Editor's Note: This commentary is based on a paper recently published by Tvetenstrand and Wolff titled "Reduced opioid use and reduced time in postanesthesia care unit following preoperative administration of sublingual sufentanil in an ambulator surgery setting" in the Journal of Clinical Anesthesia and Pain Management.
Hypothetical Case
Mrs. Smith is wheeled into the operating room (OR) for her ventral hernia repair. She is 67 years old and has moderate renal impairment (CKD Stage III), and hypertension. After a preoperative dose of intravenous (IV) acetaminophen, her anesthesiologist administers her a general anesthetic induction dose of IV propofol and IV fentanyl 50 mcg. Predictably, her blood pressure (BP) falls to 84/53 mmHg and her heart rate (HR) drops to 55 beats per minute as the combination of these agents is well known to cause hypotension and bradycardia.¹
The anesthesiologist realizes the surgeon may not make the initial incision for another minute or so, which would naturally increase the BP and HR, so he reaches for the syringe of IV ephedrine, which he has ready considering how often he needs to mitigate low BP, and doses the patient which results in a normalization of these vital signs. The case continues for 45 minutes, during which time IV fentanyl 50 mcg has to be readministered due to the rapid (< 2 min) alpha distribution half-life of the drug.² Upon arrival in the post-anesthesia care unit (PACU), Mrs. Smith is groggy and has a 6 out of 10 pain intensity (with 0 being no pain and 10 being the most severe), as the analgesia from her second intraoperative IV bolus of fentanyl has already started wearing off.
Due to her renal impairment, the anesthesiologist avoids NSAIDS and opioids with active metabolites which are renally cleared, such as morphine (morphine-3 and -6 glucuronide) and hydromorphone (hydromorphone-3-glucuronide).³⁻⁵ She receives a IV fentanyl 25 mcg dose in the PACU. Although IV fentanyl may have a short duration of effect, this is commonly selected as the optimal PACU opioid for this type of patient.
The patient’s oxygen saturation levels begin to decline secondary to the rapid peak plasma concentration of IV bolus fentanyl producing sedation, lower tidal volumes and decreased respiratory rate.⁶⁻⁷ The nurse increases the oxygen flow in her nasal canula as she physically stimulates the patient, “Wake up Mrs. Smith, take some deep breaths!” Thirty minutes later, in pain again, the patient receives another dose of IV fentanyl 25 mcg. After a total of 70 minutes in the PACU, Mrs. Smith is finally both awake and comfortable enough to be transitioned from the PACU to the Phase 2 unit to get ready to be discharged home.
Discussion
This hypothetical patient case is typical of the control group in Tvetenstrand and Wolff’s recent study published in the Journal of Clinical Anesthesia and Pain Management, which challenged a favored and long-established use of intravenous fentanyl administration as the gold standard for perioperative pain.⁸(See our HCP poll on its use)
The authors introduce the study by discussing the hemodynamic instability and frequent redosing requirements inherent with the use of IV fentanyl and were looking to evaluate another potential option.⁸ They compared overall perioperative opioid use and time in the PACU in 80 of their historical control patients who were administered IV fentanyl perioperatively to a prospective group of 47 patients undergoing similar ambulatory general surgery procedures who received a single preoperative dose of Dsuvia, a 30 mcg sufentanil sublingual tablet (SST) which comes prefilled in a plastic single-dose applicator.⁸
Differentiating IV Fentanyl from the Sufentanil Sublingual Tablet
Dsuvia was approved in the US and the European Union (as DZUVEO) in 2018 for use in acute pain in medically supervised settings only.⁹⁻¹⁰ Sufentanil, like fentanyl, has no active metabolites, but that is where the similarities appear to end between SST and IV fentanyl.¹¹ SST has a pharmacokinetic profile that is in stark contrast to the rapid peaks and valleys of IV bolus administration. The sublingual tablet dissolves within 5 minutes and the sufentanil deposits into the sublingual mucosa. Absorption of sufentanil from the sublingual tissue depot occurs over time such that the peak plasma concentrations are much lower (almost 20-fold) compared to IV dosing.¹¹˒¹² The clinical trials of SST show an onset of action within 15 minutes and a duration of analgesia of approximately 3-4 hours.¹³⁻¹⁵ These key pharmacokinetic and pharmacodynamic differences between IV fentanyl and SST is what likely promulgated Tvetenstrand and Wolff’s direct comparison.⁸
The SST-treated patients on average had more than a 50% reduction in administration of intraoperative and postoperative morphine milligram equivalents (MMEs) compared to historical IV opioid controls (MME was calculated using the Practical Pain Management Opioid Conversion Calculator).⁸˒¹⁶ This finding alone is quite interesting. With opioid stewardship becoming a new institutional standard, having an opioid that fosters MME reduction is a simple, if not counterintuitive, solution. IV fentanyl with its high, narrow plasma concentration profile exposes the patient to higher peak opioid concentrations and repeated, extended areas under the curve (AUC), resulting in unnecessary mu-opioid receptor exposure (see Figure 1A). The clinical relevance of this higher intraoperative MME is increased postoperative adverse events, increased postoperative opioid requirements and increased readmission rates.¹⁷⁻²⁰ Alternatively, SST provides a flattened AUC profile, thereby minimizing MME by avoiding excess opioid beyond what is needed for analgesia (Figure 1B).¹¹
Potential Cost-Savings & Discharge Time Reduction
Certainly, reduced intraoperative and PACU use of IV opioids can result in a more awake, alert patient who can be discharged more quickly from the PACU, as was shown in this study.⁸ The authors point out that the time to retrieve, prepare, dose, chart and monitor the patient for an IV opioid dose is time-consuming, so the decrease in discharge time of almost 20 minutes per patient, may not seem that surprising since almost 90% of SST-treated patients required no additional opioids in the PACU.⁸ Further, there were 50% fewer patients in the SST group that required adrenergic agonists compared to controls, presumably due to a reduction in intraoperative IV opioid requirements.⁸
Despite the several advantages listed above, it is important to consider economic issues, especially considering that new medications tend to be expensive when first approved, which is often used as a reason to avoid adding novel agents to a formulary.²¹ However, this study leads us to consider some possible savings with SST despite its wholesale acquisition cost (WAC, $58/dose).²² Tvetenstrand and Wolff results suggest that the consistent, prolonged plasma concentrations of SST resulted not only in less IV fentanyl ($2/100 mcg)²³ use, but also in 50% less ephedrine ($29/dose)²⁴ use intraoperatively.⁸
They also showed reduced overall use of preoperative IV acetaminophen ($47/dose)²⁵ in the intervention group, in addition to observed reductions of PACU opioids in the SST-treated patients. Reduction in PACU discharge time (18.6 min) also can be estimated as a savings ($7 per min), as presented by Dr. Sonya Pease in 2015.²⁶ If PACU throughput becomes a limiting factor for OR throughput, avoiding PACU bottlenecks that can create OR inefficiency can also produce additional savings ($15 per min for OR indirect cost savings).²⁷
Simple calculations (see Table I) suggest that reduction in supplemental IV medications (opioids, acetaminophen and ephedrine) and decreased PACU time create a potential average cost savings per patient with SST of $105 ($163 - $58). If delayed discharge from the PACU becomes the limiting factor for surgical productivity, the average cost savings per patient is increased to $384 ($442 - $58).
Overall, their study suggests that by reconsidering the perioperative opioid route of delivery, clinicians can effectively foster a reduction in MME while maintaining a therapeutic plasma concentration of sufentanil via the sublingual route, thereby achieving analgesia over an extended time period with a single dose.
Opiophobia Meets Neophobia
We recognize that shifting standards of care are difficult, especially in a busy surgical setting with opioid routines engrained into our decision-making process. Tventenstrand and Wolff illustrate a scenario where opioid stewardship and various safety initiatives favor reduced opioid exposure and minimal requirements for naloxone use perioperatively, with an added option to meet the needs for effective analgesia in the surgical patient.
Kudos to Tvetenstrand and Wolff for thinking outside the box while demonstrating an opioid option that reduced risk for hemodynamic instability, reduced reliance on IV acetaminophen, and reduced MME. Is it possible that a cost-effective, physiologically and pharmaceutically favorable sublingual opioid is available, but underutilized?
Disclosures: Mr. Dasta is a consultant to AcelRx, Heron Therapeutics, and Neumentum Pharmaceutical.