION: PR OXN reduced symptoms of constipation, improved QoL and reduced laxative intake in patients with OIC. It has a potential place early in any treatment strategy for severe pain in patients using opioids, particularly in patients who may be predisposed to constipation.

Management of trauma pain in the emergency setting: low-dose methoxyflurane or nitrous oxide? A systematic review and indirect treatment comparison.

BACKGROUND: Low-dose methoxyflurane and nitrous oxide (N2O; 50:50 with oxygen) are both self-administered, self-titrated, rapid-acting, nonnarcotic, and noninvasive inhalational agents with similar onset times of pain relief. The aim of this review was to compare the clinical efficacy, safety, and tolerability of these analgesics in emergency care. MATERIALS AND METHODS: A systematic literature search and review according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were performed using Embase, Medline, the Cochrane Library, several clinical trial registers, and emergency-medicine conference material. RESULTS: Although both compounds have been used for many years in emergency care, the search found only a few controlled studies and no head-to-head trials performed in this setting. Two double-blind, randomized studies comparing their respective study medication (low-dose methoxyflurane or N2O) to placebo were identified that could be compared in an indirect approach by using placebo as a bridging comparator. Both agents provided rapid pain relief to trauma patients, with no significant differences between them; both treatments were generally well tolerated. CONCLUSION: Both low-dose methoxyflurane and N2O are suitable options for the pain treatment of trauma patients in the emergency setting. Due to the ease of administration and portability, inhaled low-dose methoxyflurane, however, may not only offer advantages in emergency situations in remote or difficult-to-reach locations and mass-casualty situations but also be of significant value in urban and rural environments.

Oral Prolonged-Release Oxycodone/Naloxone for Managing Pain and Opioid-Induced Constipation: A Review of the Evidence.

BACKGROUND: Opioids provide effective relief from moderate-to-severe pain and should be prescribed as part of a multifaceted approach to pain management when other treatments have failed. Fixed-dose oxycodone/naloxone prolonged-release tablets (OXN PR) were designed to address the opioid class effect of opioid-induced constipation (OIC) by combining the analgesic efficacy of oxycodone with the opioid receptor antagonist, naloxone, which has negligible systemic availability when administered orally. This formulation has abuse-deterrent properties, since systemic exposure to naloxone by parenteral administration would antagonize the euphoric effects of oxycodone. METHODS: A literature search was conducted to assess the evidence base for OXN PR to treat moderate-to-severe pain and its impact on bowel function, based on published clinical trials and observational studies. RESULTS: Extensive data demonstrate that OXN PR provides effective analgesia and clinically relevant improvements in bowel function in patients with OIC and moderate-to-severe cancer-related pain and noncancer pain types such as low back pain, neuropathic pain, and musculoskeletal pain. OXN PR has also been found to improve bowel function in patients with OIC refractory to multiple types of laxatives, and improve Parkinson's disease-related pain. No unanticipated safety concerns have been reported in elderly patients. CONCLUSIONS: Evidence from clinical trials and observational studies confirms that for selected patients OXN PR significantly improves moderate-to-severe chronic pain and provides relief from OIC. Treatment should be tailored to individual patients to establish the lowest effective dose. An absence of analgesic ceiling effect was seen across the clinically relevant dose range investigated (≤ 160/80 mg/day).

Laxatives Do Not Improve Symptoms of Opioid-Induced Constipation: Results of a Patient Survey.

INTRODUCTION: Laxatives are commonly used to treat opioid-induced constipation, the commonest and most bothersome complication of opioids. However, laxatives have a nonspecific action and do not target underlying mechanisms of opioid-induced constipation; their use is associated with abdominal symptoms that negatively impact quality of life. OBJECTIVE: To assess the effects of laxatives in patients taking opioids for chronic pain. METHODS: One hundred ninety-eight UK patients who had taken opioid analgesics for at least one month completed a cross-sectional online or telephone survey. Questions addressed their pain condition, medication, and laxative use (including efficacy and side effects). The survey also assessed bowel function using the Bowel Function Index. RESULTS: Since starting their current opioid, 134 of 184 patients (73%) had used laxatives at some point and 122 (91%) of these were currently taking them. The most common laxatives were osmotics and stimulants. Laxative side effects were reported in 75%, most commonly gas, bloating/fullness, and a sudden urge to defecate. Side effects were more common in patients less than 40 years of age. Approximately half of patients said laxatives interfered with work and social activities, and one-fifth needed an overnight hospital stay because of their pain condition and/or constipation. Laxatives did not improve the symptoms of constipation, as assessed by the Bowel Function Index. Constipation was not related to opioid strength, dose of opioid, or number of laxatives taken. CONCLUSIONS: Use of laxatives to treat opioid-induced constipation is often ineffective and associated with side effects. Instead of relieving the burden of opioid-induced constipation, laxative use is associated with a negative impact.

Satisfaction, Adherence and Health-Related Quality of Life with Transdermal Buprenorphine Compared with Oral Opioid Medications in the Usual Care of Osteoarthritis Pain.

BACKGROUND: Osteoarthritis (OA) causes substantial pain and reduced health-related quality of life (HRQL). Although opioid analgesics are commonly used, the relative benefits of different opioids are poorly studied. Transdermal buprenorphine (TDB) offers an alternative to oral opioids for the treatment of moderate-to-severe chronic pain. This observational study of people with OA pain assessed satisfaction, HRQL and medication adherence. METHODS: Patients in the UK with self-reported knee and/or hip OA who had been receiving one or more of TDB, co-codamol (an oral paracetamol/codeine combination) and tramadol for at least 1 month completed an online or telephone questionnaire. Medication satisfaction scores, HRQL scores (Short-Form 36 [SF-36]), medication adherence (Morisky Medication Adherence Scale [MMAS™]), adverse events and treatment discontinuations were recorded. Linear and logistic regression models were used to compare the treatment effect of TDB with co-codamol or tramadol. RESULTS: Overall, 966 patients met the inclusion criteria; 701 were taking only one of the target medications (TDB: 85; co-codamol: 373; tramadol: 243). The largest age group was 50-59 years and 76.0 % of patients were female. The TDB group was younger, with more male patients, therefore the statistical models were adjusted for age and sex. Medication satisfaction scores were significantly higher in the TDB group than the other two groups (TDB vs. co-codamol: 3.56, 95 % confidence interval [CI] 1.90-6.68, p < 0.0001; TDB vs. tramadol: 3.22, 95 % CI 1.67-6.20, p = 0.0005). Physical Component Summary scores for HRQL and mean adherence were also higher in the TDB group, while Mental Component Summary HRQL scores were similar across the three groups. CONCLUSIONS: Patients with knee and/or hip OA pain treated with TDB were more satisfied and more adherent with their medication, and reported higher Physical Component Summary HRQL scores than those treated with co-codamol or tramadol, although demographic differences were observed between groups.

Impact of prolonged-release oxycodone/naloxone on outcomes affecting patients' daily functioning in comparison with extended-release tapentadol: a systematic review.

PURPOSE: The objective of this systematic review was to assess the clinical efficacy, safety, tolerability, and health-related quality of life outcomes associated with management of moderate-to-severe chronic pain with oxycodone/naloxone and tapentadol, focusing on the effect of these treatments on patients' daily functioning. METHODS: Literature from a wide range of sources, including Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Central Register of Controlled Trials, was searched to identify randomized controlled trials investigating tapentadol or oxycodone/naloxone for the treatment of patients with chronic pain. A network meta-analysis was conducted to determine the relative efficacy and safety profiles of these treatments. FINDINGS: Oxycodone/naloxone was significantly better than tapentadol with respect to the Patient Assessment of Constipation Symptoms total score (risk ratio = -3.60; 95% credible interval, -5.36 to -2.11) and revealed a significantly lower risk of dizziness (risk ratio = 0.72; 95% credible interval, 0.42-0.98). Oxycodone/naloxone was directionally favored, although not significantly superior to tapentadol for headache, fatigue, dry mouth, dyspepsia, and withdrawals due to lack of efficacy. For the AE outcomes of constipation, nausea, and vomiting, as well as pain efficacy and all-cause withdrawals from studies, tapentadol was directionally favored without any statistical difference from oxycodone/naloxone. However, the two treatments were not wholly comparable for the evaluation of pain efficacy because of differences in on-study rescue medication and a higher baseline pain severity in the tapentadol studies. IMPLICATIONS: Oxycodone/naloxone offers significant improvements in Patient Assessment of Constipation Symptoms total score and dizziness and was directionally favored for fatigue and headache compared with extended-release tapentadol, which may translate to improved patient daily functioning and health-related quality of life.