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Opioids are a potential new treatment for severe restless legs syndrome. We investigated the efficacy and safety of a fixed-dose combination of prolonged release oxycodone–naloxone for patients with severe restless legs syndrome inadequately controlled by previous, mainly dopaminergic, treatment. This multicentre study consisted of a 12-week randomised, double-blind, placebo-controlled trial and 40-week open-label extension phase done at 55 sites in Austria, Germany, Spain, and Sweden. Patients had symptoms for at least 6 months and an International RLS Study Group severity rating scale sum score of at least 15; patients with severe chronic obstructive pulmonary disease or a history of sleep apnoea syndrome were excluded. Patients were randomly assigned (1:1) to either study drug or matched placebo with a validated interactive response technology system in block sizes of four. Study drug was oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated according to investigator's opinion to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day; in the extension, all patients started on oxycodone 5·0 mg, naloxone 2·5 mg, twice per day, which was up-titrated to a maximum of oxycodone 40 mg, naloxone 20 mg, twice per day. The primary outcome was mean change in severity of symptoms according to the International RLS Study Group severity rating scale sum score at 12 weeks. This study is registered with ClinicalTrials.gov (number NCT01112644) and with EudraCT (number 2009-011107-23). We screened 495 patients, of whom 306 were randomly assigned and 276 included in the primary analysis (132 to prolonged release oxycodone–naloxone vs 144 to placebo). 197 patients participated in the open-label extension. Mean International RLS Study Group rating scale sum score at randomisation was 31·6 (SD 4·5); mean change after 12 weeks was −16·5 (SD 11·3) in the prolonged release oxycodone–naloxone group and −9·4 (SD 10·9) in the placebo group (mean difference between groups at 12 weeks 8·15, 95% CI 5·46–10·85; p<0·0001). After the extension phase, mean sum score was 9·7 (SD 7·8). Treatment-related adverse events occurred in 109 of 150 (73%) patients in the prolonged release oxycodone–naloxone group and 66 of 154 (43%) in the placebo group during the double-blind phase; during the extension phase, 112 of 197 (57%) had treatment-related adverse events. Five of 306 (2%) patients had serious treatment-related adverse events when taking prolonged release oxycodone–naloxone (vomiting with concurrent duodenal ulcer, constipation, subileus, ileus, acute flank pain). Prolonged release oxycodone–naloxone was efficacious for short-term treatment of patients with severe restless legs syndrome inadequately controlled with previous treatment and the safety profile was as expected. Our study also provides evidence of open-label long-term efficacy of this treatment. Opioids can be used to treat patients with severe restless legs syndrome who have had no benefit with first-line drugs. Mundipharma Research.

Pain is a common non-motor symptom of Parkinson's disease. We investigated the analgesic efficacy of prolonged-release oxycodone–naloxone (OXN PR) in patients with Parkinson's disease and chronic, severe pain. We did this phase 2 study in 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK. We enrolled patients with Hoehn and Yahr Stage II–IV Parkinson's disease, at least one type of severe pain, and an average 24-h pain score of at least 6 (assessed on an 11-point rating scale from 0=no pain to 10=pain as bad as you can imagine). Participants were randomly assigned (1:1) with a validated automated system (block size four) to either oral OXN PR or placebo for 16 weeks (starting dose oxycodone 5 mg, naloxone 2·5 mg, twice daily). Patients and investigators were masked to treatment assignment. The primary endpoint was average 24-h pain score at 16 weeks in the full analysis population. This study is registered with EudraCT (2011-002901-31) and ClinicalTrials.gov (NCT01439100). We enrolled 202 patients; 93 were assigned to OXN PR and 109 to placebo; the full analysis population consisted of 88 patients versus 106 patients. Least squares mean average 24-h pain score at 16 weeks in the full analysis population was 5·0 (95% CI 4·5 to 5·5) in the OXN PR group versus 5·6 (5·1 to 6·0) in the placebo group (difference −0·6, 95% CI −1·3 to 0·0; p=0·058). Similar proportions of patients in each group had adverse events (60/92 [65%] vs 76/109 [70%]), treatment-related adverse events (52/92 [57%] vs 62/109 [57%]), and serious adverse events (5/92 [5%] vs 7/109 [6%]). Treatment-related nausea was more common in the OXN PR group than in the placebo group (16/92 [17%] vs 10/109 [9%]), as was treatment-related constipation (16/92 [17%] vs 6/109 [6%]). The primary endpoint, based on the full analysis population at week 16, was not significant. Nonetheless, the results of this study highlight the potential efficacy of OXN PR for patients with Parkinson's disease-related pain and might warrant further research on OXN PR in this setting. Mundipharma Research.

Ibudilast, a nonselective phosphodiesterase inhibitor, is used clinically in Asia for the treatment of asthma and poststroke dizziness. Recent preclinical studies have suggested that it also inhibits glial cell activation in rodents, and may alter opioid-mediated effects, including analgesia and withdrawal symptoms. The effects of ibudilast on the abuse potential of opioids in humans are largely unknown. The present study was designed to examine the influence of ibudilast on subjective (including drug craving), reinforcing, and analgesic effects of oxycodone in human volunteers diagnosed with opioid dependence (equivalent to moderate-severe opioid use disorder). Non-treatment-seeking opioid-dependent male volunteers (n=11) underwent an in-patient detoxification with morphine, followed by maintenance on placebo (0 mg b.i.d.) and active ibudilast (50 mg b.i.d.). Under each maintenance dose, six experimental sample and choice sessions were completed involving oral oxycodone administration (0, 15, and 30 mg/70 kg, p.o.). Subjective effects of oxycodone and drug craving were measured with visual analog scales (VAS) and a Drug Effects Questionnaire. The cold pressor test was used to produce pain, and a modified progressive-ratio choice procedure was used to measure the reinforcing effects of oxycodone. Under the active ibudilast condition compared with the placebo condition, ratings of drug liking following 15 mg of oxycodone were decreased significantly. The mean drug breakpoint value was also significantly lower in the active vs the placebo ibudilast condition under the 15 mg oxycodone condition, but not significantly lower under the 30 mg oxycodone condition. Heroin craving was significantly reduced under active ibudilast vs placebo, and similar effects were observed for tobacco and cocaine craving. Furthermore, mean subjective ratings of pain were lower in the active ibudilast condition. Our data suggest that ibudilast may be useful for treating opioid use disorders and it may enhance the analgesic effects of oxycodone.

The design of this study is to compare the effectiveness of two analgesic drugs in the intervention of pain events for patients on mechanical ventilation. 414 patients from three hospitals with respiratory failure requiring mechanical ventilation were randomly assigned to oxycodone hydrochloride or flurbiprofen axetil. The primary endpoints is the difference in the proportion of patients with a Behavioral Pain Scale (BPS) score > 5 within 48 h. The secondary endpoints is to compare the dosage of sedative drugs (midazolam, propofol, dexmedetomidine) and to assess the clinical outcomes such as duration of mechanical ventilation. There was no significant difference in BPS scores between the two groups at enrollment, and BPS scores in oxycodone group were significantly lower than those in flurbiprofen axetil group at 24 and 48 h of enrollment. The proportion of patients with BPS less than 5 points in the Oxycodone hydrochloride group was also significantly lower than that in the flurbiprofen axetil group. For patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score greater than 10, subgroup analysis showed that the mechanical ventilation time of oxycodone hydrochloride group was significantly lower than that of flurbiprofen axetil group with statistical significance, and the dosage of midazolam was significantly lower than that of flurbiprofen axetil group. The length of ICU stay was significantly lower than that of flurbiprofen axetil group. Oxycodone hydrochloride was more potent than flurbiprofen axetil for analgesia for patients with respiratory failure requiring mechanical ventilation.

A single-blind, randomized controlled trial comparing oxycodone and fentanyl for patient-controlled intravenous analgesia (PCIA) after laparoscopic hysteromyomectomy found comparable pain relief between the two groups. The study included 60 participants, with NRS scores for pain at rest and when moving showing no significant differences between oxycodone and fentanyl groups at various time points postoperatively. Self-rating depression scale scores were also similar between the groups at 48 h. However, patients’ satisfaction with PCIA was higher in the oxycodone group, with 73.3% reporting being very satisfied compared to 36.7% in the fentanyl group. Additionally, the oxycodone group had fewer incidences of headaches within 48 h postoperatively compared to the fentanyl group. These findings suggest that oxycodone may offer comparable pain relief, higher patient satisfaction, and fewer headaches for patients undergoing laparoscopic hysteromyomectomy compared to fentanyl, making it a suitable option for postoperative pain management in this population. Clinical trial registration number The study was registered with CHICTR.org, ChiCTR2100051924.

Emergence agitation (EA) is more commonly observed after thoracic surgeries and can lead to serious complications. This study aimed to evaluate the effectiveness of serratus anterior plane block (SAPB) combined with oxycodone for transitional analgesia in preventing EA after video-assisted thoracoscopic surgery (VATS). A total of 121 adult patients scheduled for VATS under one-lung ventilation anesthesia were enrolled and randomly divided into three groups: preoperative SAPB without opioids for transitional analgesia near the end of the surgery (SAPB + SAL group, n  = 39); preoperative SAPB with sufentanil at 0.1 µg/kg for transitional analgesia (SAPB + SF group, n  = 42); and preoperative SAPB with oxycodone at 0.1 mg/kg for transitional analgesia (SAPB + OCD group, n  = 40). In primary outcomes, the incidences of EA in the SAPB + SAL, SAPB + SF, and SAPB + OCD groups were 38.5%, 28.6%, and 7.5% respectively. There was a statistically significant difference in EA incidence between the SAPB + OCD and SAPB + SF groups ( P  = 0.0136). In secondary outcomes, compared to the SAPB + SF group, the SAPB + OCD group experienced shorter tracheal extubation time [15(9, 25) min vs. 21.5(14.5, 32.5) min; P  = 0.0473] and PACU stay [67.5(55.0, 85.0) min vs. 87.5(70.0, 110.0) min; P  = 0.0026]; lower NRS scores at 15 min and 2 h post-extubation ( P  < 0.01), and higher Quality of Recovery-15 (QoR-15) scores post-surgery [113(98, 123) vs. 102(88, 112); P  = 0.0122]. Our results suggest SAPB combined with oxycodone for transitional analgesia, compared with sufentanil, is more effective in preventing EA after VATS and conductive to rapid recovery postoperatively. Trial registration: Chinese Clinical Trial Registry, identifier: ChiCTR2300077473, Date: 09/11/2023.

Patients undergoing thoracoscopic lobectomy often experience significant postoperative pain, which is frequently inadequately managed in elderly patients due to their unique physiological characteristics. Multimodal preventive analgesia has been shown to provide satisfactory pain relief and promote early recovery. The objective is to optimize perioperative pain management in elderly patients by multimodal preventive analgesia through a combination of serratus anterior plane block (SAPB) and oxycodone. A total of 80 elderly patients with lung cancer undergoing elective uniportal video-assisted thoracoscopic lobectomy under general anesthesia were enrolled, classified as American Society of Anesthesiologists (ASA) II or III, were randomly assigned to four groups. Group M1 received ultrasound-guided SAPB with 0.375% ropivacaine combined with intravenous oxycodone. Group M2 received intravenous oxycodone. Group M3 received SAPB, while the control group (Group C) was included for comparison. The primary outcome measures included the Visual Analogue Scale (VAS) scores at rest and during coughing immediately after postoperative tracheal extubation. Secondary outcome measures comprised VAS scores at rest and during coughing at 6 h, 24 h, 48 h, and 72 h postoperatively; intraoperative remifentanil consumption; number of activations of the Patient-Controlled Intravenous Analgesia (PCIA) pump; frequency and dosage of rescue analgesia; intraoperative vasoactive drug consumption; and incidence of postoperative adverse events. The experimental groups had significantly lower VAS scores compared to the control group at all measured time points. In the M1 group, VAS scores at 6 h and 24 h after surgery were significantly lower than those in the other two experimental groups. The secondary outcomes are statistically significant differences among the four groups. Multimodal preventive analgesia based on SAPB and oxycodone can effectively reduce perioperative pain in elderly patients undergoing thoracoscopic lobectomy, decrease intraoperative and postoperative opioid consumption, and facilitate recovery. Trial registration: ChiCTR2400088399.

Background Obese patients undergoing laparoscopic sleeve gastrectomy (LSG) are particularly at risk of opioid-related side effects. To reduce patient exposure to opioids, multimodal analgesia, which involves the use of drugs of different classes, may be utilized. One of the drugs under consideration is pregabalin. Despite an opioid-sparing potential, few studies assess the role of pregabalin as an element of multimodal analgesia in LSG. Considering the limited number and inconsistent results of available studies, we decided to conduct a randomized, prospective study on the effect of preemptive pregabalin administration in obese patients on opioid consumption, pain scores, the incidence of opioid side effects, and hemodynamical stability. Methods The study is designed as a prospective randomized controlled trial with double-blinding. Randomization will be performed in a block with a parallel 1:1 allocation. The intervention will involve receiving a pregabalin 150 mg capsule 1–2 h before the surgery, whereas the control group will receive an identically looking placebo. The primary outcome measure will be total oxycodone consumption in the first 24 h following surgery. Secondary outcome measures will be pain severity assessed using the Numerical Rating Scale (NRS) 1, 6, 12, and 24 h after surgery, postoperative sedation on the Ramsay scale, PONV impact scale, the incidence of desaturation episodes < 94%, and episodes of blurred vision at 1, 6, 12, and 24 h after surgery, intraoperative hemodynamic parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), total fluid volume, and total ephedrine dose. Patient comfort will be additionally assessed using the QoR-40 questionnaire at discharge. Discussion The study will explore the efficacy and safety of preemptive pregabalin in a dose of 150 mg as a co-analgesic used in multimodal analgesia for LSG. As studies on opioid-sparing regimes concern the safety of obese patients, we aim to contribute objective data with a relatively large study sample size. The result of the present clinical trial may support the reassessment of recommendations to use pregabalin in the studied population. Trial registration ClinicalTrials.gov NCT05804591. Registered on 07.04.2023.

Objective: An examination of whether oxycodone/naloxone prolonged-release tablets (OXN PR) can improve constipation and maintain analgesia, compared with oxycodone prolonged-release tablets (OxyPR) in patients with moderate/severe cancer pain. Methods: Randomized, double-blind, active-controlled, double-dummy, parallel-group study in which 185 patients were randomized to receive up to 120 mg/day of OXN PR or OxyPR over 4 weeks. Efficacy assessments included Bowel Function Index (BFI), Brief Pain Inventory Short-Form (BPI-SF), laxative and rescue medication use. Quality of life (QoL) and safety assessments were conducted. Results: After 4 weeks, mean BFI score was significantly lower with OXN PR; mean total laxative intake was 20% lower with OXN PR. Mean BPI-SF scores were similar for both treatments and the average rate of analgesic rescue medication use was low and comparable. QoL assessments were stable and comparable with greater improvements in constipation-specific QoL assessments with OXN PR. Overall, rates of adverse drug reactions were similar. Conclusions: OXN PR provides superior bowel function in cancer pain patients, compared with OxyPR, without compromising analgesic efficacy or safety. This study confirms that OXN PR is well tolerated and efficacious in cancer pain patients and results are in line with those seen in non-malignant pain patients.

Background and objectivesMotor-sparing peripheral nerve blocks enhance multimodal opioid-sparing strategies after total knee arthroplasty. We hypothesized that adding a popliteal plexus block to a femoral triangle block could reduce 24-hour opioid consumption after total knee arthroplasty, compared with standalone femoral triangle block or adductor canal block.MethodsThis patient- and assessor-blinded, randomized controlled trial allocated 165 patients into three equally sized parallel groups, receiving either 1) popliteal plexus block+femoral triangle block, 2) femoral triangle block, or 3) adductor canal block. Intravenous oxycodone was administered via patient-controlled analgesia pumps. The primary outcome was 24-hour postoperative opioid consumption. Secondary outcomes were preoperative maximum voluntary isometric contraction and manual muscle tests of knee and ankle movement assessed before and after the nerve block procedure together with postoperative pain scores, mobilization, and 12-hour opioid consumption.Results24-hour postoperative intravenous oxycodone consumption varied significantly between groups (p<0.01), with medians (IQR) of 6 mg (2–12) in the popliteal plexus block+femoral triangle block group, 10 mg (8–16) in the femoral triangle block group, and 12 mg (6–18) in the adductor canal block group. Median consumption in the popliteal plexus block+femoral triangle block group was reduced by −4 mg (95% CI −7.4 to –1.0, p<0.01) and −6 mg (95% CI −8.3 to –1.3, p=0.01) compared with groups of femoral triangle block and adductor canal block, respectively. No differences were found in pain scores, mobilization, or changes in preoperative muscle strength. Post hoc analysis revealed successful 24-hour opioid-free postoperative care among 12 patients with popliteal plexus block+femoral triangle block, as compared with two with femoral triangle block and six with adductor canal block.ConclusionAdding a popliteal plexus block to a femoral triangle block resulted in a statistically significant reduction of 24-hour postoperative opioid consumption after total knee arthroplasty. However, no differences were found in pain scores. Popliteal plexus block did not impair the lower leg muscles.