Sufentanil Sublingual for Acute Post-Operative Pain: A Systematic Literature Review Focused on Pain Intensity, Adverse Events, and Patient Satisfaction

More than 234 million major surgical procedures are performed every year worldwide [1] and data suggest up to 70% of these patients experience moderate-to-severe pain postoperatively [2]. Post-operative pain should be alleviated as soon and as effectively as possible to reduce suffering and to facilitate rapid recovery and mobility, thereby improving patient outcomes [3]. However, clinical pain management after surgery is far from being successful [4]. In a national survey, approximately 80% of patients experienced acute pain after surgery. Of these patients, 86% had moderate, severe, or extreme pain. Referring to the numeric rating scale (NRS) pain intensity ratings, we can classify mild pain as 0–4, moderate pain as 5–6, and severe pain as 7–10. Almost 25% of patients who received pain medications experienced adverse effects. The most common side effects were drowsiness (41%), nausea (35%), constipation (26%), sleeplessness (18%), dizziness (14%), vomiting (14%), abdominal discomfort (10%), itching (10%), mood changes (8%), and difficult urination (8%) [4].

The international guidelines recommended the use of a multimodal analgesia. Analgesic medication and techniques combined with non-pharmacological interventions have additive or synergistic effects and more effective pain relief compared with single-modality interventions [5].

Patients may control postoperative pain by self-administration of intravenous opioids using devices designed for this purpose (patient-controlled analgesia or PCA). PCA shows a number of benefits when compared with non-PCA administration of opioids. These include more effective analgesia, fewer analgesic gaps, and potentially shorter duration of stay in hospital, as well as high levels of patient satisfaction, as they are more in control of their own treatment.

Postoperative guidelines recommend oral over intravenous opioids in patients who can use the oral route [5]. Consequently, PCA devices have been developed including the sufentanil sublingual tablet system (SSTS). In July 2014, the Food and Drug Administration (FDA) approved the opioid analgesic Zalviso^® to delivery 15 mcg of sufentanil. In October 2018, the FDA approved the opioid analgesic Dsuvia^® to deliver 30 mcg of medical treatment.

The goal was to provide a noninvasive route of administration to treat moderate-to-severe acute pain in non-opioid-tolerant patients, as the current rapidly acting transmucosal opioid analgesic products are approved for opioid-tolerant cancer patients only.

The aim of the current study was to conduct a systematic literature review to establish the efficacy and safety of PCA with SSTS used in the treatment of moderate-to-severe acute post-operative pain in the hospital setting.

We performed a systematic review based on preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [6], and following a protocol written prior to starting the review. This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

The population, intervention, comparison, and outcome (PICO) criteria were applied to the research question. Patients of at least 18 years undergoing major surgical procedures were considered as the population (P); the intervention (I) was postoperative analgesia with SSTS 15 mg or SSTS 30 mg; the comparison (C) concept was not applicable to the research question; pain intensity, adverse events (AEs) and patient satisfaction after using SSTS for postoperative analgesia in patients undergoing major surgical procedures were considered the outcomes (O) for this systematic review. We included observational study, clinical trial, and randomized controlled trial published from 2000 to the present.

PICO criteria are summed in Table 1.

We identified the articles by searching electronic databases (Embase, MEDLINE, Google Scholar, and Cochrane Central Trials Register). Other relevant studies were identified from the reference lists of systematic reviews and meta-analyses.

We used a combination of terms for “sufentanil sublingual tablet system”, “post-operative or postsurgical pain”, “observational study”, “clinical trial”, and “randomized clinical trial”. We applied no language restrictions in searches. The initial search was performed in December 2019.

The studies included in this review evaluated adult patients clinically diagnosed with moderate-to-severe acute post-operative pain in a hospital setting following any type of surgery.

The primary outcome was the pain intensity assessed via NRS at 12 and 24 h. Pain intensity data assessed by means other than a 0–10 NRS were normalized to such a scale. Some studies reported the sum of pain intensity difference (SPID) at 12, 24, and 48 h.

We extracted data on the following secondary outcomes:

We determined eligibility by reading the abstract of each study identified by the search. We eliminated studies that clearly did not satisfy our inclusion criteria, and obtained full copies of the remaining studies. Two review authors read these studies independently and reached agreement by discussion.

The methodological quality of the included studies was evaluated and rated using the COSMIN checklist, which has a four-point rating scale [7, 8].

Data extracted included the following:

Different investigators recorded this outcome on different scales and at different intervals. We normalized all NRS to a 0–10 range (see Fig. 3). The majority of authors reported pain intensity between 12 and 24 h after surgery. One study, Miner JR 2018, reported NRS at 2 h. Pain intensity over the first 24 h was reported in 12 studies, which involved 2327 patients with 1844 in the SSTS group. All participants in SSTS group reported NRS ≤ 4 within 24 h after surgery. Only one trial, Van Deen DE 2018, recorded NRS at 12 h of 5 and at 24 h of 4.5. It is important to point out that this is the highest pain score recorded among patients treated with SSTS. At 48 h of treatment, all participants showed NRS ≤ 4.

General anesthesia was used for most surgical procedures. Regional or local anesthesia was used in six studies (Jove M, 2015; Meijer F, 2018; Pogatzki-Zahn E, 2019; Rispoli M, 2018; Scardino M, 2018; Van Deen DE, 2018). Pain medication with opioids and non-opioids intraoperatively and/or early postoperatively was often administered before initiating the SSTS. A paper (Costa F, 2019) reported the use of intravenous preemptive analgesia. Three studies (Hutchins JL, 2017; Lakshman S, 2016; Miner JR, 2018) did not reported data concerning pain medication.

Ten studies (Hutchins JL, 2017; Jove M, 2015; Leykin Y, 2019; Meijer F, 2018; Melson TI, 2014; Miner JR, 2018; Minkowitz HS, 2017; Ringold FG, 2015; Rispoli M, 2018; Scardino M, 2018) reported the use of rescue medication if analgesia with SSTS was insufficient. A total of 112 participants in seven studies required rescue medication (e.g., IV morphine, oral morphine, oral oxycodone, acetaminophen, ketorolac). In Rispoli M 2018, a patient reported severe pain and a single-shot para-vertebral block was performed.

Patient satisfaction results were presented as different degrees subjective satisfaction levels. We normalized all to “satisfied/not satisfied”.

Thirteen studies were available for analysis of satisfaction (see Fig. 4).

An adverse event is defined as any undesirable experience associated with the use of a medical product in a patient. A total of 958 AEs were recorded. A study, Lakshman S 2016, did not reported the number of AEs. The most frequently reported AEs were nausea, vomiting, and PONV (postoperative nausea and vomiting), headache, and oxygen desaturation (see Table 3 and Fig. 5). Most studies did not specify the timing of adverse events.

We considered NRS lower than 4 as optimal cut-off point between mild and moderate pain. This cut-off was identified as the tolerable pain threshold [27].

In Miner JR 2018, SSTS 30 mcg was evaluated over 2 h for managing moderate-to-severe acute pain in an ED setting. Mean pain intensity was 7.6 at baseline and decreased to 4.5 at 60 min and remained relatively stable (4.6) at 2 h. Based on the experience of Cepeda MS 200 [3, 28], this decrease in NRS score is meaningful of “much/very much” improvement.

In the RCTs reporting the summed pain intensity difference to baseline over the 12 and 24-h study period, SPID values were higher than the control group.

A total of 112 patients received upon request rescue medication if analgesia with the study medication was insufficient. Discontinuation due to inadequate analgesia occurred at low rates (4.4% of total participants).

Patient satisfaction was high, with a minimum of 70% satisfaction among patients treated with SSTS. It is not surprising to find greater satisfaction with SSTS. Patients have a greater degree of autonomy which reduces fears of insufficient analgesia. Instant availability of the medication contributes to greater satisfaction with the mode of treatment. The measurement of satisfaction in trials where participants are not blinded to study arm assignment creates a potential for bias. Most of the studies in our analysis were unblinded.

The most common AEs overall for SSTS 15 and 30 mcg were nausea, vomiting, and headache. As with any opioid, SSTS may be associated with respiratory or neuropsychiatric events, particularly in a postoperative setting where patients are recovering from anesthesia or have been administered concomitant CNS depressants, including other opioids during the surgery and during the initial stay in the recovery room. The most common respiratory AE was decreased oxygen saturation (5.6% of AEs). Three patients discontinued due to respiratory AE. Neuropsychiatric events among patients treated with sufentanil were headache (5.7%), dizziness (4.3%), confusional state/sedation (1.7%), somnolence (1.6%), and insomnia (1.4%). Discontinuation due to neuropsychiatric events occurred at low rates; specific events leading to discontinuation included confusional state and sopor. The most common gastrointestinal AEs were nausea (51%), vomiting (11.6%), PONV (4.2%), and constipation (3.6%). No patient required the use of naloxone. AEs observed in the studies were generally consistent with those associated with opioids and the postsurgical setting.

A total of 35 SAEs were reported among patients treated with SSTS; only 17 were considered related to treatment: one SAE occurred in a SSTS 30 mcg treated patients, the others in the SSTS 15 mcg group. All events were resolved, with the study drug withdrawn.

The safety profile of sufentanil is well established based on more than 30 years of experience with sufentanil used for general anesthesia and for epidural analgesia.