Conditions: Spine Fusion Pain, Postoperative Opioid Use
Keywords: sufentanil SL Postoperative Pain Spine Surgery
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 199
Healthy volunteers: no

Brief summary:
In this study the investigators plan to examine the perioperative use of sufentanil sublingual (SL) in the analgesic regimen for spine surgery, one of the most common surgeries performed in the US. Patients undergoing spinal fusion surgery often experience severe pain during the first three postoperative days. Currently, no data are available for this patient population which routinely experiences moderate to severe acute pain. The investigators will analyze whether sufentanil SL is associated with lower opioid consumption in the post anesthesia care unit and pain scores.

Detailed description:
Sufentanil, unlike morphine and hydromorphone, avoids the issue of active metabolites that can lead to prolonged, untoward effects, which can complicate postoperative care and affect patient discharge. One study found that sufentanil SL 30 mcg was well tolerated, with no unexpected adverse events, no clinically meaningful vital sign changes, and a safety profile that was as expected for this postoperative patient population. In addition, the use of sufentanil SL in the emergency department indicates that sufentanil SL was a potentially feasible option for managing moderate-to-severe acute pain in that setting. Another study of adult patients undergoing major surgery in five hospitals in the Netherlands who received the sufentanil SL for postoperative pain relief as part of multimodal pain management showed that sufentanil SL effectively managed postoperative pain in abdominal and orthopedic surgeries. Finally, a randomized, open-label non-inferiority study that enrolled patients scheduled for elective major open abdominal or orthopedic surgery assessed the proportion of patients who responded "good" or "excellent" at the 48-hour timepoint on the Patient Global Assessment of method of pain control. The results showed that 78.5% vs. 65.6% of patients achieved "success" for sufentanil SL vs. intravenous patient-controlled analgesia (morphine), respectively, demonstrating non-inferiority as well as statistical superiority for treatment effect. Patients using sufentanil SL reported more rapid onset of analgesia and patient and nurse ease of care and satisfaction scores were higher than intravenous patient-controlled analgesia (morphine). Adverse events were similar between the 2 groups, and sufentanil SL had fewer patients experiencing oxygen desaturations below 95% compared to intravenous patient-controlled analgesia (morphine). Future studies are needed to determine patient populations that benefit most from the sufentanil SL, assess the added values versus intravenous patient-controlled analgesia, and determine the pharmacoeconomics of the system.

Purpose:

In this study the investigators plan to examine the perioperative use sufentanil SL in the analgesic regimen for spine surgery, one of the most common surgeries performed in the United States. Patients undergoing spinal fusion surgery often experience severe pain during the first three postoperative days. Currently, no data are available for this patient population which routinely experiences moderate to severe acute pain. The investigators will analyze whether sufentanil SL is associated with lower opioid consumption, number of fentanyl boluses given, post-anesthesia care unit and hospital length of stay, side effects of opioid use (i.e., nausea, vomiting, constipation), and hospitalization costs (i.e., pharmacoeconomics).

Hypotheses:

1. The perioperative use of sufentanil SL 30 mcg in a prospective cohort of patients undergoing spine surgery will be associated with lower postoperative numeric rating scale pain scores (numerical rating score (NRS); primary outcome) than observed in two historical control groups that did not receive sufentanil SL: one group that received intraoperative remifentanil infusion and one that received intraoperative sufentanil infusion.
2. The perioperative use of sufentanil SL will be associated with lower opioid consumption, number of fentanyl boluses given, post-anesthesia care unit length of stay than observed in two historical control groups of patients receiving remifentanil or sufentanil infusions without perioperative sufentanil SL.

Methods:

The study design is a prospective cohort study with historical controls. There will be 1 prospectively recruited study arm (30 patients receiving the study drug sufentanil SL) and 2 historical control arms (one that received an intraoperative remifentanil infusion, 80 patients, and the other that received an intraoperative sufentanil infusion, 80 patients, both without sufentanil SL).

Inclusion criteria include patients undergoing spine surgery (1- 3 levels) who are opioid-naïve, 18-75 years old, considered American Society of Anesthesiologists (ASA) physical status 1-3 and also includes patients with impaired renal function.

Exclusion criteria include those with microdiscectomy, have chronic opiate use, significant respiratory depression, acute or severe bronchial asthma, chronic lung disease, known or suspected gastrointestinal obstruction including paralytic ileus, liver disease ((defined as alkaline phosphatase (ALP) \> 56, aspartate aminotransferase (AST)\> 100), known allergy or hypersensitivity to sufentanil or its components, baseline dementia, serotonin syndrome, adrenal insufficiency, severe hypotension, increased intracranial pressure, brain tumors, head injury, impaired consciousness, malignant hyperthermia, ASA physical status \>3, age \>75, and pregnant patients.

Outcomes:

Primary:

Pain scores in post-anesthesia care unit (PACU)

Secondary:

Length of stay: PACU Length of stay: inpatient Hospital stay Pain scores: inpatient Hospital stay Opioid consumption: PACU Opioid consumption: inpatient Hospital stay

As shown above, the above primary and secondary outcomes will also be collected in the prospective cohort to obtain estimates that can be used to power future randomized controlled trials.

Safety assessments will include adverse events and use of concomitant medications, periodic monitoring of vital signs (blood pressure, heart rate, and respiratory rate), and continuous monitoring of oxygen saturation in the post-anesthesia care unit.

Intraoperative Management:

The prospective study arm will receive general endotracheal anesthesia consisting of total intravenous anesthesia maintained with continued infusions of propofol (80-200 mcg/kg/min) and sufentanil (0.2-0.3mcg/kg/hr). Anesthesia induction will be achieved with propofol (1.5-2.5mg/kg), succinylcholine (1mg/kg), and sufentanil (10-20 mcg). The study group will receive sufentanil SL 30 mcg at surgery end, but prior to emergence from anesthesia, and after the patient is turned supine. Antiemetic prophylaxis will be administered (ondansetron).

Postoperative Management:

Note that sufentanil SL will be ordered as q1hr prn, meaning that repeat doses must be administered at least 1 hr apart.

In the post-anesthesia care unit, patients will be ordered to receive sufentanil SL 30 mcg prn 1 hr for breakthrough pain (for numerical rating scale, NRS \> 3) as the 1st line analgesic, with hydromorphone as the rescue analgesic if the patient is still experiencing pain (NRS \>3). The following opioid administration schema will be used for pain management in the post-anesthesia care unit:

* 1st line: sufentanil SL 30mcg (NRS \>3). 2nd line: hydromorphone 0.2-0.6 mg (NRS \>3)
* If upon arrival to the PACU the patient is still experiencing pain with NRS \>3 but cannot yet receive a repeat dose of sufentanil SL (because of having received 1st dose in the operating room less than 1 hour ago), then the patient can receive hydromorphone 0.2-0.6 mg prn until eligible to receive sufentanil SL.
* If at any time the patient's NRS \>3 after 20 min following an administration of either sufentanil SL or fentanyl, the patient can receive a repeat dose of fentanyl until again eligible to receive sufentanil SL.

Once the patient is transferred to the floor, both groups will receive the standard of care postoperative pain management orders (ie oral and intravenous prn analgesia for NRS \> 3).

Sample Size/Statistical analysis:

Assuming a within-group standard deviation in post-anesthesia care unit NRS pain score of 2.5 points, enrollment of 30 patients in the prospective group and inclusion of at least 80 patients in each retrospective control group will provide at least 80% power at a two sided alpha level of 0.025 (0.05/2 pair-wise comparisons) to detect a minimal clinically important difference of 2 points between the prospective group and each of the retrospective groups using linear regression.

All outcomes will be compared between the prospective group and each of the retrospective groups using linear regression weighted by inverse probability of treatment weights. Probability of treatment (i.e., propensity scores) will be calculated using logistic regression with the following covariates: age, sex, body mass index, American Society of Anesthesiologists class, surgical invasiveness tier, reoperation, history of anxiety, anxiolytic use, history of depression, and antidepressant use.

Arms:
arm 1: Each patient will receive 30mcg of sufentanil SL prior to extubation in the operating room, and then as needed in the recovery room, guided by pain scores.

Interventions: intervention 1: Sublingual Tablet
Intervention descriptions: intervention 1: sufentanil SL 30mcg administered sublingually to patients undergoing spine surgery before extubation and during recovery

Protocol document:
Prot_SAP_000.pdf: 
 
1
Full Proposal 
Study Title: Use of Dsuvia in Patients Undergoing Spine Surgery 
Version Date: 10/28/2022 
 
Background: 
Dsuvia is a novel drug recently approved by the FDA (2018) for moderate to severe acute pain. It 
has a unique mode of delivery as a small sublingual tablet (Figure 1), and there is evidence to 
suggest it may provide significant benefit to surgical patients with moderate to severe pain. Based 
on published data as well as recently completed studies, there is strong evidence to suggest that DSUVIA 
can decrease other opioid consumption including long-acting opioids in major surgery, provide better 
pain control, and decrease PACU length of stay and earlier discharges. 
 
Sufentanil, unlike morphine and hydromorphone, avoids the issue of active metabolites that can 
lead to prolonged, untoward effects, which can complicate postoperative care and affect patient 
discharge. A study by Minkowitz et al1 found that sufentanil sublingual tablet (SST, Disuvia) 30 
mcg was well tolerated, with no unexpected adverse events, no clinically meaningful vital sign 
changes, and a safety profile that was as expected for this postoperative patient population. In 
addition, Miner et al2 studied the use of SST in the emergency department and found that SST 
was a potentially feasible option for managing moderate-to-severe acute pain in that setting. A 
study by Meijir et al3 studied adult patients undergoing major surgery in five hospitals in the 
Netherlands who received the SSTS for postoperative pain relief as part of multimodal pain 
management. The authors showed that the SSTS effectively managed postoperative pain in 
abdominal and orthopedic surgeries. A study by Melson et al4,  a randomized, open-label 


 
2
noninferiority study that enrolled patients scheduled for elective major open abdominal or 
orthopedic surgery assessed the proportion of patients who responded “good” or “excellent” at 
the 48-hour timepoint on the Patient Global Assessment (PGA48) of method of pain control. The 
results showed that 78.5% vs. 65.6% of patients achieved PGA48 "success" for SSTS vs. IV 
PCA morphine, respectively, demonstrating non-inferiority as well as statistical superiority for 
treatment effect. Patients using SSTS reported more rapid onset of analgesia and patient and 
nurse ease of care and satisfaction scores were higher than IV PCA morphine. Adverse events 
were similar between the 2 groups, and SSTS had fewer patients experiencing oxygen 
desaturations below 95% compared to IV PCA morphine Future studies are needed to determine 
patient populations that benefit most from the SSTS, assess the added values versus 
intravenous patient-controlled analgesia, and determine the pharmacoeconomics of the system3. 
 
More recently, a study by Cassavaugh K et al.5 analyzed data from a hospital comparing 140 
DSUVIA-treated patients with 157 matched historical controls. DSUVIA was dosed either 30 minutes 
before the end of surgery for longer surgeries or just prior to induction for shorter surgeries. Patients were 
a combination of inpatient and outpatients (same-day surgery). The data shows an overall 56% decrease 
in PACU IV morphine milligram equivalents (mean MME ± SE) opioid requirements compared to 
control group receiving typical IV opioids (8.1 ± 0.5 to 3.6 ± 0.4; p<0.001). The PACU Phase 1 discharge 
time also was significantly decreased compared to the control group (80 ± 2 min vs 66 ± 2 min; p<0.001). 
From a safety perspective, 3 patients out of 157 required naloxone in the PACU to reverse respiratory 
depression in the control group and no naloxone was required in the DSUVIA group. PACU time is 
estimated to cost between $6-$8 per minute, therefore the time saved more than pays for the drug and can 
increase efficiency and possibly caseload. The investigator’s conclusion is that DSUVIA is a high 
therapeutic index opioid that has an extended duration of action into the PACU period thereby either 


 
3
avoiding opioids completely in the PACU in many patients (48.5% of patients in the DSUVIA group vs 
16.6% of patients in the control group), or significantly decreasing the amount of IV opioids required in 
the PACU and therefore decreasing PACU discharge time.  
 
Another recent study, by Tvetenstrand CD et al.6 was conducted in a hospital with ambulatory 
abdominal surgery patients with DSUVIA dosed 30 minutes prior to induction. A total of 47 
patients were in the DSUVIA arm and 81 matched historical controls were compared. This study 
showed a decrease in overall IV opioid requirements  and a decreased Phase 1 PACU time.  No 
patients required naloxone for respiratory depression in either group.  
 
Sufentanil is a drug with a rapid onset (15 min) and high potency (30 mg= morphine 5mg) (pka 
= 8.0 and solubility coefficient greater than 2000). It is highly bioavailable and highly lipophilic 
with a high therapeutic opioid index (LD50/ED50). It has a much lower Cmax compared with IV 
sufentanil. It reaches 70 % Cmax in 30 minutes, lasting as long as 3 hours. Based on existing 
outcomes data, we hypothesize that there will be a clinically significant difference in spine 
surgery patients as compared to the historical controls. 
 
Purpose:   
In this study we plan to examine the perioperative use of Dsuvia (sufentanil SL; FDA approval 
2018) in the analgesic regimen for spine surgery, one of the most common surgeries performed 
in the US. Patients undergoing spinal fusion surgery often experience significant pain during the 
first three postoperative days7. Currently, no data are available for this patient population which 
routinely experiences moderate to severe acute pain requiring significant opioid use.  We will 
analyze whether Dsuvia (sufentanil SL) is associated with lower pain scores, frequency of rescue 


 
4
opioids, lower overall opioid consumption, PACU and hospital length of stay, and side effects of 
opioid use (i.e., nausea, vomiting, constipation, respiratory effects).  
 
Hypotheses:  
1. The perioperative use of Dsuvia 30 mcg SL in a prospectively recruited cohort of patients 
undergoing spine surgery will be associated with lower postoperative numeric rating 
scale pain scores (NRS; primary outcome) than observed in two historical control groups 
that did not receive Dsuvia: one group that received intraoperative remifentanil infusion 
and one that received intraoperative sufentanil infusion. 
 
2. The perioperative use of Dsuvia (sufentanil SL) will be associated with lower overall 
opioid consumption, lower frequency of rescue opioids, lower PACU and hospital length 
of stay, and fewer side effects of opioid use (i.e., nausea, vomiting, constipation, 
respiratory complications) than observed in two historical control groups of patients 
receiving remifentanil or sufentanil infusions without perioperative Dsuvia.  
 
Methods: 
The study design is an Observational Longitudinal (OL) study with historical controls. There will 
be 1 prospectively recruited study arm (patients receiving the study drug Dsuvia) and 2 historical 
control arms (one that received an intraoperative remifentanil infusion and the other that received 
an intraoperative sufentanil infusion, both without Dsuvia). 
 
 
Inclusion criteria:  


 
5
Patients undergoing spine surgery (1-3 levels) who are opioid-naïve (no opioid use 30 days prior 
to surgery), 18-75 years old, ASA physical status 1-3.   
 
Exclusion criteria: 
Microdiscectomy, chronic opioid users, significant respiratory depression, acute or severe 
bronchial asthma, chronic lung disease,  known or suspected gastrointestinal obstruction 
including paralytic ileus, liver disease (defined as alkaline phosphatase (ALP) > 56, aspartate 
aminotransferase (AST)> 100), known allergy or hypersensitivity to sufentanil or its 
components, baseline dementia, serotonin syndrome, adrenal insufficiency, severe hypotension, 
increased intracranial pressure, brain tumors, head injury, impaired consciousness, malignant 
hyperthermia, ASA physical status >3, age >75, pregnant patients. 
 
IV. STUDY SCHEMA: 
 
Patients undergoing spine surgery (1 or more levels) 
 
 
Observational Longitudinal (Study) ARM 
 
RETROSPECTIVE (Control) ARM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Preoperative Phase  
 
 
 intraoperative sufentanil infusion (80 pts) 
 
 
 
 
 
 
 
 
and 
 
 
 
 
 
 
 intraoperative remifentanil infusion (80 pts) 
Screening for Eligibility Criteria: 
informed consent 
demographics 
history and physical 
concomitant medications 
 
 
 
 
 
Patient Recruitment (ie. Study Arm, target: 25pts) 
 
 
 
 
 
 
 
 


 
6
             
Dsuvia 30mcg SL 
 
 
 
 
 
 
 
 
 
 
 
Intraoperative Phase 
General endotracheal anesthesia (TIVA with propofol/sufentanil) 
Standardized anesthetic technique (see protocol below) 
Dsuvia x1 prior to emergence from anesthesia  
 
 
Postoperative Phase 
Pain scores (NRS) q15 min up to 2 hrs 
Concomitant Medication use/opioid consumption 
Dsuvia prn q1hr as 1st line (NRS >3); Fentanyl prn as 2nd line, or 1st  
line if repeat Dsuvia cannot yet be given and NRS is >3 (see PACU schema below) 
 
Up to 3 doses of Dsuvia may be administered in the PACU (each at least 1 hr apart) 
 
 
Hospitalization Phase 
Follow up during inpatient hospital stay 
Concomitant Medication use/pain scores 
Both arms: standard of care analgesia (PO and IV prn) 
Quality of Recovery (QoR); patient satisfaction (study arm only) 
 
 
Post-discharge Phase 
Follow up following discharge  
Prescription opioid use 
 
 
 
Outcomes:  
 
Primary:  
Mean postoperative pain scores (PACU) 
 
Secondary:  
Mean postoperative pain scores (inpatient) 
opioid consumption (MMEs, PACU and inpatient) 
Frequency of opioid rescue medications given 
PACU LOS (min) 
hospital LOS (days)  
nausea, vomiting, constipation, respiratory events 
sedation level (PACU)  
quality of recovery (QoR 15)  
utilization of prescription opioids following discharge  


 
7
 
 
As shown above, the following secondary outcomes will also be collected in the Study cohort to 
obtain estimates that can be used to power future randomized controlled trials: sedation level, 
quality of recovery (QoR-15)8, patient satisfaction score (satisfaction with the level of pain 
control, 6-point scale4), and utilization of prescription opioids following discharge.   
 
Safety assessments will include adverse events (AEs) and use of concomitant medications, 
periodic monitoring of vital signs (blood pressure, heart rate, and respiratory rate), and 
continuous monitoring of oxygen saturation in the PACU. 
 
Detailed Clinical Protocol 
Preoperative:  
The surgeon will approach the patient and introduce the study and one of the investigators will 
explain the study to the patient. The surgeon will assess subject at their visit. At this visit, the 
surgeons will identify any patients that may benefit from Dsuvia. The information will be 
provided to one of the investigators. The investigator will subsequently review their eligibility 
and inclusion criteria. If the subject continues to meet all the criteria, the investigator will explain 
the study with the patient. Thereafter the patients will be provided the consent forms for their 
review and a 24/7 contact number for any questions regarding this study. All patient questions 
will be answered and informed consent will be obtained by one of the investigators who is a 
licensed physician listed on the protocol. The patient will be provided contact information. A co-
investigator will be available to answer 


 
8
questions on a 24 hour basis. It will be explained to the patient that they will be permitted to 
withdraw from the study at any time for any reason until their day of surgery. On arrival at the 
preoperative area, the patient will be assigned a code by one of the investigators. Prior to 
premedication, all patients will be made familiar with the use of numeric rating scale (NRS): 0-10 
(no pain to the worst pain imaginable). The baseline NRS score will be recorded. All routine 
standard practices for surgery, anesthesia, and perioperative care will be followed with the 
exception of the study intervention. All patients will be premedicated with midazolam (0.025-
0.05 mg/kg) 
 
Intraoperative Management:  
The Study arm will receive general endotracheal anesthesia (GETA). Anesthesia induction will 
be achieved with propofol (1.5-2.5mg/kg), succinylcholine (1mg/kg), and Fentanyl (50-100 mcg) 
bolus. Anesthesia maintenance will consist of TIVA (total intravenous anesthesia) with 
continued infusions of propofol (80-200 mcg/kg/min) and sufentanil (0.2-0.3mcg/kg/hr). The 
study group will receive Dsuvia 30 mcg at surgery end, administered by the anesthesiologist, 
timed to occur prior to emergence from anesthesia, and after the patient is turned supine. 
Antiemetic prophylaxis will be administered (ondansetron) per standard practice. The patient 
will then be transferred to the PACU. 
 
Postoperative Management: 
Note that Dsuvia will be ordered as q1hr prn, meaning that repeat doses must be administered at 
least 1 hr apart (up to 3 doses can be administered in the PACU).  


 
9
Postoperative pain scores will be recorded by the PACU nurse and the research assistant. This 
will be obtained by using NRS scale every 15 mins up to 2 hours.  
In the PACU, patients will be ordered to receive Dsuvia 30 mcg q1 hr prn for breakthrough pain 
(for NRS > 3) as the 1st line analgesic, with fentanyl as the rescue analgesic if the patient is still 
experiencing pain (NRS >3). The following opioid administration schema will be used for pain 
management in the PACU:  
 
• 1st line: Dsuvia SL 30mcg (NRS >3). 2nd line: Fentanyl 25-50mcg (NRS >3) 
• If upon arrival to the PACU the patient is still experiencing pain with NRS >3 but cannot 
yet receive a repeat dose of Dsuvia (because of having received 1st dose in the OR less 
than 1 hour ago), then the patient can receive fentanyl 25-50mcg prn until eligible to 
receive Dsuvia.  
• If at any time the patient’s NRS >3 after 20 min following an administration of either 
Dsuvia or fentanyl, the patient can receive a repeat dose of fentanyl until again eligible to 
receive Dsuvia.  
 
Once the patient is transferred to the floor, both groups will receive the standard of care 
postoperative pain management orders (ie PO and IV prn analgesia for NRS > 3). 
 
Patients who require additional doses of Dsuvia will be monitored for respiratory depression for 
at least one hour after the last administration of the drug dose. 
 
Sample Size/Statistical analysis:  


 
10
The primary outcome is nurse-collected mean pain scores. Assuming a within-group standard 
deviation in PACU NRS pain score of 2.5 points7, enrollment of 30 patients in the study group 
and inclusion of at least 80 patients in each retrospective control group will provide at least 80% 
power at a two sided alpha level of 0.025 (0.05/2 pair-wise comparisons) to detect a minimal 
clinically important difference of 2 points9 between the Study group and each of the retrospective 
groups using linear regression.  
 
To account for any potential lack of comparability in baseline characteristics between patients in 
the Study and retrospective groups, all outcomes will be compared between the prospective 
group and each of the retrospective groups using doubly robust estimation incorporating both 
multivariable linear regression adjustment and inverse probability of treatment weights based on 
the propensity score10. Doubly robust estimation will allow for unbiased treatment effect 
estimates even if one of the two models (i.e., propensity score model or outcome model) is miss-
specified. The multivariable linear regression models for the outcomes will adjust for the 
following covariates: age, sex, BMI, ASA class, surgical invasiveness tier, reoperation, history of 
anxiety, anxiolytic use, history of depression, and antidepressant use. Analytic weights will be 
based on the inverse of the propensity score, calculated via logistic regression as the probability 
of being in the Dsuvia group conditional upon the aforementioned covariates included in the 
multivariable outcome model. 
 
 
Investigator Name/Institution:  
 
Linda S. Aglio, MD, MS 
Associate Professor of Anaesthesia 
Director, Neuroanesthesia 


 
11
Brigham and Women’s Hospital 
Harvard Medical School 
Department of Anesthesiology, Perioperative and Pain Medicine 
75 Francis Street – CWN L1 
Boston, MA 02115 
Tel: (617) 732-8222 
Email: laglio@bwh.harvard.edu  
 
 
 
Senior Project Manager: 
Sarah Corey 
Email:  smcorey@partners.org  
 
Research Assistant: 
TBA 
 
Staff Statistician: 
Kara Fields, MS 
Email: kgfields@bwh.harvard.edu 
 
 
 
 
 
References 
 
1. 
Minkowitz HS, Leiman D, Melson T, Singla N, DiDonato KP, Palmer PP. Sufentanil 
Sublingual Tablet 30 mcg for the Management of Pain Following Abdominal Surgery: A 
Randomized, Placebo-Controlled, Phase-3 Study. Pain Pract. 2017;17:848-858. 
2. 
Miner JR, Rafique Z, Minkowitz HS, DiDonato KP, Palmer PP. Sufentanil sublingual 
tablet 30mcg for moderate-to-severe acute pain in the ED. Am J Emerg Med. 
2018;36:954-961. 
3. 
Meijer F, Cornelissen P, Sie C, et al. Sublingual sufentanil for postoperative pain relief: 
first clinical experiences. J Pain Res. 2018;11:987-992. 
4. 
Melson TI, Boyer DL, Minkowitz HS, et al. Sufentanil sublingual tablet system vs. 
intravenous patient-controlled analgesia with morphine for postoperative pain control: a 
randomized, active-comparator trial. Pain Pract. 2014;14:679-688. 
5. 
Cassavaugh K et al. Outcomes of Disuvia in patients undergoing major surgery. 
Manuscript in Preparation, 2020. Source: AcelRx Pharmaceuticals. 
6. 
Tvetenstrand CD et al. Prospective study of preoperative DSUVIA for ambulatory 
surgery. Manuscript in preparation 2020. Source: AcelRx Pharmaceuticals. 


 
12
7. 
Murphy GS, Szokol JW, Avram MJ, et al. Clinical Effectiveness and Safety of 
Intraoperative Methadone in Patients Undergoing Posterior Spinal Fusion Surgery: A 
Randomized, Double-blinded, Controlled Trial. Anesthesiology. 2017;126:822-833. 
8. 
Stark PA, Myles PS, Burke JA. Development and psychometric evaluation of a 
postoperative quality of recovery score: the QoR-15. Anesthesiology. 2013;118:1332-
1340. 
9. 
Farrar JT, Young JP, Jr., LaMoreaux L, Werth JL, Poole RM. Clinical importance of 
changes in chronic pain intensity measured on an 11-point numerical pain rating scale. 
Pain. 2001;94:149-158. 
10. 
Funk MJ, Westreich D, Wiesen C, Sturmer T, Brookhart MA, Davidian M. Doubly 
robust estimation of causal effects. Am J Epidemiol. 2011;173:761-767. 
 
 
 
Figure 1: Packing and components of Dsuvia (Sufentanil SL)