Pooled Phase III Safety Analysis of Sufentanil Sublingual Tablets for Short-Term Treatment of Moderate-to-Severe Acute Pain

Figures & data

Table 1. Patient study pools for safety analysis.

Procedure (Clinicaltrials.gov identifier)	Study design^†	Comparator	Number of patients in pooled safety analysis/full study	Study duration	Rescue medication	Ref.
SST 30 mcg
Phase III
Ambulatory abdominal surgery (NCT02356588)	Multicenter, randomized double-blind placebo controlled	Placebo	161/161	48 h	IV morphine	[19]
Emergency department trauma or injury (NCT02662556)	Multicenter, open-label	None	76/76	2 h (single-dose cohort; n = 40) 5 h (multiple-dose cohort; n = 36)	IV morphine or oral oxycodone elixir	[21]
Inpatient and outpatient surgery (NCT02447848)	Multicenter, open-label	None	140/140	12 h	IV morphine	[20]
SST 15 mcg^‡
Phase II
Knee replacement (NCT00859313)	Multicenter, open-label	None	18/30	12 h	None
Total knee replacement (NCT00612534)	Multicenter, randomized double-blind placebo controlled	SST 5 mcg; SST 10 mcg; placebo	27/94	12 h	None	[23]
Open abdominal surgery (NCT00718081)	Multicenter, randomized double-blind placebo controlled	SST 10 mcg; Placebo	14/88	12 h	None	[23]
Phase III
Open abdominal surgery or knee/hip replacement (NCT01539538)	Multicenter, randomized double-blind active control	IV morphine	94/357	72 h	IV morphine	[18]
Open abdominal surgery (NCT01539642)	Multicenter, randomized double-blind placebo controlled	Placebo	78/172	72 h	IV morphine	[17]
Total knee or hip replacement (NCT01660763)	Multicenter, randomized double-blind placebo controlled	Placebo	196/419	72 h	IV morphine	[16]

^†For eligibility, all patients must have had a pain intensity rating of ≥4, on a numeric rating scale from 0 to 10 [24,25].

^‡Analysis included a subset of patients from the SST 15 mcg studies who received two doses of SST 15 mcg within 20–25 min (30-mcg dose-equivalent).

IV: Intravenous; SST: Sufentanil sublingual tablet.

Figure 1. Disposition of patients included in the pooled safety analysis.

(A) Patients who received two doses of SST 15 mcg within 20–25 min (30-mcg dose-equivalent). (B) Prior to 24-h assessment.

SST: Sufentanil sublingual tablet.

Table 2. Patient demographics and baseline characteristics in the sufentanil sublingual tablet clinical studies (pooled).

Characteristics	SST 15 mcg^† (n = 323)	SST 30 mcg (n = 323)	Total SST (n = 646)	Total placebo (n = 158)	Total (N = 804)
Age group, years, n (%)
<55	57 (17.6)	223 (69.0)	280 (43.3)	78 (49.4)	358 (44.5)
55 to <65	102 (31.6)	66 (20.4)	168 (26.0)	39 (24.7)	207 (25.7)
65 to <75	100 (31.0)	26 (8.0)	126 (19.5)	25 (15.8)	151 (18.8)
≥75	64 (19.8)	8 (2.5)	72 (11.1)	16 (10.1)	88 (10.9)
Age, years
Median (range)	65.0 (19–86)	48.0 (18–84)	57.0 (18–86)	55.0 (20–87)	56.0 (18–87)
Mean (SD)	64.0 (12.1)	47.2 (13.2)	55.6 (15.2)	53.5 (15.8)	55.2 (15.4)
Sex, n (%)
Female	209 (64.7)	178 (55.1)	387 (59.9)	103 (65.2)	490 (60.9)
Male	114 (35.3)	145 (44.9)	259 (40.1)	55 (34.8)	314 (39.1)
Race, n (%)
White	279 (86.4)	238 (73.7)	517 (80.0)	121 (76.6)	638 (79.4)
Black or African–American	39 (12.1)	67 (20.7)	106 (16.4)	26 (16.5)	132 (16.4)
Other	5 (1.5)	17 (5.3)	23 (3.6)	11 (7.0)	34 (4.2)^‡
Ethnicity, n (%)
Hispanic or Latino	10 (3.1)	76 (23.5)	86 (13.3)	21 (13.3)	107 (13.3)
BMI group, n (%), kg/m^2
<30	176 (54.5)	199 (62.4)	375 (58.4)	89 (56.3)	464 (58.0)
30–40	119 (36.8)	101 (31.7)	220 (34.3)	62 (39.2)	282 (35.3)
>40	28 (8.7)	19 (6.0)	47 (7.3)	7 (4.4)	54 (6.8)
BMI, kg/m^2
Median (range)	29.3 (17.5–62.0)	27.5 (17.5–67.0)	28.7 (17.5–67.0)	29.0 (15.8–52.0)	28.7 (15.8–67.0)
Mean (SD)	30.3 (6.9)	29.3 (6.9)	29.8 (6.9)	30.0 (5.7)	29.9 (6.7)
ASA classification, n (%)
I	NR	156 (48.3)	156 (48.3)	37 (68.5)	193 (51.2)
II	NR	137 (42.4)	137 (42.4)	13 (24.1)	150 (39.8)
III	NR	30 (9.3)	30 (9.3)	4 (7.4)	34 (9.0)
Surgery type, n (%)
Abdominal	74 (22.9)	190 (58.8)	264 (40.9)	87 (55.1)	351 (43.7)
Orthopedic	247 (76.5)	28 (8.7)	275 (42.6)	69 (43.7)	344 (42.8)
Nonsurgical (trauma patients)	0	76 (23.5)	76 (11.8)	0	76 (9.5)
Other surgery	2 (0.6)	29 (9.0)	31 (4.8)	2 (1.3)	33 (4.1)

^†A subset of patients who received two doses of SST 15 mcg within 20–25 min (30-mcg dose-equivalent).

^‡Includes Asian (n = 8; 1.0%), American–Indian or Alaska Native (n = 7 [0.9%]), Native Hawaiian or other Pacific Islander (n = 1 [0.1%]) and others (n = 18 [2.2%]).

ASA: American Society of Anesthesiologist; NR: Not reported; SD: Standard deviation; SST: Sufentanil sublingual tablet.

Table 3. Adverse events in the sufentanil sublingual tablet clinical studies (pooled): all adverse events and adverse events related^† to study treatment.

Patients, n (%)	SST 15 mcg^‡ (n = 323)	SST 30 mcg (n = 323)	Total SST^§ (n = 646)	Total placebo (n = 158)	SST^§ vs placebo, difference, % (95% CI)
All AEs
Number of AEs
None	62 (19.2)	193 (59.8)	255 (39.5)	61 (38.6)
≥1	261 (80.8)	130 (40.2)	391 (60.5)	97 (61.4)	-0.9 (-9.4 to 7.6)
All AEs^¶ (≥2% of patients in any study group)
Nausea	155 (48.0)	80 (24.8)	235 (36.4)	49 (31.0)	5.4 (-2.7 to 13.5)
Headache	34 (10.5)	29 (9.0)	63 (9.8)	15 (9.5)	0.3 (-4.8 to 5.4)
Pyrexia	56 (17.3)	0	56 (8.7)	13 (8.2)	0.5 (-4.3 to 5.3)
Vomiting	41 (12.7)	12 (3.7)	53 (8.2)	6 (3.8)	4.4 (0.7, 8.1)
Anemia	33 (10.2)	0	33 (5.1)	3 (1.9)	3.2 (0.5, 5.9)
Dizziness	18 (5.6)	13 (4.0)	31 (4.8)	4 (2.5)	2.3 (-0.6 to 5.2)
Pruritus	24 (7.4)	7 (2.2)	31 (4.8)	4 (2.5)	2.3 (-0.6 to 5.2)
Hypotension	14 (4.3)	8 (2.5)	22 (3.4)	6 (3.8)	-0.4 (-3.7 to 2.9)
Oxygen saturation decreased	20 (6.2)	6 (1.9)	26 (4.0)	1 (0.6)	3.4 (1.5 to 5.3)
Constipation	20 (6.2)	1 (0.3)	21 (3.3)	1 (0.6)	2.7 (0.9 to 4.5)
Hypertension	11 (3.4)	3 (0.9)	14 (2.2)	5 (3.2)	-1.0 (-4.0 to 2.0)
Insomnia	12 (3.7)	0	12 (1.9)	3 (1.9)	0.0 (-2.4 to 2.4)
Tachycardia	9 (2.8)	4 (1.2)	13 (2.0)	2 (1.3)	0.7 (-1.4 to 2.8)
Hypocalcemia	12 (3.7)	0	12 (1.9)	2 (1.3)	0.6 (-1.5 to 2.7)
Leukocytosis	11 (3.4)	0	11 (1.7)	3 (1.9)	-0.2 (-2.6 to 2.2)
Sinus tachycardia	11 (3.4)	0	11 (1.7)	2 (1.3)	0.4 (-1.6 to 2.4)
Somnolence	3 (0.9)	7 (2.2)	10 (1.5)	3 (1.9)	-0.4 (-2.7 to 1.9)
Anemia postoperative	10 (3.1)	0	10 (1.5)	1 (0.6)	0.9 (-0.6 to 2.4)
Body temperature increased	10 (3.1)	0	10 (1.5)	1 (0.6)	0.9 (-0.6 to 2.4)
Confusional state	8 (2.5)	1 (0.3)	9 (1.4)	2 (1.3)	0.1 (-1.9 to 2.1)
Dyspepsia	9 (2.8)	1 (0.3)	10 (1.5)	1 (0.6)	0.9 (-0.6 to 2.4)
Hypoalbuminemia	10 (3.1)	0	10 (1.5)	1 (0.6)	0.9 (-0.6 to 2.4)
Hypokalemia	10 (3.1)	0	10 (1.5)	1 (0.6)	0.9 (-0.6 to 2.4)
Muscle spasms	7 (2.2)	1 (0.3)	8 (1.2)	3 (1.9)	-0.7 (-3.0 to 1.6)
Anxiety	8 (2.5)	0	8 (1.2)	2 (1.3)	-0.1 (-2.1 to 1.9)
Flatulence	1 (0.3)	4 (1.2)	5 (0.8)	5 (3.2)	-2.4 (-5.2 to 0.4)
Hyponatremia	8 (2.5)	0	8 (1.2)	1 (0.6)	0.6 (-0.9 to 2.1)
Hypoxia	6 (1.9)	1 (0.3)	7 (1.1)	2 (1.3)	-0.2 (-2.1 to 1.7)
Urinary retention	8 (2.5)	0	8 (1.2)	0	1.2 (0.4 to 2.0)
Pharyngolaryngeal pain	5 (1.5)	2 (0.6)	7 (1.1)	0	1.1 (0.3 to 1.9)
Procedural nausea	0	3 (0.9)	3 (0.5)	3 (1.9)	-1.4 (-3.6 to 0.8)
Sedation	5 (1.5)	0	5 (0.8)	0	0.8 (0.1 to 1.5)
AEs related^† to study treatment
Number of related AEs
None	145 (44.9)	218 (67.5)	363 (56.2)	105 (66.5)
≥1	178 (55.1)	105 (32.5)	283 (43.8)	53 (33.5)	10.3 (2.0 to 18.6)
AEs^¶ related to treatment (≥2% of patients in any study group)
Nausea	110 (34.1)	74 (22.9)	184 (28.5)	35 (22.2)	6.3 (-1.1 to 13.7)
Vomiting	32 (9.9)	10 (3.1)	42 (6.5)	6 (3.8)	2.7 (-0.8 to 6.2)
Headache	15 (4.6)	17 (5.3)	32 (5.0)	10 (6.3)	-1.3 (-5.4 to 2.8)
Dizziness	13 (4.0)	13 (4.0)	26 (4.0)	4 (2.5)	1.5 (-1.4 to 4.4)
Pruritus	19 (5.9)	6 (1.9)	25 (3.9)	2 (1.3)	2.6 (0.3 to 4.9)
Oxygen saturation decreased	18 (5.6)	5 (1.5)	23 (3.6)	1 (0.6)	3.0 (1.1 to 4.9)
Hypotension	10 (3.1)	6 (1.9)	16 (2.5)	5 (3.2)	-0.7 (-3.7 to 2.3)
Constipation	19 (5.9)	1 (0.3)	20 (3.1)	0	3.1 (1.8 to 4.4)
Somnolence	3 (0.9)	5 (1.5)	8 (1.2)	3 (1.9)	-0.7 (-3.0 to 1.6)
Confusional state	8 (2.5)	1 (0.3)	9 (1.4)	1 (0.6)	0.8 (-0.7 to 2.3)
Insomnia	5 (1.5)	0	5 (0.8)	0	0.8 (0.1 to 1.5)

^†Related AEs are defined as possibly or probably related to study drug.

^‡A subset of patients who received two doses of SST 15 mcg within 20–25 min (30-mcg dose equivalent).

^§SST includes 15 mcg (n = 323) and 30 mcg (n = 363) doses.

^¶AE mapping was based on Medical Dictionary for Regulatory Activities version 11.0.

AE: Adverse event; NA: Not applicable; SST: Sufentanil sublingual tablet.

Table 4. Serious adverse events.

Serious AE^† (n = 1 each)	Study type	Treatment	Severity	Relationship to treatment	Outcome	Ref.
Angina pectoris	Phase III; open-label; emergency department	SST 30 mcg	Moderate	Possibly related	Dose not changed and patient recovered	[21]
Atrial fibrillation	Phase III; placebo-controlled; orthopedic surgery	SST 15 mg	Moderate	Not related	Dose not changed and patient recovered	[16]
Confusional state^‡	Phase III; placebo-controlled; orthopedic surgery	SST 15 mcg	Moderate	Possibly related	Dose not changed and patient recovered	[16]
Hemiparesis	Phase III; placebo-controlled; abdominal surgery	Placebo	Severe	Possibly related	Drug withdrawn and patient recovered	[19]
Hypoxia^‡	Phase III; placebo-controlled; orthopedic surgery	SST 15 mcg	Moderate	Not related	Dose not changed and patient recovered	[16]
Oxygen saturation decreased^§	Phase III; placebo-controlled; orthopedic surgery	SST 15 mcg	Severe	Probably related	Drug withdrawn and patient recovered	[16]
Postoperative ileus	Phase III; active comparator; mixed surgery	SST 15 mcg	Severe	Not related	Dose not changed and patient recovered	[18]
Pulmonary embolism^‡	Phase III; placebo-controlled; orthopedic surgery	SST 15 mcg	Mild	Not related	Dose not changed and patient recovered	[16]
Syncope	Phase III; placebo-controlled; abdominal surgery	Placebo	Moderate	Possibly related	Drug withdrawn and patient recovered	[19]

^†A serious AE was defined as any event that was fatal or life-threatening, permanently or substantially disabling or incapacitating (i.e., substantial disruption of ability to conduct normal life functions), prolonged hospitalization, a congenital anomaly or was an important medical event.

^‡Three of the serious AEs (confusional state, hypoxia and pulmonary embolism) occurred in the same patient.

^§Oxygen saturation = 40% (naloxone administered).

AE: Adverse event; SST: Sufentanil sublingual tablet.

Table 5. Higher versus lower 24-h dosing of sufentanil sublingual tablet in Phase III studies ≥24 h: lowest oxygen saturation by treatment and dose group.

Patients, n (%)	SST 15 mcg studies^†		SST 30 mcg studies
	<300 mcg (0–24 h) (n = 107)	≥300 mcg (0–24 h) (n = 180)	<300 mcg (0–24 h) (n = 81)	≥300 mcg (0–24 h) (n = 26)
Oxygen saturation, %
≥95	72 (67.3)	139 (77.2)	59 (72.8)	23 (88.5)
93–94	18 (16.8)	26 (14.4)	15 (18.5)	2 (7.7)
90–92	10 (9.3)	11 (6.1)	7 (8.6)	0
<90	7 (6.5)	4 (2.2)	0	1 (3.8)
Mean (SD)	93.5 (6.2)	94.5 (1.7)	95.2 (1.6)	95.4 (2.2)
Median	95.0	95.0	96.0	96.0
Min, max	(40, 100)	(83, 99)	(91, 98)	(86, 98)

^†Patients who received two doses of SST 15 mcg within 20–25 min (30-mcg dose-equivalent).

Max: Maximum; Min: Minimum; SD: Standard deviation; SST: Sufentanil sublingual tablet.

Table 6. Median drug utilization: morphine equivalent per sufentanil sublingual tablet dose based on duration of exposure.

Hours	Median SST usage^† (n = 177)^‡	Median IV morphine usage (n = 180)^‡	Morphine equivalent per SST dosage strength
Hours 0–5	90.0 mcg	15.0 mg	SST 15 mcg = 2.5 mg IV MS SST 30 mcg = 5.0 mg IV MS
Hours 0–48	525.0 mcg	61.5 mg	SST 15 mcg = 1.8 mg IV MS SST 30 mcg = 3.5 mg IV MS

^†Total SST usage calculated by multiplying the ‘15-mcg’ dose by the number of SST 15-mcg doses used. For hours 0–5, SST 90 mcg = SST 15 mcg × 6 doses. For hours 0–48, SST 525.0 mcg = SST 15 mcg × 35 doses.

^‡Data from patients in the active comparator study (SST 15 mcg PCA vs IV morphine PCA) [18].

IV: Intravenous; MS: Morphine sulfate; SST: Sufentanil sublingual tablet.

Minkowitz HS , LeimanD , MelsonT , SinglaN , DiDonatoKP , PalmerPP . Sufentanil sublingual tablet 30 mcg for the management of pain following abdominal surgery: a randomized, placebo-controlled, phase-3 study . Pain Pract.17 ( 7 ), 848 – 858 ( 2017 ).

 PubMed Web of Science ®Google Scholar

Miner JR , RafiqueZ , MinkowitzHS , DiDonatoKP , PalmerPP . Sufentanil sublingual tablet 30 mcg for moderate-to-severe acute pain in the emergency department . Am. J. Emerg. Med.36 ( 6 ), 954 – 961 ( 2018 ).

 PubMed Web of Science ®Google Scholar

Hutchins JL , LeimanD , MinkowitzHS , JoveM , DiDonatoKP , PalmerPP . An open-label study of sufentanil sublingual tablet 30mcg in patients with postoperative pain . Pain Med.19 ( 10 ), 2058 – 2068 ( 2018 ).

 PubMed Web of Science ®Google Scholar

Minkowitz HS , SinglaNK , EvashenkMAet al. Pharmacokinetics of sublingual sufentanil tablets and efficacy and safety in the management of postoperative pain . Regional Anesth. Pain Med.38 ( 2 ), 131 – 139 ( 2013 ).

 PubMed Web of Science ®Google Scholar

Melson TI , BoyerDL , MinkowitzHSet al. Sufentanil sublingual tablet system vs. intravenous patient-controlled analgesia with morphine for postoperative pain control: a randomized, active-comparator trial . Pain Pract.14 ( 8 ), 679 – 688 ( 2014 ).

 PubMed Web of Science ®Google Scholar

Ringold FG , MinkowitzHS , GanTJet al. Sufentanil sublingual tablet system for the management of postoperative pain following open abdominal surgery: a randomized, placebo-controlled study . Regional Anesth. Pain Med.40 ( 1 ), 22 – 30 ( 2015 ).

 PubMed Web of Science ®Google Scholar

Jove M , GriffinDW , MinkowitzHS , Ben-DavidB , EvashenkMA , PalmerPP . Sufentanil sublingual tablet system for the management of postoperative pain after knee or hip arthroplasty: a randomized, placebo-controlled study . Anesthesiology123 ( 2 ), 434 – 443 ( 2015 ).

 PubMed Web of Science ®Google Scholar

Boonstra AM , StewartRE , KökeAJet al. Cut-off points for mild, moderate, and severe pain on the numeric rating scale for pain in patients with chronic musculoskeletal pain: variability and influence of sex and catastrophizing . Front. Psychol.7 ( 1466 ), 1 – 9 , [ eCollection 2016 ] ( 2016 ).

 PubMedGoogle Scholar

Krebs EE , CareyTS , WeinbergerM . Accuracy of the pain numeric rating scale as a screening test in primary care . J. Gen. Intern. Med.22 , 1453 – 1458 ( 2007 ).

 PubMed Web of Science ®Google Scholar

Data sharing statement

The authors certify that this manuscript reports the secondary analysis of clinical trial data that have been shared with them, and that the use of this shared data is in accordance with the terms (if any) agreed upon their receipt. The source of this data is: Clinicaltrials.gov identifiers: NCT02356588, NCT02662556, NCT02447848, NCT00859313, NCT00612534, NCT00718081, NCT01539538, NCT01539642 and NCT01660763.