01. ARX-01 is a pre-programmed, handheld system that allows post-operative patients to self-dose with sublingual Sufentanil NanoTabs to manage their post-operative pain .
02. Mar 12: The first PIII double-blind RCT started Mar 12 (NCT01539642). 150 adults who have had open abdominal surgery will receive ARX-01 15mcg NanoTabs or placebo (2:1) for post-operative pain for a minimum of 48 hours and, as needed, up to 72 hours after randomization. The primary outcome is time-weighted summed pain intensity difference (SPID) over 48-hours. The study is due to complete Dec 12. The PIII programme includes a second RCT for post-operative pain control following major joint replacement surgery, and an open-label active-comparator study comparing ARX-01 to IV morphine PCA [1,2].
03. Apr 12: The second study has started. The multicentre, randomized, open-label study will compare the Sufentanil NanoTab PCA System to IV PCA with morphine, in the treatment of acute post-operative pain immediately after major abdominal or orthopaedic surgery in 400 patients. The primary objective is to demonstrate non-inferiority of ARX-01 as determined by patient global satisfaction with the method of pain relief. Patients will be treated for post-operative pain for a minimum of 48 hours after randomization. Top-line data expected in H2 2012.The third PIII study will start in the Q3 2012, will be an RCT comparing ARX-01 to placebo in treating post-operative pain following major joint replacement surgery .
04. Aug 2012: Dosing in third PIII study started. This third study will randomise 400 pts 3:1 to receive 15 mcg Sufentanil NanoTabs or placebo NanoTabs, both delivered via the ARX-01 system at a maximum dosing rate of one NanoTab every 20 minutes to control pain. Patients will be followed for a minimum of 48 hours and, as needed, up to 72 hours. The primary endpoint is the sum of the pain intensity difference to baseline, over the 48 hour study period, or SPID-48. Secondary endpoints include pain relief scores, patient global satisfaction ratings, and use of rescue medication. The ease of set up and operation of the ARX-01 system for nursing staff and patients, respectively, will also be measured through questionnaires. Topline results are expected to be available during the first quarter of 2013. 
05. Nov 12: Top line results from a PIII study reported. The randomized, open-label study enrolled 359 adult patients compared the ARX-01 sublingual Sufentanil NanoTab PCA System (15mcg/dose) vs IV PCA with morphine (1mg/dose) for the treatment of acute post-operative pain immediately following major abdominal or orthopaedic surgery. Patients were treated for a minimum of 48 hours and up to 72 hours. The Sufentanil NanoTab PCA System was non-inferior (p<0.001) to IV PCA morphine for the primary endpoint of PGA over the 48-hour study period as determined by the combined % of patients with PGA ratings of ‘good’ or ‘excellent’ (78.5% vs. 66.1% respectively) the non-inferiority assessment was based on a lower limit of -15% for the 95% CI around the difference between these percentages. The 95% CI was +3.2% to +21.6% for the 48 hour PGA and a statistical analysis for superiority could be performed. This found the NanoTab System was statistically superior to IV PCA morphine for the PGA endpoint (p=0.009). Similar number of patients dropped out of the study prematurely due to lack of efficacy (7.3% vs. 8.3% respectively) or due to an adverse event (7.9% vs. 11.1% respectively). Nurses setting up treatments and managing patients in the study reported a greater Overall Satisfaction (3.93 vs. 3.32 out of 5, p<0.001) and Overall Ease of Care (4.26 vs. 3.82, p=0.018) with the Sufentanil NanoTab PCA System. Likewise, patients in the study reported that they had greater Overall Satisfaction (4.15 vs. 3.83 out of 5, p=0.003) and greater Overall Ease of Care (4.45 vs. 4.07, p<0.001) with the NanoTab System 
06. Mar 13: Top-line data results reported from the first of two pivotal placebo-controlled PIII studies. The randomized, double-blind, placebo-controlled study enrolled 178 adult patients immediately following major abdominal surgery. Patients were treated for post-operative pain for a minimum of 48 hours, and up to 72 hours. Morphine was allowed as rescue medication; pre-rescue pain scores were imputed to minimize the impact of rescue opioid on efficacy evaluations. The primary endpoint was pain intensity over the 48-hour vs baseline (Summed Pain Intensity Difference [SPID-48]), which was significantly greater in patients receiving sufentanil NanoTabs (105.6 vs 55.6, p=0.001). SPID was also significantly greater in the sufentanil group at 24 and 72 hours (p<0.001 and p=0.004, respectively). 70.2% of the sufentanil group completed the 48-hour study period vs 51.7% of placebo patients. Reasons for drop-out in the sufentanil and placebo groups included adverse events (5.3% and 6.9%) and lack of efficacy (16.7% and 31.0%) .
07. May 13: Top-line data showed that primary efficacy endpoint was achieved in a placebo-controlled PIII study (n=426) of investigational sublingual Sufentanil NanoTab PCA System for treatment of moderate -to-severe acute pain immediately following major orthopaedic surgery. Pts were randomized 3:1, with 315 pts randomised to sufentanil treatment and 104 to placebo treatment; treated for a minimum of 48 hours, and up to 72 hours. Both treatments were delivered by the pt, as needed, using the NanoTab System with a 20-minute lock-out period. Results demonstrated that pts receiving sufentanil NanoTabs realized a significantly greater SPID-48 during the study period than placebo-treated pts (+76.1 vs -11.5, p<0.001). Secondary endpoint data showed that SPID at 24 hours and 72 hours was also significantly greater in the sufentanil-treated patients than in the placebo group (<0.001 in each case). Adverse events reported in the study were generally mild or moderate in nature and were similar in both placebo and treatment groups for the majority of adverse events .
08. Dec 13: AcelRx Pharmaceuticals has signed an agreement giving Germany´s Grünenthal European and Australian marketing rights 
09. Oct 14: Publication of Zalviso (sufentanil sublingual tablet system, SSTS) PIII trial (IAP310) which evaluated safety and efficacy in pts with post-operative pain following open abdominal surgery. Zalviso was better at managing pain over 48 hrs as measured by Summed Pain Intensity Difference to Baseline (SPID-48), than placebo (p=0.001). Treatment-related adverse events were similar between groups, with fewer Zalviso patients dropping out of the study due to inadequate analgesia compared to placebo (17.4% vs 31.8%; p=0.035) and using approximately half as much rescue morphine (1.8 doses vs. 3.8 doses).[13,14]
10. Jun 15: Results of PIII (n=419) trial published in Anesthesiology. Summed pain intensity difference from baseline to 48 hours was reported to be better in the sufentanil group compared with placebo (p<0.001), although patients on sufentanil reported a higher incidence of nausea and pruritus .
11. Nov 15: AcelRx pharmaceuticals present a subgroup analysis from three PIII studies at Obesity Week 2015 - titled "Efficacy and Safety of the Sufentanil Sublingual Tablet System (SSTS) in Class I and II Obese Patients: The Effect of BMI on Analgesic Response". Overall the data showed that Zalviso provides faster onset of pain relief in obese post-surgical pts vs. IV PCA of morphine. Significant differences in pain intensity were observed as early as 45 mins after the first dose (p<0.05), a trend that continued until 6 hours after the initial dose (p<0.001), after which time pain intensity scores equilibrated between the two groups. Results of the sub-group analysis also show that obese pts using Zalviso experienced statistically fewer adverse events than did those receiving IV PCA morphine. While overall adverse event rates were comparable, incidence rates of anaemia, leukocytosis (increase in white blood cells), vomiting, hypoalbuminaemia (decrease in albumin levels), hyponatraemia (decrease in sodium levels), urinary retention and pruritus (itching) were all significantly lower in the Zalviso arm compared to the morphine arm (p=0.05) .