EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial.

BACKGROUND: Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia. METHODS: In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22-89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22-28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987. FINDINGS: 92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores -2.29 [SD 1.75] vs -1.60 [1.66]; difference of adjusted least square means -0.69 [SE 0.25]; 95% CI -1.19 to -0.20; p=0.0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo. INTERPRETATION: EMA401 (100 mg twice daily) provides superior relief of postherpetic neuralgia compared with placebo at the end of 28 days of treatment. EMA401 was well tolerated by patients. FUNDING: Spinifex Pharmaceuticals.

Intravenous Oxycodone Versus Other Intravenous Strong Opioids for Acute Postoperative Pain Control: A Systematic Review of Randomized Controlled Trials.

INTRODUCTION: Optimal pain management is crucial to the postoperative recovery process. We aimed to evaluate the efficacy and safety of intravenous oxycodone with intravenous fentanyl, morphine, sufentanil, pethidine, and hydromorphone for acute postoperative pain. METHODS: A systematic literature search of PubMed, Cochrane Library, and EMBASE databases was performed for randomized controlled trials published from 2008 through 2017 (inclusive) that evaluated the acute postoperative analgesic efficacy of intravenous oxycodone against fentanyl, morphine, sufentanil, pethidine, and hydromorphone in adult patients (age ≥ 18 years). Outcomes examined included analgesic consumption, pain intensity levels, side effects, and patient satisfaction. RESULTS: Eleven studies were included in the review; six compared oxycodone with fentanyl, two compared oxycodone with morphine, and three compared oxycodone with sufentanil. There were no eligible studies comparing oxycodone with pethidine or hydromorphone. Overall, analgesic consumption was lower with oxycodone than with fentanyl or sufentanil. Oxycodone exhibited better analgesic efficacy than fentanyl and sufentanil, and comparable analgesic efficacy to morphine. In terms of safety, there was a tendency towards more side effects with oxycodone than with fentanyl, but the incidence of side effects with oxycodone was comparable to morphine and sufentanil. Where patient satisfaction was evaluated, higher satisfaction levels were observed with oxycodone than with sufentanil and comparable satisfaction was noted when comparing oxycodone with fentanyl. Patient satisfaction was not evaluated in the studies comparing oxycodone with morphine. CONCLUSIONS: Our findings suggest that intravenous oxycodone provides better analgesic efficacy than fentanyl and sufentanil, and comparable efficacy to morphine with less adverse events such as sedation. No studies comparing intravenous oxycodone with pethidine or hydromorphone were identified in this review. Better alignment of study methodologies for future research in this area is recommended to provide the best evidence base for a meta-analysis. FUNDING: Mundipharma Singapore Holding Pte Ltd, Singapore.

South African guideline for the use of chronic opioid therapy for chronic non-cancer pain.

Chronic pain may have a significant impact on health-related quality of life and can be difficult to manage. In carefully selected patients, and as part of a comprehensive pain management strategy, opioid analgesia may help to achieve long-term pain control with a manageable side-effect profile and a low risk of serious adverse effects. However, appropriate evaluation, including biopsychosocial screening and risk screening is essential before initiating an opioid and during continued therapy. This guideline aims to assist practitioners in screening and selecting appropriate patients with chronic non-cancer pain to initiate, monitor and continue pain management with opioid therapy.