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Opioid analgesics are commonly used for acute low back pain and neck pain, but supporting efficacy data are scarce. We aimed to investigate the efficacy and safety of a judicious short course of an opioid analgesic for acute low back pain and neck pain. OPAL was a triple-blinded, placebo-controlled randomised trial that recruited adults (aged ≥18 years) presenting to one of 157 primary care or emergency department sites in Sydney, NSW, Australia, with 12 weeks or less of low back or neck pain (or both) of at least moderate pain severity. Participants were randomly assigned (1:1) using statistician-generated randomly permuted blocks to guideline-recommended care plus an opioid (oxycodone–naloxone, up to 20 mg oxycodone per day orally) or guideline-recommended care and an identical placebo, for up to 6 weeks. The primary outcome was pain severity at 6 weeks measured with the pain severity subscale of the Brief Pain Inventory (10-point scale), analysed in all eligible participants who provided at least one post-randomisation pain score, by use of a repeated measures linear mixed model. Safety was analysed in all randomly assigned eligible participants. The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000775516). Between Feb 29, 2016, and March 10, 2022, 347 participants were recruited (174 to the opioid group and 173 to the placebo group). 170 (49%) of 346 participants were female and 176 (51%) were male. 33 (19%) of 174 participants in the opioid group and 25 (15%) of 172 in the placebo group had discontinued from the trial by week 6, due to loss to follow-up and participant withdrawals. 151 participants in the opioid group and 159 in the placebo group were included in the primary analysis. Mean pain score at 6 weeks was 2·78 (SE 0·20) in the opioid group versus 2·25 (0·19) in the placebo group (adjusted mean difference 0·53, 95% CI –0·00 to 1·07, p=0·051). 61 (35%) of 174 participants in the opioid group reported at least one adverse event versus 51 (30%) of 172 in the placebo group (p=0·30), but more people in the opioid group reported opioid-related adverse events (eg, 13 [7·5%] of 174 participants in the opioid group reported constipation vs six [3·5%] of 173 in the placebo group). Opioids should not be recommended for acute non-specific low back pain or neck pain given that we found no significant difference in pain severity compared with placebo. This finding calls for a change in the frequent use of opioids for these conditions. Australia's National Health and Medical Research Council, University of Sydney Faculty of Medicine and Health, and ReturnToWorkSA.

Background In emergency medicine, pain is a frequent reason for consultation. However, there is a great variation in its management which is often insufficient. The use intravenous morphine alone or multimodal analgesia with paracetamol is recommended for severe pain. But robust data are lacking to justify the association of paracetamol with morphine versus morphine alone for pain management in the emergency room (ER). The aim of our study is therefore to assess if in patients with acute pain of moderate to severe intensity with a numerical verbal scale (NVS) ≥5 in the ER, the intravenous administration of morphine alone is not inferior to the administration of intravenous morphine combined with paracetamol at 30 min from the first administration of the study drug. Methods ADAMOPA is a prospective, non-inferiority, multicenter, placebo-controlled, parallel-group, randomized (1:1), double-blind trial. Subjects will be enrolled in the ER if they experience moderate to severe, acute, non-traumatic, and traumatic pain, defined as an NVS ≥5. The primary endpoint will be the between-group difference in mean change in NVS pain scores among patients receiving the combination of intravenous morphine plus paracetamol or intravenous morphine given alone, measured from the time before administration of the study medication to 30 min later. Discussion This trial will determine the clinical utility of the association of paracetamol with morphine for pain management in the emergency room. The ADAMOPA trial will be conducted in accordance with the International Council on Harmonization Good Clinical Practices. Trial registration EudraCT number: 2019-002149-39. ClinicalTrials.gov identifier: NCT04148495. Date of trial registration: November 1, 2019.

Regular paracetamol is the recommended first-line analgesic for acute low-back pain; however, no high-quality evidence supports this recommendation. We aimed to assess the efficacy of paracetamol taken regularly or as-needed to improve time to recovery from pain, compared with placebo, in patients with low-back pain. We did a multicentre, double-dummy, randomised, placebo controlled trial across 235 primary care centres in Sydney, Australia, from Nov 11, 2009, to March 5, 2013. We randomly allocated patients with acute low-back pain in a 1:1:1 ratio to receive up to 4 weeks of regular doses of paracetamol (three times per day; equivalent to 3990 mg paracetamol per day), as-needed doses of paracetamol (taken when needed for pain relief; maximum 4000 mg paracetamol per day), or placebo. Randomisation was done according to a centralised randomisation schedule prepared by a researcher who was not involved in patient recruitment or data collection. Patients and staff at all sites were masked to treatment allocation. All participants received best-evidence advice and were followed up for 3 months. The primary outcome was time until recovery from low-back pain, with recovery defined as a pain score of 0 or 1 (on a 0–10 pain scale) sustained for 7 consecutive days. All data were analysed by intention to treat. This study is registered with the Australian and New Zealand Clinical Trial Registry, number ACTN 12609000966291. 550 participants were assigned to the regular group (550 analysed), 549 were assigned to the as-needed group (546 analysed), and 553 were assigned to the placebo group (547 analysed). Median time to recovery was 17 days (95% CI 14–19) in the regular group, 17 days (15–20) in the as-needed group, and 16 days (14–20) in the placebo group (regular vs placebo hazard ratio 0·99, 95% CI 0·87–1·14; as-needed vs placebo 1·05, 0·92–1·19; regular vs as-needed 1·05, 0·92–1·20). We recorded no difference between treatment groups for time to recovery (adjusted p=0·79). Adherence to regular tablets (median tablets consumed per participant per day of maximum 6; 4·0 [IQR 1·6–5·7] in the regular group, 3·9 [1·5–5·6] in the as-needed group, and 4·0 [1·5–5·7] in the placebo group), and number of participants reporting adverse events (99 [18·5%] in the regular group, 99 [18·7%] in the as-needed group, and 98 [18·5%] in the placebo group) were similar between groups. Our findings suggest that regular or as-needed dosing with paracetamol does not affect recovery time compared with placebo in low-back pain, and question the universal endorsement of paracetamol in this patient group. National Health and Medical Research Council of Australia and GlaxoSmithKline Australia.

To evaluate if adding esketamine and clonidine has positive effects on postoperative pain, postoperative nausea and vomiting, and quality of recovery in patients who are at high risk for postoperative pain. Patient- and assessor-blinded, superiority, randomised controlled trial. Single centre between 2022 and 2024. 125 adult patients, ASA I – II, planned for elective laparoscopic surgery and risk-classified as high risk of pain, based on perceived pain associated with venous cannulation. Patients were randomised to either an anaesthesia protocol, including an intravenous bolus of esketamine (0.25 mg.kg−1) after induction and clonidine (1 μg.kg−1) during maintenance phase (EC), or standard of care (SOC) no esketamine or clonidine included. Primary outcome: worst pain intensity in the PACU. Secondary outcomes: worst pain, and proportion having NRS ≥ 4, at 24 h (during rest and movement), worst pain and proportion having NRS ≥ 1, at 3- and 6-months (during rest and movement), postoperative recovery at 24 h, PONV in the PACU and at 24 h. Rescue dose opioids in the PACU was an exploratory outcome. Worst pain scores in the PACU were 5.7 in the EC group and 5.5 in SOC group (P = 0.78). After 24 h, no difference in postoperative pain (rest; 5.8 vs 6.1, P = 0.35, movement; 6.1 vs 6.2, P = 0.68), postoperative recovery (P = 0.92) or PONV (P = 0.80) was found. Proportion of patients with NRS ≥ 4 in the PACU was 50 % vs 48 % (P = 0.55) and at 24 h 73 % vs 81 % at rest (P = 0.27) and 76 % vs 81 % during movement (P = 0.50). Rescue opioids in the PACU were similar (5.9 mg vs 6.6 mg, P = 0.47). There were no differences in persistent pain at 3 or 6 months at rest (P = 0.72, P = 0.12) or movement (P = 0.48, P = 0.18). Adding esketamine and clonidine, as an individualised multimodal anaesthesia strategy, did not influence acute or persistent postoperative pain, early recovery, need of rescue opioids or PONV in patients, who were assessed as high risk for APOP. [Display omitted] •Adding esketamine and clonidine did not improve APOP in patients predicted as high-risk for postoperative pain.•Adding esketamine and clonidine did not improve recovery or PONV in patients predicted as high-risk for postoperative pain.•The pursuit for individualised anaesthesia and analgesia needs further refinement.

Postoperative pain is significant in cardiac surgical patients. Perioperative analgesia with intermittent administration of opioids can result in significant fluctuations in serum opioid concentrations. Methadone should provide a rapid onset and long-term pain relief upon a single intravenous dose at induction of anesthesia, and may reduce chronic postsurgical pain (CPSP) in cardiac surgical patients. The feasibility of using intravenous methadone in Chinese cardiac surgical patients, and its effect on acute and chronic pain management after cardiac surgery will be evaluated. A single-center, prospective, randomized-controlled pilot trial. Adult cardiac surgical patients will be randomized to receive 0.2 mg/kg methadone or morphine at induction of anesthesia. Patient-controlled analgesia morphine protocol, oral paracetamol and dihydrocodeine will be given for postoperative analgesia. Venous blood sampling for plasma methadone concentration will be obtained at regular intervals from study drug infusion to 96 hours after administration. The primary outcome will be a description of study feasibility, encompassing recruitment and retention, protocol adherence and stakeholder acceptability. Secondary outcomes include the time of ventilator weaning to spontaneous breathing, time of extubation, morphine requirements within 24 hours and 72 hours after surgery, time to first morphine rescue, postoperative pain scores, patient satisfaction, and length of stay in ICU and hospital. Opioid-related side effects including sedation, nausea and vomiting, and time to first bowel opening will be recorded. CPSP will be assessed with Neuropathic Pain Scale and Pain Catastrophizing Scale at 3 and 6 months after surgery. Randomized controlled trials on intravenous methadone in cardiac surgical patients are scarce, with none in Chinese populations. This study, supported by plasma methadone concentration analysis, will establish a basis for future large-scale research aimed at improving recovery through optimized pain management. ClinicalTrials.gov NCT05913284.

Purpose Paclitaxel is associated with an acute pain syndrome (P-APS- and chronic chemotherapy-induced peripheral neuropathy (CIPN). P-APS is associated with higher risk of CIPN. Omega-3 fatty acids have well-established anti-inflammatory and neuroprotective properties. The primary purpose of this pilot study was to assess whether omega-3 fatty acids could decrease P-APS and thus CIPN. Methods Patients scheduled to receive weekly paclitaxel for breast cancer were randomized to receive 4 g of omega-3 acid ethyl esters (Lovaza) or placebo, beginning 1 week prior and continued until paclitaxel was stopped. Patients completed acute pain questionnaires at baseline, daily after each treatment, and 1 month after completion of therapy. Results Sixty patients (49 evaluable) were randomized to treatment versus placebo. Seventeen (68.0%) patients receiving the omega-3 fatty acids intervention experienced P-APS, compared to 15 (62.5%) of those receiving placebo during the first week of treatment ( p = 0.77). Over the full 12-week study, 21 (84.0%) patients receiving the omega-3 fatty acid intervention experienced P-APS, compared to 21 (87.5%) of those receiving placebo ( p = 1.0). Secondary outcomes suggested that those in the intervention arm used more over-the-counter analgesics (OR: 1.65, 95% CI: 0.72–3.78, p = 0.23), used more opiates (OR: 2.06, 95% CI: 0.55–7.75, p = 0.28), and experienced higher levels of CIPN (12.8, 95% CI: 7.6–19.4 vs. 8.4, 95% CI: 4.6–13.2, p = 0.21). Conclusions The results of this pilot study do not support further study of the use of omega-3 fatty acids for the prevention of the P-APS and CIPN. Trial registration Number: NCT01821833

Adequate pain control is essential; however, acute pain is often undertreated in prehospital care. This study aimed to evaluate three analgesic regimens for treating acute pain in an ambulance setting. PreMeFen is a randomised, open-label, non-inferiority, three-arm, phase 3 trial conducted in the working areas of the ground ambulance service of the Innlandet Hospital Trust, Norway. Patients aged 18–69 years and 70 years and older with traumatic or medical acute pain scoring 4 or higher on the Numeric Rating Scale (NRS) were randomly assigned (1:1:1) to receive in titration doses 3 mL inhalational methoxyflurane, 50 μg or 100 μg intranasal fentanyl, or 0·05 mg/kg or 0·1 mg/kg intravenous morphine, respectively, depending on the age group. The primary endpoint was change in pain NRS score from baseline to 10 min after treatment start and was analysed per protocol. The non-inferiority margin was 1·3. This trial is registered with ClinicalTrials.gov (NCT05137184) and is completed. Between Nov 12, 2021, and April 22, 2023, 632 patients were assessed for eligibility, and 338 were randomly assigned to methoxyflurane (n=112), fentanyl (n=115), or morphine (n=111). 281 patients were included in the per-protocol population. 145 (52%) of 281 patients were female and 136 (48%) were male. Median age was 61 years (IQR 47–75). The baseline NRS score was 7·6 (SD 1·8). Mean NRS score changes after 10 min were –3·31 (SD 2·67) for methoxyflurane, –1·98 (2·28) for fentanyl, and –2·74 (2·12) for morphine. Comparing changes in mean NRS score while adjusting for baseline showed that methoxyflurane was non-inferior to fentanyl (–1·33 [95% CI –2·01 to –0·64]) and morphine (–0·36 [–1·03 to 0·31]). Intranasal fentanyl was not non-inferior to morphine at 10 min (0·91 [0·27 to 1·55]). Adverse events occurred in 26 (24%) of 109 patients in the morphine group, 27 (24%) of 112 in the fentanyl group, and 24 (22%) of 111 in the methoxyflurane group. Two serious adverse events, respiratory depression (grade 2) and loss of consciousness (grade 3), occurred in the same patient in the methoxyflurane group. There were no treatment-related deaths. Inhalational methoxyflurane is non-inferior to intranasal fentanyl and intravenous morphine for acute pain management in the prehospital environment, assessed 10 min after administration. Inhalational methoxyflurane serves as a valuable non-intravenous alternative in the early phase of treatment and might bridge the gap to longer-acting analgesics. Norwegian Air Ambulance Foundation and Innlandet Hospital Trust.

Background Acute lumbosacral radiculopathy from disc herniation is common and particularly painful. The challenge is to provide sufficient relief to patients until the natural regression of the herniated disc allows them to heal, primarily using conservative medical treatment combining physical measures, antinociceptive analgesics, and systemic anti-inflammatory drugs. Nerve root impingement is likely to cause acute neuropathic pain, which is not currently managed by standard conservative medical treatment. We hypothesised that a short course of gabapentin could improve pain management in acute lumbosacral radiculopathy from disc herniation. Methods The GRADE (Gabapentin versus placebo for the treatment of acute lumbosacral RAdicular pain caused by Disc hErniation) study is a prospective, randomized, multicenter, double-blind, superiority phase III trial comparing a 3-day regimen of gabapentin to placebo with a 1:1 ratio. Patients with acute lumbosacral radiculopathy from disc herniation with symptoms of less than 3 months are included in 6 centres in France. The primary outcome is the change in the radicular pain Visual Analogue Scale between Day 1 and Day 4. Intention-to-treat analysis will be applied primarily. Discussion Ethics approval was obtained from the committee for the protection of persons (Comité de Protection des Personnes Sud-Ouest et Outre-Mer 1: 1-21-023 ID 11548). The findings from this study, whether positive or negative, will be published in peer-reviewed journals and will be presented at national and international conferences. The results will inform future recommendations on the pain management in acute lomboradicular pain. Trial registration number EudraCT: 2020-002849-42 Clinicaltrials NCT04865042. 19 April 2021.