ARX-01 Sufentanil NanoTab® PCA System
Acute pain management in the hospital, in particular post-operative analgesia, remains a challenge for healthcare providers. The post-operative pain market in the United States, Europe and Japan is growing steadily and is expected to reach $6.5 billion by 2018, yet despite its size, the market remains underserved. Annually, approximately 16 million procedures requiring post-operative pain control using intravenous patient-controlled analgesia (IV PCA) are conducted in the United States and 5 main European countries (UK, France, Germany, Spain and Italy), typically utilizing morphine or hydromorphone1. Studies report that up to 75% of patients experience inadequate pain relief after surgery. Inadequate pain relief can lead to decreased mobility, which increases the risks of other medical complications, including deep vein thrombosis and partial lung collapse, and can result in extended hospital stays.
There are many deficiencies associated with the current use of IV PCA that can negatively impact patient safety, well-being and recovery, including:
- Side effects associated with the most commonly used opioid, morphine, and its active metabolites
- Infection risk, analgesic gaps and decreased mobility associated with the invasive nature of IV delivery, and
- Medication errors, which in some instances may be fatal, due to the complexity of IV PCA pumps. Many IV PCA medication errors are the result of human factors such as programming errors.
According to published literature, the estimated annual error rates are 407 errors per 10,000 people treated with IV PCA in the United States. The most common and serious types of errors involve human factors, such as mis-programming the PCA pump or administering the wrong dose3. In 2002 and 2003, approximately 5% of operator errors reported to the FDA resulted in patient deaths. Approximately 56,000 adverse events were reported to the FDA between 2005 and 2009, prompting 70 Class II infusion pump recalls of devices that could cause temporary or reversible adverse effects and 14 Class I infusion pump recalls of devices that could cause serious injury or death. These issues with infusion pumps have resulted in the issuance of new draft guidance by the FDA, significantly increasing the data required to be submitted by manufacturers to address safety problems.
ARX-01 has the potential to address many of the key disadvantages of IV PCA, including:
- Reducing the incidence of drug-related side effects,
- Eliminating the risk of IV PCA-related infections, reducing analgesic gaps and enhancing mobility, and
- Eliminating the risk of pump programming errors.
ARX-01 is designed to provide a favorable safety, efficacy and tolerability profile, enabling ARX-01 to become the new standard of care for patient-controlled analgesia. Use of ARX-01 may result in increased patient satisfaction and reduced overall healthcare costs.
Key Features and Potential Benefits of ARX-01 as Compared to IV PCA Standard of Care:
| Key Features and Potential Benefits of ARX-01 | Unmet Need with Current Standard of Care (IV PCA) |
|---|---|
| Sublingual route of delivery, eliminates the risk of IV-related analgesic gaps and the risk of IV complications.8 | IV catheters can become infiltrated, kinked or dislodged resulting in analgesic gaps and other complications.2 Peripheral IV catheters are associated with bacteremia and phlebitis.8 |
| Preprogrammed PCA system designed for sufentanil NanoTab delivery, eliminates the risk of pump programming errors. | Opioid analgesics are associated with a high rate of medication errors. Due to the narrow therapeutic window for opioids and the complexity of IV PCA, the potential for patient harm is high.3 The most common and serious types of errors involve human factors, such as mistakes in programming or administering the wrong drug or dose.3 |
| In three Phase 2 studies completed with sufentanil NanoTabs, the average time interval between doses was approximately 80 minutes. This compares favorably to the typical redosing intervals for IV PCA of 20-40 minutes. | Due to the brief duration of effective analgesia that results from each IV PCA dose, patients need to frequently re-dose to maintain analgesia. Based on the mean use of morphine during the first 24 hours of PCA use, a retrospective study of patients receiving IV PCA morphine suggested that patients needed to redose more frequently than every 20-40 minutes to maintain analgesia.4 We believe this can be demanding for patients and result in interruptions in analgesia, especially when patients fall asleep and wake up in pain. |
| In clinical studies, patients dosed with sufentanil NanoTabs exhibited a low incidence of somnolence and oxygen desaturation. | Published data indicates a much higher rate of somnolence (approximately 50%) and oxygen desaturation (approximately 10%) during standard IV PCA.5,6 More specifically, morphine can cause dysphoria in elderly patients and sedation is common in patients receiving morphine and hydromorphone.7 |
ARX-01 Development Status
AcelRx has reported positive results from three Phase 2 studies with sublingual sufentanil NanoTabs, including multicenter, double-blind, randomized, placebo-controlled, Phase 2 studies in patients undergoing elective unilateral knee replacement surgery and major abdominal surgery, and an open-label Phase 2 system functionality study of the handheld component of ARX-01 in unilateral knee replacement surgery (see publications and press releases). The primary efficacy endpoint in these studies was SPID-12 (a cumulative measure of the difference in pain intensity over the 12-hour study compared to baseline). The group treated with sufentanil NanoTabs 15 mcg showed a statistically significant reduction in pain intensity over the study period (p<0.02 for knee surgery and p<0.001 for abdominal surgery). The sufentanil NanoTab 10 mcg group also showed a statistical significant reduction in pain intensity and pain relief following abdominal surgery (p<0.001). In addition, at an End of Phase 2 meeting with FDA, AcelRx received guidance from the FDA on the path to approval for ARX-01.
References
1: Campbell Alliance analysis of post-operative pain market (analysis on file)
2: Panchal SJ, Damaraju CV, Nelson WW, Hewitt DJ, Schein JR. System-related events and analgesic gaps during postoperative pain management with the fentanyl iontophoretic transdermal system and morphine intravenous patient-controlled analgesia. Anesth Analg 2007;105:1437-41
3: Meissner B, Nelson W, Hicks R, Sikirica V, Gagne J, Schein J. The rate and costs attributable to intravenous patient-controlled analgesia errors. Hosp Pharm 2009;44:312-24.
4: Macintyre P.E, Jarvis D.A.Pain, 1996, 64:357-364
5: Dolin SJ and Cashman JN. Tolerability of acute postoperative pain management: nausea, vomiting, sedation, pruritis, and urinary retention: evidence from published data. Br J Anaesth 2005, 95 (5): 584–91
6: Cashman JN and Dolin SJ. Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data. Br J Anaesth. 2004, 93(2):212-23
7: Wheeler M, Oderda GM, Ashburn MA, Lipman AG. Adverse events associated with postoperative opioid analgesia: a systematic review. J Pain 2002;3:159-80.
8: Webster J, Osborne S, Rickard C, Hall J. Clinically-indicated replacement versus routine replacement of peripheral venous catheters. Cochrane Database Syst Rev 2010;3:CD007798.
9. Schein JR, Hicks RW, Nelson, WW, Sikirica V, Doyle DJ, Patient-controlled analgesia-related medication errors in the postoperative period: causes and prevention. Drug Safety 2009; 32(7):549-559
ARX-01 Publications and Press Releases
AcelRx reports positive Phase 1 results for ARX-01 at the American Society of Anesthesiologists (ASA) Annual Meeting in October 2009.
AcelRx reports positive Phase 2 results from a multicenter, double-blind, randomized, placebo-controlled, dose-finding study in patients undergoing elective unilateral knee replacement surgery.
AcelRx reports positive Phase 2 results from a multicenter, double-blind, randomized, placebo-controlled study in patients undergoing major abdominal surgery.
Sufentanil NanoTab PCA System has shown to be easy to use and highly reliable in an open-label Phase 2 study assessing the functionality of the handheld component