Clinicians on Sufentanil Sublingual Tablet Safety Study

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Dsuvia was approved by the Food and Drug Administration in November 2018
Dsuvia was approved by the Food and Drug Administration in November 2018

AcelRx announced results from a pooled analysis of clinical studies assessing the safety of sufentanil sublingual tablet (Dsuvia) for the short-term management of moderate-to-severe acute pain in medically supervised settings. The findings have been published in Pain Management.

The pooled analysis (N=804) evaluated clinical studies of sufentanil sublingual tablet (SST) at 30mcg dose equivalents over ≤72 hours for moderate-to-severe acute pain management in both postoperative and emergency room patients; a subset of postoperative patients from Phase 2/3 SST 15mcg studies who received 2 doses within 20-25 minutes of each other (30mcg dose-equivalent) were also included. 

Results showed that adverse events (AEs) were observed in 60.5% of patients in the SST group compared with 61.4% in the placebo group; 43.8% of patients who received SST experienced treatment-related AEs vs 33.5% of placebo patients (10.3% difference; 95% CI: 2.0–18.6). Nausea (28.5%), vomiting (6.5%), and headache (5.0%) were the most common treatment-related AEs reported. In a study involving 75 emergency room patients administered SST 30mcg, no evidence of cognitive impairment was observed following treatment. "Findings from the pooled analysis support that SST is well-tolerated, with most AEs considered mild or moderate in severity, for the treatment of moderate-to-severe acute pain in medically supervised settings," the authors reported.

The study also assessed the morphine equivalence of SST based on data from an active-comparator study (N=357) evaluating 2 patient-controlled analgesic (PCA) systems. The authors noted that "Within the first 5 hours after initiation of the first dose of treatment with SST 15mcg PCA or IV morphine PCA (the time during which active morphine metabolites will not yet have accumulated and exerted analgesic effects), SST 15mcg was calculated to be equal to approximately 2.5mg IV morphine based on drug utilization in each treatment group over this 5-hour period (or 5mg IV morphine for 30mcg SST)."

Dsuvia was approved by the Food and Drug Administration (FDA) in November 2018 for use in adults in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

“With the increasing demographic of patients with obesity or who are elderly, multiple IV attempts [for opioid analgesia] are often required, which increases discomfort, time and costs,” said Dr Pamela Palmer, CMO of AcelRx, discussing the differences between SST and morphine. “So there are multiple advantages to Dsuvia in medically supervised settings in the civilian environment in addition to the advantages in the battlefield.” SST development was partially supported by the Department of Defense to create a new treatment for battlefield analgesia.

Clinical Pain Advisor interviewed Pamela Palmer, MD, PhD, cofounder and chief medical officer of AcelRx, and James Miner, MD, professor of emergency medicine at the University of Minnesota Medical School, and first author on the article.

Clinical Pain Advisor: Could you elaborate on the benefits offered by DSUVIA compared with morphine and other narcotic analgesics?

Dr Palmer: Conventional opioid analgesia in medically supervised settings for the most part falls into 2 categories: intravenous (IV) opioids and oral (swallowed) opioids. DSUVIA uses a novel sublingual approach, as no other transmucosal opioid is approved for acute pain in patients who are not tolerant to nonopioid treatments. The sublingual route allows DSUVIA to provide rapid analgesia (within 15 minutes in an emergency department study conducted by AcelRx), and avoids the time, discomfort, and cost of setting up an IV line. Oral opioids have been shown to have a slower onset of action than transmucosal opioids or IV opioids, so they often are not used in the emergency department setting when a patient is in severe pain.   

The active drug in DSUVIA is sufentanil, which does not have any active metabolites, reducing the potential for delayed adverse effects, including nausea, vomiting, and respiratory depression. Active metabolites are an issue with morphine and hydromorphone (Dilaudid). Both of these commonly used IV opioids have active metabolites that are cleared by the kidney, so patients with renal impairment can be at risk for a higher rate of side effects with these medications because of delayed clearance of the metabolites. The label for DSUVIA states that sufentanil clearance is not affected by mild to moderate renal impairment. 

Therefore, DSUVIA is a simple, easy-to-use replacement for setting up an IV line and dosing with an IV opioid in emergency departments or any other short-term setting, such as same-day surgery, where getting on top of the patient's pain quickly is important for quality patient care and timely patient discharge.

DSUVIA development was partially supported by the Department of Defense as a new treatment for battlefield analgesia to replace intramuscular morphine. Infection, needle-stick injuries, and slow onset of analgesia complicate the use of intramuscular morphine dosing in the battlefield. 

Clinical Pain Advisor: Any thoughts on future directions for research in this area, particularly for your company?

Dr Palmer: We are planning to resubmit our second product candidate Zalviso® this year to the US Food and Drug Administration. Zalviso received a Complete Response Letter in 2014 and an additional study was completed, as it has been approved in the European Union since 2015. DSUVIA is also approved in the European Union as of 2018 (known as DZUVEO).

Clinical Pain Advisor: Any other advantages of DSUVIA you would like to mention?

Dr Palmer: Patient and nurse satisfaction from our clinical trials is high with DSUVIA. No one likes being stuck with a needle and with the increasing demographic of patients with obesity or who are elderly, multiple IV attempts are often required, which increases discomfort, time, and costs, especially if advanced techniques are required, such as ultrasound guidance. So there are multiple advantages to DSUVIA in medically supervised settings in the civilian environment in addition to the advantages in the battlefield.

Clinical Pain Advisor: What gaps does having sublingual sufentanil as an option fill in the treatment of postsurgical/acute pain? 

Dr Miner: My specialty is the emergency department, but the advantages are the same in both settings. DSUVIA allows a simple, straightforward, and noninvasive route of administration to be used in the place of an IV. The clinical trials show that results are comparable in the postoperative, emergency trauma, and injury contexts from an efficacy and safety standpoint. Given the statistical improvement in pain intensity within 15 minutes after dosing and an average duration of action as measured by the average redosing time of 3 hours, this analgesic profile is a nice fit for the short-term treatment of moderate to severe acute pain in a medically supervised setting. Intravenous morphine can have delayed onset of action given its prolonged blood/brain equilibration time of almost 3 hours. Intravenous fentanyl has an onset within minutes, but a short duration of action of around 30 minutes, and therefore requires frequent redosing.  

In the emergency department, we are always concerned about patient throughput, so that we are not faced with patients waiting for hours in the waiting room. I plan to use DSUVIA in place of intravenous opioids for patients for whom it is difficult to start IVs and in those who may not need an IV in the first place, for example, in patients who do not require IV hydration or antibiotics — these patients are being given an IV only for pain management.

Clinical Pain Advisor: How do your study results address safety concerns regarding misuse/abuse of fentanyl and its derivatives?

Dr Miner: DSUVIA is a schedule II drug and will be stored and disposed of similar to all other schedule II drugs in the hospital. Unlike IV opioids in the hospital, DSUVIA has a Risk Evaluation and Mitigations Strategy (REMS) program, which AcelRx and the US Food and Drug Administration defined jointly. The key aspect of the REMS program is that DSUVIA will only be distributed to REMS-certified medically supervised settings. Medically supervised settings must attest that DSUVIA will not be dispensed to patients for use outside of the certified setting.  

Importantly, the restricted distribution of DSUVIA mitigates the vast majority of the risks for diversion. Data from the most recent (2017) annual federal report from the Substance Abuse and Mental Health Services Administration show that only 0.5% of abused opioids are stolen from medically supervised settings. Therefore, limiting DSUVIA use to only these settings will help avoid the abuse that plagues the outpatient opioid products.

Clinical Pain Advisor: Anything else you would like to mention about DSUVIA?

Dr Miner: In my experience, dosing DSUVIA in the emergency department for the clinical trial, I was impressed with the lack of cognitive impairment. Based on the Six-Item Screener cognitive impairment measure, we found that more than 97% of patients had either the same or an improved score 1 hour after dosing compared with their predosing score. Having seen a significant degree of cognitive effects of IV morphine and IV hydromorphone in patients over the years, I welcome a noninvasive analgesic with minimal cognitive effects that will allow me to rapidly treat my patients who are in moderate to severe pain.

AcelRx announced results from a pooled analysis of clinical studies assessing the safety of sufentanil sublingual tablet (Dsuvia) for the short-term management of moderate-to-severe acute pain in medically supervised settings. The findings have been published in Pain Management.

The pooled analysis (N=804) evaluated clinical studies of sufentanil sublingual tablet (SST) at 30mcg dose equivalents over ≤72 hours for moderate-to-severe acute pain management in both postoperative and emergency room patients; a subset of postoperative patients from Phase 2/3 SST 15mcg studies who received 2 doses within 20-25 minutes of each other (30mcg dose-equivalent) were also included. 

Results showed that adverse events (AEs) were observed in 60.5% of patients in the SST group compared with 61.4% in the placebo group; 43.8% of patients who received SST experienced treatment-related AEs vs 33.5% of placebo patients (10.3% difference; 95% CI: 2.0–18.6). Nausea (28.5%), vomiting (6.5%), and headache (5.0%) were the most common treatment-related AEs reported. In a study involving 75 emergency room patients administered SST 30mcg, no evidence of cognitive impairment was observed following treatment. "Findings from the pooled analysis support that SST is well-tolerated, with most AEs considered mild or moderate in severity, for the treatment of moderate-to-severe acute pain in medically supervised settings," the authors reported.

The study also assessed the morphine equivalence of SST based on data from an active-comparator study (N=357) evaluating 2 patient-controlled analgesic (PCA) systems. The authors noted that "Within the first 5 hours after initiation of the first dose of treatment with SST 15mcg PCA or IV morphine PCA (the time during which active morphine metabolites will not yet have accumulated and exerted analgesic effects), SST 15mcg was calculated to be equal to approximately 2.5mg IV morphine based on drug utilization in each treatment group over this 5-hour period (or 5mg IV morphine for 30mcg SST)."

Dsuvia was approved by the Food and Drug Administration (FDA) in November 2018 for use in adults in a certified medically supervised healthcare setting, such as hospitals, surgical centers, and emergency departments, for the management of acute pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

For more information visit futuremedicine.com.

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